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A study of the Neurology and Neuropathology

of a single case of atraumatic brain injury
in a five-month old infant
and arising from the administration of the
DPT Vaccine in 1960

[Anonymised]

Alan Challoner MA MChS

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CONTENTS
Introduction ........................................................................................................ 1
The Central Nervous System (CNS) ................................................................. 4
The Neuroscience of Behaviour: An Introduction ........................................ 22
Localization of Brain Lesions and Developmental Functions ...................... 25
The Organization of Memory during Developmental Age ........................ 30
Theory of Mind and Brain Damage ................................................................ 31
Childhood Aphasic Syndromes and the Localization of Lesions .............. 40
Cognitive Deficit after closed head injury in children ................................. 44
Language in children with early brain damage ......................................... 45
The Neuropsychology of Brain Damage as it relates to MDL ..................... 53
Problems of an Adverse Living Environment ................................................. 55
Semantic Memory Impairments ...................................................................... 65
Elements of Language and Communication ............................................... 66
Aspects of Aphasia & Agraphia that affect MDL ....................................... 71
Disorders of Skilled Movements, Perception and Awareness ..................... 83
The Emotional Brain ........................................................................................... 103
The Hypothalamus ............................................................................................ 104
The Amygdala ................................................................................................... 106
Fear conditioning .............................................................................................. 132
Emotional disorders in relation to unilateral brain damage ....................... 140
Sleep.................................................................................................................... 144
Working Memory and Cognition..................................................................... 147
Pervasive Development Disorders .................................................................. 164
The Neuro-Behavioural Examination of Children .......................................... 170

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A study of a sin gle case of atraumatic brain injury in a five-month old infant
and arising from the administration of the DPT Vaccine in 1960

Redefining MDLs Brain Damage:

Aiding the design of her future care
Inside this damaged head there is a long history of pain and suffering but by
the very nature of that damage she cannot tell you how she feels. There is a
need for compassion and understanding that is given freely to others who
suffer the consequences of different sorts of adversity.
This could be the first attempt at a neurological work-up in a case of vaccineinduced brain injury. It is my hope that MDL will not have suffered in vain but
that this study will encourage others to take it further so that there can be a
fund of knowledge that prevents others from carrying the same burden of
oppression.

INTRODUCTION
British research in the 1980s into whole-cell DTP1, which is now rarely available in developed
countries, suggested that such severe neurologic events occur after approximately 1 in
140,000 doses of the DPT vaccine (0.0007%).
In 1994, the Institute of Medicine of the US National Academy of Sciences published a
report stating that if the first symptoms of neurological damage occurred within the first
seven days following vaccination with whole-cell pertussis vaccine, the evidence was
compatible with the possibility that it could be the cause of permanent brain damage in
otherwise apparently healthy children.
There has been little scientific research into the way in which the DPT whole-cell vaccine
brings about the damage to the brain. However, there has been some work done on this in
an effort to try and discover how it might be possible. 2,3

Miller D; Wadsworth J; Diamond J & Ross E. Pertussis vaccine and whooping cough as risk
factors in acute neurological illness and death in young children. Dev Biol Stand. 1985;61:38994.

Challoner, A. http://www.scribd.com/doc/19408267/Brain-Damage-Caused-by-Vaccination

Challoner, A. http://www.scribd.com/doc/25042444/Towards-a-Better-Understanding-ofEarly-Atraumatic-Brain-Injury

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The nature of the brain damage so caused does not follow a pattern that is evident from
case to case due to the sporadic nature of the precipitating event, the age of onset and
the varying characteristics of individual brains. This causes a great deal of difficulty for
those who are called upon to care for affected individuals and often it is found that their
brain damage is ignored because it is too complicated for people to understand; even by
the professionals. Currently there are no FDA approved pharmacotherapies for the
treatment of traumatic brain injury and it must be recognized that almost all forms of
treatment for TBI are geared towards the minimization of secondary injury, as it is assumed
that primary injury is irreversible. 4,5
In traumatic brain injury the brain may be injured in a specific location or the injury may be
diffused to many different parts of the brain. It is this indefinite nature of brain injury that
makes treatment unique for each individual patient. In the past twenty years, a great deal
has been learned about brain function, and we learn more every day. We can make
guesses about the nature of the problems an individual may have from knowing the
location of a lesion. Diagnostic procedures such as CT scans and MRI's can also provide
information about a brain injury. Rehabilitation specialists can also learn about an injury by
observing the day to day activities of the patient.
Following very early acquired brain injury, it is much more tempting and less intellectually
challenging to believe that the person just lacks intelligence and therefore giving credence
to a view that they should be included in the Learning Disability Service provision. 6 This
egregious error has serious consequences for those who are truly brain damaged. Dealing
with the brain damaged individual, calls up much more serious scientific knowledge and
understanding of neuropsychology. By subverting assessments into a lower classification of
need there is a pseudo-legitimate encouragement for the use of lesser skills in both
assessment and quality of care. Neurologic diseases can have a major impact on
functional capacity and they require individual management considerations depending
upon the extent of impairment. This relates to the autism spectrum disorder as well as
traumatic neurologic disease. 7 Especial attention also needs to be given to dental care as
examinations can be difficult for various reasons. 8
Intellectual disability has traditionally been an exclusion criterion in research studies. At one
time, clinical lore believed that children with intellectual disability did not have behavioural
problems and that any inappropriate behaviour displayed was secondary to their mental
handicap. Research in children with intellectual disabilities is hindered as most studies do
not use standardised diagnostic interviews or criteria, and they are excluded from virtually
all treatment studies. This has ethical implications as little is known about diagnosis in and

Kulbe, J R; Hill, R L; Singh, I N; Wang, J & Hall, ED. Synaptic mitochondria sustain more
damage than non-synaptic mitochondria following traumatic brain injury and are protected
by cyclosporine A. Journal of Neurotrauma. September 2016; doi:10.1089/neu.2016.4628

Janich, K; Ha S N; Patel, M; Saman Shabani, S; Montoure, A & Ninh Doan, N. Management of

Adult Traumatic Brain Injury: A Review. Trauma Treat 2016, 5:3. DOI: 10.4172/2167-1222.1000320

Cornwell, KL. People registered disabled with learning difficulties tend to fall through the net.
BMJ. 2004 Oct 16; 329(7471): 917. doi: 10.1136/bmj.329.7471.917-a PMCID: PMC523160

Patil, A; Tamgond, S; Sandhyarani B; Shigli, A; Sharmila Patil, S & Bharati, SG. An Update on
Dental Outlook for Autism. Autism Open Access 2016, 6:3; http://dx.doi.org/10.4172/21657890.1000176

Robbins, MR. Neurologic Diseases in Special Care Patients. Dental Clinics of North America;
Vol. 60, Issue 3, July 2016; pp707-735

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treatment of these children, and they are often undiagnosed and untreated. This is now
being remedied and the work of Harding, Emerson & Baine is welcomed. 9
In the case of injury from DPT whole cell vaccination, it was a long established belief in
medical circles that this didnt happen and even today there is still some residual doubt
that does not help to establish a considerate care plan. However, the potential dangers of
the DPT vaccination in that form were brought to the attention of readers of the BMJ in 1958
when it was suggested that any infant who responds badly to the first incidence of
vaccination by DPT should not have any further doses in the series. 10 Further inequalities
need to be prevented, and attempts are required to promote high quality research into this
disadvantaged group. 11
Contemporary research indicates that juvenile traumatic brain injury evolves into a chronic
brain disorder and this process starts almost immediately after the injury. Atraumatic brain
injury (aTBI) refers to physical trauma to the brain that arises from non-physical means such
as toxins passing the blood/brain barrier and these lead to cognitive and other
dysfunctions. ATBI is particularly serious in infants and young children, often leading to longterm functional impairments. Although clinical research is useful for quantifying and
observing the effects of these injuries, few studies have empirically assessed the long-term
effects of juvenile TBI (jTBI) on behaviour and histology. 12
Age of onset is a very important aspect of outcome. Until fairly recently, the impact of
early brain insult [EBI] has been considered to be less significant than for later brain injuries,
consistent with the notion that the young brain is more flexible and able to reorganize in the
context of brain insult. However, Anderson et al have reviewed childhood head trauma
through a range of ages from pre-natal to after age ten years. This study aimed to
evaluate this notion by comparing cognitive and behavioural outcomes for children
sustaining EBI at different times from gestation to late childhood. 13
Magnetic resonance imaging and histological data reveals that the effects of jTBI are
evolving for up to 6 months post-injury, with reduced cortical thickness, decreased corpus
callosum area and CA1 neuronal cell death in jTBI animals distant to the impact site. These
findings suggest that this model of jTBI produces long-term impairments comparable to
those reported clinically. Although some deficits are stable over time, the variable nature of
other deficits (e.g., memory) suggest that the effects of a single jTBI produce a chronic
brain disorder with long-term complications. (Kamper et al ibid, 2013)
Groups were similar with respect to injury and demographic factors. Children were
assessed for intelligence, academic ability, everyday executive function and behaviour.

Harding, C. Health care and risk of early death for people with learning disabilities.
Developmental Medicine & Child Neurology, 2017. doi: 10.1111/dmcn.13376.

10

Berg JM. Neurological complications of pertussis immunization. British Medical Journal 2:24-27;
1958.

11

Ahuja, AS. Emotional needs of children with intellectual disabilities are unidentified. BMJ. 2004
Oct 16; 329(7471): 917. doi: 10.1136/bmj.329.7471.917 PMCID: PMC523128

12

Kamper JE, Pop V, Fukuda AM, Ajao DO, Hartman RE, Badaut J. Juvenile traumatic brain
injury evolves into a chronic brain disorder: Behavioral and histological changes over 6
months. Exp Neurol. 2013 Dec;250:8-19. doi: 10.1016/j.expneurol.2013.09.016.

13

Anderson, A.; Spencer-Smith, M.; Rick Leventer R.; Lee Coleman, L.; Anderson, P.; Williams, J.;
Greenham, M. & Rani Jacobs, R. Childhood brain insult: can age at insult help us predict
outcome? Brain (2009) 132 (1): 45-56.

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Results showed that children with EBI were at increased risk for impairment in all domains
assessed. Furthermore, children sustaining EBI before age 2 years recorded global and
significant cognitive deficits, while children with later EBI performed closer to normal
expectations, suggesting a linear association between age at insult and outcome. In
contrast, for behaviour, children with EBI from 7 to 9 years performed worse than those with
EBI from 3 to 6 years, and more like those with younger insults, suggesting that not all
functions share the same pattern of vulnerability with respect to age at insult.
An understanding of MDLs case is based almost entirely on experience. She does not have
the capacity for mental consideration of abstract ideas. She does not think about things
unless they are imposing themselves upon her attention.
With subjects like MDL, there is a tendency to want to relate such problems to mental
health interpretations and practices because those are what the Learning Disability Service
normally deals with. However, this is a serious over-simplification, not to say, an erroneous
one if the subject is primarily brain damaged and has some antecedent learning problems
as a result of that damage. The two cannot be combined or the benefits of proper
assessment and care will be forfeited to the subjects misfortune.
This paper has two purposes: one, of demonstrating the problems that MDL has acquired
through her brain injury and two, to offer a very great saving in time for those who need to
know how this rare type of brain damage affects an individual who has been
misunderstood for so long. Due to the long-term administration of psychotropic drugs she is
unable to offer any cooperation in a neurological assessment and that makes such an
assessment almost impossible.

____________________

The Central Nervous System (CNS)

There are three major divisions of the central nervous system - the spinal cord, the subcortex and the cortex. The cortex is the outer layer of the brain; these two are considered
here.
The neurons of the central nervous system form a cohesive structure which floats in the
cerebrospinal fluid (CSF). Within the central nervous system, the spinal cord includes the
neurons housed in the bony casing of the spinal vertebrae, while the cortical level is represented by the neurons of the outer layers of the cerebral hemispheres. The subcortical level
includes those cells of the CNS which lie above the spinal cord and below the cortex.

The Brain

In evolutionary terms the brain consists of a primitive central core

the brain stem, the thalamus and the cerebellum. This group of structures is collectively
referred to as the limbic system. The outer layer of the brain the new brain or neocortex
has evolved upon the limbic system. Despite this evolutionary division, the various
structures are interconnected in a complex fashion.
The brain stem forms a stalk which supports the other brain structures. It contains ascending
and descending fibres which transmit information to or from higher brain centres. There are
also neurons within the brain stem which relay incoming information directly to motor
efferents. These brain stem reflexes include sucking, swallowing, sneezing, coughing,
yawning, breathing, and the control of blood pressure. That the reflexes are organized
within the brain stem is demonstrated by their presence in children born without a cerebral
cortex.
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The cells in the central part of the brain stem make up the reticular formation. This region
receives input from all sensory systems and maintains a continuous barrage of impulses ascending to the cortex. The reticular formation is involved in the control of sleeping, waking
and many other physiological and behavioural functions.
Located on top of the brain stem but still deep beneath the surface of the brain is the
thalamus. A major function of the thalamus is to relay information to and from the cortex.
Many nuclei of the thalamus receive input from sensory afferent fibres and project it to the
cortex.
All senses except smell have relay centres in specific nuclei of the thalamus. Within these
nuclei sensory information is modified before being relayed to the cortex. Some thalamic
nuclei relay information from the cortex down through the spinal cord to the skeletal
muscles. Other thalamic nuclei are involved in coordination of reflex movements of the
eyeball and the pupillary reflex.
Surrounding the thalamus is a number of long nuclei. A group of these nuclei which form
the basal ganglia are associated primarily with movement, whereas others appear to play
a major role in emotional and regulatory behaviours.
Another structure important for movement control is the cerebellum, which is situated on
the top surface of the brain stem and below the cortex. The cerebellum acts to smooth
and refine muscular action. The cerebellum works with information from equilibrium sensors
(vestibular sensory system) and information concerning the position of limbs and the stretch
of muscles (proprioceptors). [See p 98] In addition, the cerebellum ensures that motor
commands from higher centres are coordinated and result in well-regulated movement.
There are an enormous number of muscles involved in even simple actions such as using a
knife and fork, or walking. A professional card player can deal cards with exceptional
speed and precision. This probably involves reading off a carefully prepared program of
this action which is stored and refined by the cerebellar neurons. Loss of even simple
abilities can follow brain damage to the areas that control them.
Situated in front of and slightly below the thalamus is the hypothalamus. This brain region is
important in the regulation of glandular secretions, eating, drinking, sexual behaviour,
emotional behaviour, and body temperature. The hypothalamus is unusual in that it
manufactures chemicals (hormones) which are transmitted, via the bloodstream, to the
adjacent pituitary gland. Hypothalamic hormones control the pituitary gland's manufacture
of a number of hormones which are carried by the blood stream to control both the
manufacture and release of the hormones of other glands. Thus the hypothalamus functions as an important link between the brain and the glandular effector system.
Pituitary Dysfunction after Traumatic Brain Injury
Partial or complete pituitary
dysfunction affects 33-50% of all traumatic brain injury (TBI) survivors and is a significant
contributor to the overall disability burden. The hypophyseal vessels are anatomically
vulnerable to raised intracranial pressure and pituitary ischaemia or haemorrhage. Posttraumatic hypopituitarism (PTHP) can affect all grades of severity of injury and is often
difficult to diagnose, as its features largely overlap with common post-concussive
symptoms. PTHP has a wide range of manifestations, including fatigue, myopathy, cognitive
difficulties, depression, behavioural changes or life-threatening complications such as
sodium dysregulation and adrenal crisis. A full investigation of the hypothalamic-pituitary
axis requires specialized neuroendocrine assessment, including stimulation tests, as random
hormone levels can be misleading in this context. Patients with PTHP may receive

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suboptimal rehabilitation unless the underlying hormone deficiency is identified and
treated. 14
This dysfunction is important for all; however, until recently there has been little knowledge
gained on this potential complication in children and adolescents. Traumatic brain injury
carries a considerable burden of disabilities and leads to a variety of endocrine
dysfunctions in 28-69% of adult acute head-injured patients. In the acute posttraumatic
phase, adrenal insufficiency and electrolyte disorders are critical conditions. 15
Acerini et al have shown that hypopituitarism may occur after both mild and severe TBI,
with growth hormone and gonadotrophin deficiencies appearing to be most common
abnormalities. Central precocious puberty has also been documented. 16 They suggest
that given the critical role of anterior pituitary hormones in the regulation of growth,
pubertal and neurocognitive development in childhood, early detection of hormone
abnormalities following TBI is important; and that a multidisciplinary approach should be a
follow-up together with endocrine assessment for the long-term management and
rehabilitation of children and adolescents who survive moderate to severe head injury. 17
Later research by Auble et al emphasizes that endocrine dysfunction is common after
accidental traumatic brain injury. However they say that prevalence of endocrine
dysfunction after inflicted traumatic brain injury (iTBI) is not known. In their research the
objective was to examine endocrinopathy in children after moderate to severe iTBI.
This showed that children with history of iTBI had a high risk for endocrine dysfunction,
including elevated prolactin and growth abnormalities. This effect of inflicted TBI has not
been well-described in the literature. Larger, multi-center, prospective studies would
provide more data to determine extent of endocrine dysfunction in iTBI. They recommend
that any child with history of iTBI be followed closely for growth velocity and pubertal
changes; and suggest that if growth velocity is slow, prolactin level and a full endocrine
evaluation should be performed. 18
Elenitza reports that psychotropic drugs affect the regulatory mechanisms of different
neuroendocrine axis. She has reviewed the interactions between psychotropic drugs and
prolactin, the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-gonadal
axis. She confirms that hyperprolactinemia can cause galactorrhea, amenorrhea, sexual
disfunction, impaired spermatogenesis and increased risk for osteoporosis and fractures.
Atypical antipsychotics cause less hyperprolactinemia than conventional antipsychotics
but lithium has important effects on thyroid function. During lithium treatment, affectively ill
patients show, in varying degrees and combinations, reduced levels of thyroid hormones
and clinical evidence of subclinical hypothyroidism, overt hypothyroidism and goiter. It is

14

Zaben M, El Ghoul W, Belli A. Post traumatic head injury pituitary dysfunction. Disabil
Rehabil. 2012 Jul 10.

15

Einaudi, S & Bondone, C. The effects of head trauma on hypothalamic pituitary function in
children and adolescents. Current Opinion in Pediatrics 19(4):465 (2007) PMID 17630613.

16

In January 1970, just prior to MDLs 10th birthday, the GP reported: On 21 January I was called
again as the child had been in bed for over a week, refusing to eat speak or get up. I
examined all systems with no positive findings, but noticed that she was undergoing very
rapid pubertal changes. Her mother said that she began irregular menses at nine years.

17

Acerini, CL. & Tasker, RC. Traumatic brain injury induced hypothalamic pituitary dysfunction a
paediatric perspective. Pituitary 10(4):373 (2007) PMID 17570066.

18

Auble B; Rose S; Bollepalli S; Weis T; Makoroff K; Khoury J & Colliers T. Hypopituitarism in

pediatric survivors of inflicted traumatic brain injury. J Neurotrauma. 2013 Sep 12.

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important therefore that MDL has regular assessments of her medication so that there is
vigilance regarding the possibility of endocrinology side effects. 19
Bou Khali & Richa have suggested that because many patients take more than one
psychotropic drug, an understanding of the effects of every class of these drugs is very
important to manage any thyroid abnormalities that can happen with these patients. They
conclude that, patients receiving lithium, phenothiazines, and tricyclic antidepressants
should be closely monitored for the development of thyroid function abnormalities. 20
Recent literature reports suggest that valproic acid, may be associated with polycistic
ovarian syndrome. Until additional data is available, women starting valproate therapy
should be warned about the possibility of endocrinology side effects.
Following assessment of children (aged two months to 20 years) after TBI, Casano-Sancho
recommended that there should be prospective follow-up of children after their injury.
Firstly, because the impairment of pituitary function cannot be predicted, and secondly, to
avoid the potential consequences of pituitary dysfunction. They also consider that
prospective clinical trials are needed before recommending a systematic screening after
TBI and/or Growth Hormone Therapy either in post-pubertal children or in pre-pubertal
children who grow normally. 21
Giuliano et al found that patients examined at one year or several years from complicated
mild TBI had a high occurrence of isolated Growth Hormone deficiency, which was
associated with visceral adiposity and metabolic alterations (in some cases, central
hypothyroidism). Their findings suggest that patients with complicated mild TBI should be
evaluated for GH deficiency even after several years from trauma. 22
Liver Dysfunction after Traumatic Brain Injury
Nizamutdinov et al have found that
dentaperipheral contributions involving the digestive and immune systems are emerging as
factors involved in the various symptomology associated with TBI. They hypothesized that TBI
would alter hepatic function, including bile acid system machinery in the liver and brain.
Their research results show activation of the hepatic acute phase response by 2 hours after
TBI, hepatic infammation by 6 hours after TBI and a decrease in hepatic transcription
factors, Gli 1, Gli 2, Gli 3 at 2 and 24 hrs after TBI. Bile acid receptors and transporters were
decreased as early as 2 hrs after TBI until at least 24 hrs after TBI. Quantifcation of bile acid
transporter, ASBT- expressing neurons in the hypothalamus, revealed a signifcant decrease
following TBI. These results are the frst to show such changes following a TBI, and are
compatible with previous studies of the bile acid system in stroke models. The data support

19

Elenitza IM. Endocrinologic adverse effects of psychotropic drugs. Vertex. 2005 JanFeb;16(59):43-8. PMID: 15785788 [Article in Spanish]

20

Bou Khalil R & Richa S. Thyroid adverse effects of psychotropic drugs: a review. Clin
Neuropharmacol. 2011 Nov-Dec;34(6):248-55. doi: 10.1097/WNF.0b013e31823429a7.

21

Casano-Sancho P; Surez L; Ibez L; Garca-Fructuoso G; Medina J & Febrer A. Pituitary

dysfunction after traumatic brain injury in children is there a need for ongoing endocrine
assessment? Clin Endocrinol (Oxf). 2013 May 7. doi: 10.1111/cen.12237.

22

Giuliano, S; Talarico, S; Bruno, L; Nicoletti, FB; Ceccotti, C & Belfiore. A. Growth hormone
deficiency and hypopituitarism in adults after complicated mild traumatic brain injury.
Endocrine. 2016 Nov 23. [Epub ahead of print]

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the emerging idea of a systemic infuence to neurological disorders and point to the need
for future studies to better defne specifc mechanisms of action. 23
Slim et al have also noted that those who have been prescribed atypical antipsychotic
(AAP) medication present questions about their tolerability over the endocrine, metabolic,
and cardiovascular axes. They find that atypical antipsychotic drugs are associated, to
differing extents, with mild elevation of aminotransferases related to weight gain, AAPinduced metabolic syndrome, and nonalcoholic fatty liver disease. Although the hepatic
safety of new AAPs seems improved over that of chlorpromazine, they can occasionally
cause idiosyncratic liver injury with varying phenotypes. AAPs are a group of
heterogeneous, chemically unrelated compounds with distinct pharmacological and
pharmacokinetic properties and substantially different safety profiles, which precludes the
notion of a class effect for hepatotoxicity risk and highlights the need for an individualized
therapeutic approach. 24
It is therefore very important to be aware of the fact that physical or chemical damage to
these areas may also bring about hormonal dysfunction.

The Cerebral Cortex

The most conspicuous parts of the human brain are

the two folded masses which together form the cerebral hemispheres. The two
hemispheres are separated by a deep fissure running from front to back, beneath which
they are connected by a bundle of fibres called the corpus callosum. The corpus callosum
is the largest and most important of the connecting or commissural fibre systems of the
brain.
The functions of the cerebral cortex:

How we know what we are doing within our environment (Consciousness)

How we initiate activity in response to our environment

Judgments we make about what occurs in our daily activities

Controls our emotional response

Controls our expressive language

Assigns meaning to the words we choose

Involves word associations

Memory for habits and motor activities

The observable problems of the cerebral cortex:

23

Nizamutdinov, D; Mukherjee, S; Zeitouni, S; Frampton, G; Hurst, J; Shapiro, LA, DeMorrow, S;

McMillin, M; Paul Clint S. Bricker, PCS & Kain, J. Hepatic alterations are accompanied by
changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic

brain injury. Sci. Rep. 7, 40112; 2017.

24

Slim M; Medina-Caliz I; Gonzalez-Jimenez A; Cabello MR; Mayoral-Cleries F; Lucena MI;

Andrade RJ. Hepatic Safety of Atypical Antipsychotics: Current Evidence and Future
Directions. Drug Saf. 2016 Oct;39(10):925-43. doi: 10.1007/s40264-016-0436-7.

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Loss of simple movement of various body parts (Paralysis)

Inability to plan a sequence of complex movements needed to complete multistepped tasks, such as making coffee (Sequencing)

Loss of spontaneity in interacting with others. Loss of flexibility in thinking

Persistence of a single thought (Perseveration)

Inability to focus on task (Attending)

Mood changes (Emotionally Labile)

Changes in social behaviour. Changes in personality

Difficulty with problem solving

Inability to express language (Broca's Aphasia)

Each hemisphere is approximately the size of a clenched fist. Each hemisphere is filled
largely by message-carrying fibres. However, much of the work of the brain is done in the
cells which form the outermost layers of the cerebral hemispheres. These layers are called
the cortex.
The importance of the cortex is indicated by the fact that primitive organisms, such as fish
and frogs, have no real cortex. As behavioural complexity increases, the size of the cortex
increases correspondingly. The appearance of the cortex tends to change with the complexity of the organism. In primitive animals such as the rat the cortex is smooth, whereas in
primates the cortex is convoluted with large folds (fissures) and ridges (gyri). The
convolutions greatly increase the surface area of the cortex although much of it is hidden
from view.
Many fissures may slightly differ from individual to individual but the large fissures are fairly
constant. These main fissures are the central fissure and the lateral fissure, which facilitate
the division of each hemisphere into four lobes - the frontal lobe, the parietal lobe, the
temporal lobe, and the occipital lobe. These divisions simplify the relating of brain function
to cortical location.
All sensory systems have neural pathways which terminate in sensory projection areas of the
cortex. This does not imply a direct connection between receptors and the cortex but
rather a sequence of neurons. The sensory projection areas of both hemispheres are
generally of equal size.
The cortical projection areas are essential for the proper sensing of particular stimuli. Visual
information projects to the occipital lobe, auditory information to the temporal lobe,
somato-sensory information (touch, pressure, etc.) to the parietal lobe.
Parts of each projection area appear to serve as primary areas (since damage to them
leads to total loss of that sensation). Regions bordering each primary projection appear to
serve an integrative function. For example, damage to the occipital lobes may result in
some loss of vision although the eyes and optic nerves are in perfect working order.
Damage to regions bordering on the visual cortex results in normal visual sensation but with
deficits in integrating the visual sensation experienced. The results support the view that,
while for conscious perception the appropriate part of the cortex needs to be intact,
rudimentary sensory functioning can continue without it.

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The motor and somato-sensory maps have two features in common. First, there is virtually a
total cross-over of somato-sensory input and motor output. The left hemisphere receives
information about the right side of the body and controls movements of limbs on that side
and vice-versa.
Learning and Memory Disturbances of Perception
People with damage to the
cortex just in front of the visual projection areas are still capable of visual sensations, but
these sensations are not adequately integrated. The general name for this type of
perceptual disturbance is agnosia (not knowing).
One variety of agnosia is the inability to recognize faces. Such cases reflect the problems of
testing brain-damaged people. Are patients simply misunderstanding the questions, or do
they have defective perceptual ability? Exhaustive individual testing is required to
overcome these problems. In addition to these functions it now seems that areas of the
parietal lobe may play an important part in directing eye movements and perhaps even
directing attention.
Other cortical regions are critical for the integration or recognition of auditory and tactile
material and they are centred around the major auditory and somato-sensory projection
areas.
Memory of Skilled Movements
Damage to association areas around the
motor strip (in front of the central fissure) affects the memory of skilled movements. These
patients are unable to remember or organize the sequence of movements making up
particular skills. They can copy but cannot initiate the movement. The general name for this
loss of motor memory is apraxia.
Geschwind 25 defines apraxias as disorders of the execution of learned movement which
cannot be accounted for by weakness, incoordination or sensory loss, or by incomprehension of or inattention to commands. He quotes the example of a patient who could carry
out commands with his right hand (e.g. combing his hair or using a hammer), but when told
to use his left hand made no response. He could copy the task with his left hand if the
examiner performed it, but was apparently unable to integrate the movement sequence
himself. The fact that he could copy the task with his left hand rules out weakness or incoordination. Further, as he could perform the task with his right hand, inattention,
uncooperativeness or incomprehension were also ruled out.
Speech & Language
Damage to association areas of the left temporal lobe produces language disturbances. A
loss of language ability, due to brain damage, is called aphasia. Such disruptions are not
primarily due to sensory or motor deficits, but to the inadequate handling of symbolic
processes.
Aphasia damages a person's ability to use or understand words. It does not impair the
person's intelligence. People who have aphasia may have difficulty speaking and finding
the "right" words to complete their thoughts. They may also have problems understanding
conversation, reading and comprehending written words, writing words, and using
numbers.
The two major cortical areas for language Broca's area and Wernicke's area are
linked neurally. The location and extent of these areas has been the subject of dispute,

25

Geschwind, N. Specializations of the Human Brain. Sci Am. 1979 Sep;241(3):180-99.

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and they do not have definite anatomical boundaries. Damage to these areas produces
gradients of language loss.
Broca's area is at the base of, and just in front of, the central fissure. If it is damaged,
disturbances of speech production result. These patients have great difficulty in speaking,
and what speech they have is emitted slowly, with great effort and poor articulation. Some
may have only a one-word vocabulary, and few can produce whole sentences. In
addition, a similar disability usually occurs in their written language. However, they generally
comprehend both spoken and written language.
The language loss produced by damage to Broca's area is not due simply to paralysis or
muscular problems patients can often sing the tune of a melody using la-la. The
essential deficit is one of integration because the neural machinery that integrates
language production is damaged. It may be that Broca's area governs the transformation
of language into speech or writing.
Wernicke's area is a region in the left temporal lobe, below the lateral fissure and adjacent
to the primary projection area for hearing; damage to this area results in the inability to
understand both speech and writing. In those so affected, speech and writing are
produced effortlessly but are essentially meaningless a scrambled sequence of
meaningless, inappropriate and often unintelligible words and non-words. Interestingly, the
basic grammatical skeleton appears preserved but there is a lack of denotation. Wernicke's
area seems to govern the recognition and synthesis of language patterns.
There are close neural connections between Wernicke's area and Broca's area. Geschwind
(Idem) believes that the act of speaking involves the formulation of a concept into an
auditory form in Wernicke's area, and then relaying it to Broca's area where the language is
put into the complex programming of the speech organs.
Language association areas in the non-dominant hemisphere
Language
functions appear to be controlled by association areas in the left hemisphere of the brain.
This raises a question about the function of the comparable regions of the right hemisphere.
It was once thought that the right hemisphere was relatively unimportant since massive
strokes to the right hemisphere had very little effect on language. However, the significance
of the association areas in the right hemisphere is now becoming evident. The evidence is
derived largely from the study of patients with damage to the corpus callosum, so that their
two hemispheres function relatively independently. Other evidence has come from patients
with massive damage to their left (dominant) hemisphere, so that they are totally without
language functions (global aphasics). For some skills the right hemisphere is superior to the
left.
Spatial abilities (such as copying block-designs) and musical abilities are apparently more
disrupted by damage to the right hemisphere than to the left. Thus the right hemisphere is
not illiterate. Furthermore, it has been found that people who have lost the use of the
association areas in their left, (dominant) hemisphere, have considerable residual semantic
and syntactic capacities which can be realized through response systems other than
speech. Gazzaniga 26 found that such patients can perform many language operations
using only their right hemisphere and, for example, could quickly learn the, same or
different judgements.

26

Gazzaniga, MS & Hillyard, SA. Language and Speech Capacity of the Right Hemisphere.
Neuropsychologia, 1971, Vol. 9, pp. 273 to 280. Pergamon Press.

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FRONTAL LOBES

The two frontal lobes constitute approximately 25% of brain

volume, yet the functions of this massive amount of brain remain obscure. The frontal lobes
were once believed to be the seat of intelligence, since the most intelligent animals
appear to have the largest frontal lobes. Recent evidence suggests, however, that the role
played by the frontal lobes is considerably more complex.

In the early 1930s, Jacobsen removed both frontal lobes from the brains of a group of
monkeys27. After they had recovered from the operation they were subjected to a number
of behavioural tests. The monkeys were found to perform particularly poorly on a delayed
response task. Each monkey was shown a piece of food which was then hidden under one
of two cups; after a short delay the animal had to select that cup. A correct response
yielded the food. Since the monkeys without frontal lobes performed poorly on this task,
Jacobsen concluded that the frontal lobes were important for immediate memory.
However, recent evidence suggests that this interpretation is not correct. If the monkeys
were in darkness during the delay, their performance was near normal, suggesting that the
frontal lobes play a role in attention or distractibility rather than immediate memory. This
interpretation is consistent with the findings of research on human subjects with frontal lobe
damage.
There is a useful source of evidence that comes from testing normal people who have
accidentally suffered frontal lobe damage (for example, through war or car accidents).
Post-operatively such people do not become imbeciles, hence it is unlikely that intelligence
is localized in the frontal lobes. Generally, behavioural changes due to frontal lobe
damage are subtle, affecting both intellectual behaviour and personality. It should be
noted however that these research subjects were fully mentally developed adults prior to
their brain injury. The outcome is not the same if the injury occurs during very early infancy
or before the brain has developed to any significant degree to life outside the womb.
The behaviour of patients with frontal lobe damage is generally stereotyped or
perseverative. It appears that these people find it difficult to let go of a concept once it is
formed. Humans with damage to the frontal lobes are easily distracted. This distractibility
may be reflected in their response to tests of intellectual functioning, although overall
intelligence test scores are typically unchanged. These patients also have difficulty
explaining the meaning of complex material, or in picking out significant objects in a
picture. Luria 28 characterizes these difficulties as follows:
In normal subjects the derivation of the meaning of a picture develops because of
well-structured analytic or synthetic activity. In frontal patients this derivation is
disturbed by ancillary associations evoked by fragmentary observations.
The thinking of these patients is often described as being very concrete they have
difficulty explaining the meaning of a metaphor and in perceiving object relations and
analogies.
In addition to intellectual changes, subtle changes in personality often occur; for example,
there is a tendency to become more extroverted, while exhibiting a lack of purpose or
initiative. The fact that the loss of the frontal lobes has no measurable effect on intelligence

27

Jacobsen, CF. Functions of Frontal Association Area in Primates. Arch Neurol

Psychiatry. 1935;33(3):558-569.

28

Luria AR & Homskaya ED. Disturbances in the regulative role of speech with frontal lobe
lesions. In: Warren JM, Akert K, Eds. The Frontal Granular Cortex and Behaviour. New York:
McGraw Hill, 1964.

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test scores may be due to the unreliability of the intelligence tests used. They may be
neither measuring the correct things nor weighting various sub-tests appropriately. 29

CLINICAL AND ANATOMIC ASPECTS

For over a century, the frontal lobes have

been an enigma to brain scientists. Significant progress has been made in the past several
decades, but many anatomic and functional aspects remain mysterious. The frontal lobes,
particularly in humans, are massive in relation to other, better understood cortical areas,
and it was long considered that the frontal lobes were the seat of human intelligence. This
proved untrue, at least as intelligence is defined by psychometric testing. The functions of
the frontal lobes in human behaviour remain a mystery.30
In 1973 the Russian psychologist A. R. Luria31 proposed a simple outline of brain functions.
He suggested that subcortical structures, particularly the midbrain and diencephalon, functioned to produce tonic regularity. He further stated that the posterior cortex the
premotor and motor aspects of the frontal lobe and all cortex posterior to these areas
carried out primary sensorimotor functions, and that the comparatively massive prefrontal
cortex functioned to regulate mental activities. This tripartite description of mental functions
was further elaborated by Albert32 who suggested the terms fundamental, instrumental,
and superordinate to define the activities of the brainstem, posterior cortex, and prefrontal
cortex respectively.
The frontal lobe is the largest lobe in the brain, yet often it is not specifically evaluated in
routine neurologic examinations. This may in part be due to the attention to detail and to
the rigorous testing strategies that are required to probe frontal lobe functions. As
successful completion of any cognitive task considered a frontal lobe function requires
multiple brain regions both within and outside the frontal lobe. Dysfunctions of the frontal
lobe can give rise to relatively specific clinical syndromes. When a patient's history suggests
frontal lobe dysfunction, detailed neurobehavioral evaluation is necessary.
Classic neuroanatomy divides the cortical surface of the frontal lobes into three major
segments:
1. Motor the narrow strip of cortical tissue located just anterior to the rolandic fissure;
2. Pre-motor the larger area of frontal tissue anterior to the motor strip that acts as a
motor association cortex (Brodmann areas 6 and 8); and
3. Pre-frontal the vast amount of frontal cortex anterior to the pre-motor cortex,
including a significant amount of the anterior/lateral cortex, most of the medial
frontal cortex, and the entire orbital frontal cortex.
In the classification suggested by Luria (idem) the motor and pre-motor areas of the frontal
lobes would be included in the sensori-motor division and the pre-frontal cortex would carry
out the regulatory activities. The prefrontal regulatory functions are important for

29

Atrens, D & Curthoys, I. The Neurosciences and Behaviour: An Introduction. Academic Press
1982.

30

Benson, DF & Miller, BL. Frontal Lobes: Clinical and Anatomic Aspects. . In Feinberg, T E &
Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

31

Luria AR. The Working Brain: An Introduction to Neuropsychology (Haig B, trans). New York,
Basic Books; 1973.

32

Albert ML. Subcortical dementia, in Katzman R, Terry RD, Bick KI (Eds): Alzheimer's Disease, Senile Dementia and Related Disorders. New York, Raven Press, 1978, pp 173-180.

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psychology.
Given the unique connectivity between the frontal regions and deeper brain structures,
lesions of these areas or their connections generate relatively distinctive clinical behaviours.

The dorso-lateral frontal cortex is concerned with planning, strategy formation, and
executive function. Patients with dorso-lateral frontal lesions tend to have apathy,
personality changes, abulia33, and lack of ability to plan or to sequence actions or
tasks. These patients have poor working memory for verbal information (if the left
hemisphere is predominantly affected) or spatial information (if the right hemisphere
bears the lesion brunt).
The frontal operculum contains the centre for expression of language. Patients with
left frontal operculum lesions may demonstrate Broca aphasia and defective verb
retrieval, whereas patients with exclusively right opercular lesions tend to develop
expressive aprosodias (See pages 69/70).
The orbitofrontal cortex is concerned with response inhibition. Patients with
orbitofrontal lesions tend to have difficulty with disinhibition, emotional lability, and
memory disorders. Patients with such acquired sociopathy, or pseudopsychopathic disorder, are said to have an orbital personality. Personality changes
from orbital damage include impulsiveness, puerility, a jocular attitude, sexual
disinhibition, and complete lack of concern for others.
Patients with superior mesial lesions affecting the cingulate cortex typically develop
akinetic mutism34.
Patients with inferior mesial (basal forebrain) lesions tend to manifest anterograde
and retrograde amnesia and confabulation.

Of considerable significance in discussions of the neural basis of prefrontal psychological

functions are the connections of frontal cortex with other brain areas. The prefrontal cortex
receives direct or indirect input from most ipsilateral cortical areas and from the opposite
hemisphere via callosal connections. In addition, prefrontal cortex receives strong input
from a number of significant subcortical sources:
1. The limbic system,
2. The reticular system,
3. The hypothalamus, and
4. Neurotransmitter systems.
The pre-frontal cortex is the only cortical area that receives strong sensori-motor, limbic, and
reticular input. Additional input of hypothalamic and autonomic data and the effects of
many neurotransmitters place prefrontal cortex in a strong position to monitor both intrinsic
and extrinsic stimuli and to exert regulatory control of brain functions.

Pre-frontal Functions

Behavioural functions performed by the prefrontal

cortex have proved difficult to delineate. To date, almost all information has been derived

33

Abulia is a state in which an individual seems to have lost will or motivation. It is not a
separate condition; rather, it is a symptom associated with various forms of brain injury. It may
occur in association with a variety of conditions, including stroke, brain tumour, traumatic
brain damage, bleeding into the brain, and exposure to toxic substances.

34

Akinetic mutism: A state in which a person is unspeaking (mute) and unmoving (akinetic).

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from behavioural aberrations seen following frontal brain damage. In the past several
decades some psychological tests aimed directly at the assessment of prefrontal function
have been devised (see Wisconsin Card Sorting Test (WCST)35 below p 16), and, more
recently, psychological testing has been combined with functional brain imaging
techniques to provide valuable insights. In general, however, psychological tests of
prefrontal function demand inferences from data obtained through primary sensori-motor
functions, which of themselves may be impaired. A second problem in studying prefrontal
function is a lack of clearly delineated neuropathology.
The main domains affected include:
Complex motor behaviour (see Limb Apraxia below, p82)
Planning & sequencing (See Acalculia below, p79)
Attention (see Limb Apraxia below, p82)
Memory (See several references esp. ps10/18/32/33+)
Language (see Aspects of Aphasia & Agraphia below, ps. 70/77)
It is the damage to the frontal lobes and its consequences that confound those who attempt
to assess MDL.
Perhaps because of these problems, the underlying impairment in frontally damaged
patients has yet to be satisfactorily established. Some of the characteristics that appear in
MDLs damage to this area are:

Little spontaneity of behaviour

Unconcern about non-personal matters
Low overt emotion (not including sympathetic system induced anxiety36)
Reduced ability to plan ahead

The cognitive impairments of patients with prefrontal damage are apparent in a variety of
tasks. The domains affected include complex motor behaviour; planning and sequencing,
attention, memory, and language. (See trans-cortical motor aphasia p 78) In
comparison with other types of brain damage which disrupt cognitive development, frontal
damage acquired early in life appears to provide the neurological substrate for a special
type of learning disability in the realms of insight, foresight, social judgement, empathy, and
complex reasoning 37.
There have been those who have felt that MDL has at times shown inappropriate behaviour
towards others. However, this stems from the fact that she has a lack of recognition of
anothers personal space. She does not have the ability to judge social situations and how
and when to approach other people. At times there is also increased motor activity and
almost always this is as a result of anxiety.

35

Grant AD & Berg EA. A behavioural analysis of reinforcement and ease of shifting to new
responses in a Weigl-type card sorting. J Exp Psychol 38:404411,1948

36

When we are faced with something that is frightening, the body floods the system with
adrenaline. This hormone attempts to help us to deal with the 'danger'. Adrenaline activates
the Sympathetic Nervous System which is a sub-branch of the Autonomic Nervous System. It
controls specific bodily organs to prepare us for fight or flight. These reactions are beyond
the control of our consciousness and can be responsible for anxiety. The anxiety is
maintained and often internalised if we cannot respond with either fight or flight.

37

Price, BH; Daffner KR; Stowe RM & Mesulam, MM. The comportmental learning disabilities of
early frontal lobe damage. Brain: a journal of neurology, Vol. 113 (Pt 5) (October 1990), pp.
1383-1393.

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Anxiety is an important physiological and psychological response in humans, especially for
those with intellectual and/or developmental disabilities. It can contribute to improved
attention, performance and survival in threatening situations. However, when the response
becomes over-learned, habitual, or otherwise dysfunctional, increased anxiety can lead to
disruptive behaviour, inefficient brain patterns, and avoidance of pleasurable
experiences.38
Many toxins can affect the cerebral cortex and in those cases the symptom picture is as
defuse as in MDLs case. The toxins from the DPT vaccination of course are the cause of her
brain damage.

COGNITIVE AND NEUROPSYCHOLOGICAL ASPECTS

As mentioned above,
the prefrontal cortex plays a crucial role in normal intelligent behaviour. However, a more
precise characterization of the functions of prefrontal cortex has been elusive. A wide
range of tasks have been found to be sensitive to prefrontal damage. One of the most
common is the WCST, in which patients are given a series of cards and asked to sort them
by placing each into one of four piles. The cards vary according to three attributes:

the number of objects drawn on the card

the shape of the objects

their colour

The piles are to be started beneath four reference cards, which also vary along these same
dimensions, so that each possible value of each attribute will be represented in exactly one
pile. The subject is given a deck of cards and asked to place each, in sequence, into one
of the four piles. The only feedback given to the subject is the word right or wrong after
each card.
MDL would be incapable of making any successful attempt at this test. She would not
understand the instructions but also she would not be able to recognise the differences
between the cards and therefore would not be able to complete the sequencing tasks.
Milner39,40 tested a variety of neurosurgical patients on the WCST and found that as
compared to patients with lesions elsewhere in the brain, patients with damage to the
dorso-lateral prefrontal cortex made an unusually high number of errors and achieved
fewer categories. These differences can be attributed mainly to perseveration. While the
dorso-lateral prefrontal group committed non-perseverative errors at rates similar to those
of the control groups, their rates of perseverative errors were significantly higher. A number
of other studies have confirmed the basic finding that the WCST is particularly sensitive to
frontal damage. 41,42,43

38

Reeve, A. Anxiety - Challenges of Normal and Abnormal Responses. A Chapter from Health
Care for People with Intellectual and Developmental Disabilities across the Lifespan Springer,
2016; pp 1559-1571

39

Milner B. Effects of different brain lesions on card sorting. Arch Neurol 9:90-100, 1963.

40

Milner B. Some effects of frontal lobectomy in man, in Warren J, Akert K (eds): The Frontal
Granular Cortex and Behavior. New York: McGraw-Hill, 1964.

41

Drewe EA. The effect of type and area of brain lesion on Wisconsin Card Sorting Test
performance. Cortex 10:159-170, 1974.

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Sequencing Tasks

The term sequencing can describe anything from concrete

motor sequences, such as sequences of hand motions, to more abstract behavioural
sequences, such as the morning routine of preparing to go to work. Of the sequencing
errors made by frontal-damaged patients, many but not all are perseverative in nature. 44,45
A number of studies of simple manual and oral movement sequences have indicated that
frontal lesions are most disruptive of these abilities. 46,4748 Anecdotal reports suggest that the
problem extends to the sequencing of more abstract kinds of actions. For example,
Penfield and Evans49 describe a patient who could perform all the individual actions
necessary to prepare a meal but could not actually prepare the meal without someone to
tell her the order in which to do things.
Tasks that require planning of a sequence in advance may also depend on the frontal
areas. Shallice50 tested frontal-damaged patients on the Tower of London test, a variant of
the Tower of Hanoi game, designed specifically to require subjects to use advance
planning. Left-frontal damaged patients showed a disproportionate impairment at this
task.

Verbal Fluency

Asked to produce words beginning with a particular letter,

frontal-damaged patients (even those with no overt aphasic signs) will typically produce
few unique responses, often repeating earlier responses. This frequently reported clinical
finding has been supported by a variety of experimental studies. Although her
understanding of words is reasonable, MDL cannot complete semantic tests like offering
words that begin with a particular letter.
An early study by Milner (1964 idem) demonstrated that patients with left frontal damage
were impaired at a written test of verbal fluency when compared to a group with temporal
lobe excisions. Benton51 later confirmed the relative importance of the left frontal areas in
the now more common oral version of the test. Janowsky and co-workers52 have

42

Nelson HE. A modified card sorting test sensitive to frontal lobe defects. Cortex 12:313-324,
1976.

43

Anderson SW; Damasio H; Jones RD & Tranel D. Wisconsin card sorting test performance as a
measure of frontal lobe damage. J Clin Exp Neuropsychol13:909-922, 1991.

44

Luria AR. Two kinds of motor perseveration in massive injury of the frontal lobes. Brain 88:1-10,
1965.

45

Sandson J & Albert M. Varieties of perseveration. Neuropsychologia 22:715-732, 1984.

46

Jason GW. Manual sequences learning after focal cortical lesions. Neuropsychologia 23:483496, 1985.

47

Kimura D. Left-hemisphere control of oral and brachial movements and their relation to
communication. Phi/os Trans R Soc Lond B 298:135-149,1982.

48

Kolb B. & Milner B. Performance of complex arm and facial movements after focal brain
lesions. Neuropsychologia 19:491-503, 1981.

49

Penfield W & Evans J. The frontal lobe in man: A clinical study of maximum removals. Brain
58:115133,1935.

50

Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B 298:199-209, 1982.

51

Benton AL. Differential behavioural effects of frontal lobe disease. Neuropsychologia 6:53-60,
1968.

52

Janowsky JS; Shimamura AP & Squire LR. Source memory impairment in patients with frontal
lobe lesions. Neuropsychologia 27:1043-1056, 1989.

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compared verbal fluency in frontal-damaged patients with a variety of control groups and
found that patients with left or bilateral frontal lesions but not right frontal lesions were
impaired at verbal fluency. Jason (idem) found deficits in gesture fluency in frontal-damaged groups. MDL also has very little gesture activity which again seems to confirm her
frontal damage.
Neuro-imaging studies have tended to confirm the importance of prefrontal areas in
fluency tasks. Parks and co-workers53 used positron emission tomography (PET) to compare
the brain activity of subjects performing a verbal fluency task with controls in a resting state
and found increases in activation bilaterally in both the frontal and temporal lobes.
Previous studies of verbal fluency have reported higher rates of perseverative responses in
both Alzheimer's disease and traumatic brain injury relative to control groups. These
perseverations could arise from a number of impairments-for example, failures in working
memory, inhibitory control, or word retrieval and different clinical populations may show an
increase in perseveration because of different underlying deficits. 54

Context Memory
Although most frontal-damaged patients are not amnesic,
they have nevertheless been found to have impairments on certain memory tasks. The
most widely documented impairments involve memory for contextual information, either
the source of a correctly recalled fact or its temporal context. Schacter55 has applied the
term spatio-temporal context to the type of memory that is impaired in frontal-damaged
patients.
In conditional associative learning, frontal-damaged patients are impaired at learning and
associating between a set of stimuli (e.g., coloured lights) and a set of available responses
(e.g., a set of abstract designs). 56,57 Lesions placed in the posterior dorso-lateral prefrontal
cortex of nonhuman primates (an area adjacent and posterior to the lesions causing
impairments in self-ordered tasks) will markedly impair performance on conditional
association learning tasks in which the monkey must perform different responses conditional
upon the presence of a particular stimulus.58 Furthermore, Petrides and colleagues have
shown that performance of a conditional associative learning task in normal human
subjects activates this same region of posterior dorso-lateral frontal cortex59.
MDL can respond with recognition of words presented to her on a card but fails to memorize
the word for recall when the card is not in view. Likewise if she is verbally presented with a
choice of three items she will inevitably choose the last one. However, when presented

53

Parks RW; Loewenstein DA & Dodrill KL, et al. Cerebral metabolic effects of a verbal fluency
test: A PET scan study. J Clin Exp Neuropsycholl0:565575,1988.

54

Fischer-Baum, S; Miozzo, M; Laiacona, M & Capitani E. Perseveration during verbal fluency in

traumatic brain injury reflects impairments in working memory. Neuropsychology. 2016 Apr 7.

55

Schacter DL. Memory, amnesia, and frontal lobe dysfunction. Psychobiology 15:21-36, 1987.

56

Petrides M. Deficits on conditional associative learning tasks after frontal- and temporal-lobe
lesions in man. Neuropsychologia 23:601-614,1985.

57

Petrides M. Nonspatial conditional learning impaired in patients with unilateral frontal but not
unilateral temporal-lobe excisions. Neuropsychologia 28:137-149,1990.

58

Petrides M. Deficits in non-spatial conditional associative learning after periarcuate lesions in

the monkey. Behav Brain Res 16:95-101, 1985.

59

Petrides M; Alivisatos B; Evans AC & Meyer E. Dissociation of human mid-dorsolateral from

posterior dorsolateral frontal cortex in memory processing. Proc Natl Acad Sci USA 90:873-877,
1993.

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with the same three items visually, she may well choose differently. Although she has not
been examined or assessed in these contextual abilities, it is almost certain that MDL would
not complete satisfactorily tasks of self-order and conditional associative learning.
Janowsky and colleagues60 investigated memory for recently learned facts and memory for
the source of the facts in a group of frontal damaged patients. Although the patients were
normal in their ability to recall the facts, they frequently attributed the facts to incorrect
sources. Shimamura and co-workers61 found that frontal damaged patients, while
unimpaired at recall and recognition of words printed on cards, were impaired at placing
the cards in their original sequence of presentation. They also tested the same patients on
a similar test of famous events (from 1941 to 1985), also finding that frontal-damaged
patients recognized the events but were impaired at judging the decade in which the
events occurred.

Theories of Frontal Lobe Function

Theories of frontal lobe function vary in
the breadth of phenomena they are intended to explain. In some cases they are aimed at
explaining performance in just one task, whereas in others they are intended to account for
most or all of the cognitive changes that follow prefrontal damage.
Given the diversity of tasks affected by prefrontal damage, from the execution of simple
manual sequences to the sorting of cards according to abstract categories, it might seem
unlikely that prefrontal cortex has a single underlying cognitive function. Although most
patients who are impaired at one task will also be impaired at some others, across-theboard impairment is rare. Prospects for a unified theory of frontal lobe function seem even
slimmer when the known functional anatomy of the frontal lobes is considered.
Pre-frontal cortex alone includes the frontal eye fields, which are implicated in the control
of voluntary eye movements, and Broca's area, which is implicated in language processes.
Dorso-lateral prefrontal damage is more closely associated with cognitive deficits, while
orbito-frontal damage seems to be related to more obvious changes in personality.
Consistent and reliable differences in function have been found even between different
areas within the dorso-lateral areas (Petrides 1993 idem)). Hemispheric asymmetries have
been widely noted. The left frontal lobe is more strongly and more often implicated in tasks
that involve verbal materials, while the right is most clearly implicated in some tasks involving non-verbal materials. 62 Some frontal-damaged patients seem to show
perseveration at a variety of tasks, ranging from concrete motor tasks to the sorting of cards
into abstract categories.63,64

Abstract Thinking

Goldstein 65,66 proposed that the frontal lobes were especially

60

Janowsky JS; Shimamura AP & Squire LR. Source memory impairment in patients with frontal
lobe lesions. Neuropsychologia 27:1043-1056, 1989.

61

Shimamura AP; Janowsky JS & Squire LR. Memory for the temporal order of events in patients
with frontal lobe lesions and amnesic patients. Neuropsychologia 28:803-813, 1990.

62

Kimberg, DY; DEsposito, M & Farah, MJ. Frontal Lobes: Cognitive and Neuropsychological
Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology.
McGraw-Hill, New York, 1997.

63

Luria AR. Two kinds of motor perseveration in massive injury of the frontal lobes. Brain 88:1-10,
1965.

64

Sandson J & Albert M. Varieties of perseveration. Neuropsychologia 22:715-732, 1984.

65

Goldstein K. Mental changes due to frontal lobe damage. J PsychoI17:187-208, 1944.

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important for abstract thought and that the abstract attitude could not be adopted by
patients with extensive frontal damage. Although it may well be true that many frontaldamaged patients think concretely, this hypothesis does not explain many of the central
phenomena of frontal damage. MDL seems to have little ability for abstract thought.

Planning

Many authors have attributed a planning function to the frontal

lobes 67,68,69 and Duncan70 has framed this idea in terms of recent cognitive science models
of problem solving. He proposes that human purposive activity requires a list of goals and a
set of action structures resembling scripts. Goal-directed behaviour is produced by a
process similar to that of Newell and Simon's71 means-end analysis. In effect, the goals
inhibit those action structures that are not relevant to their achievement. The authors
suggest that a defect in the use of the goal list to constrain behaviour is responsible for the
behaviour of frontal-damaged patients. This account can explain failure on many but not
all of the tasks mentioned earlier. For example, it does not explain context memory
difficulties. MDL always needs to be reminded about how many things are to be done and
what to do next. Planning ability is not something that she seems to have or to know about.

Inhibition
The theory that the frontal lobes serve an inhibitory function,
suppressing dominant action tendencies in favour of more goal-appropriate behaviour, has
been proposed recently to account for a variety of data, including normal human
development and physiologic experiments with monkeys. Diamond72 has argued, from the
development of reaching behaviours of infants and infant monkeys, that the prefrontal
cortex serves such a function in inhibiting inappropriate reaches to formerly rewarded
locations. She also suggests that this explanation may generalize to explain frontal deficits
at the WCST as well as capture behaviour, the intrusion of familiar but contextually
inappropriate actions that have sometimes been noted after frontal damage.
Similarly, Dempster73 has proposed that inhibitory functions in the frontal cortex, in particular
the suppression of irrelevant stimuli or associations, may account for a wide variety of
patterns in both cognitive development and cognitive aging as well as data from frontal
damaged patients. Roberts and co-workers74 argue that frontal inhibitory processes (as
well as working memory see below p 146) underlie patterns of performance in normal and

66

Goldstein K & Scheerer M. Abstract and concrete behavior: An experimental study with
special tests. Psychol Monogr 43:1-15,194.

67

Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B 298:199-209, 1982.

68

Benton AL. Differential behavioural effects of frontal lobe disease. Neuropsychologia 6:53-60,
1968.

69

Luria AR & Homskaya ED. Disturbance in the regulative role of speech with frontal lobe
lesions, in Warren JM, Akert K (eds.): The Frontal Granular Cortex and Behavior. New York:
McGraw-Hill, 1964, pp 353-371.

70

Duncan J. Disorganisation of behaviour after frontal lobe damage. Cog Neuropsychol 3:271290, 1986.

71

Newell A & Simon HA. Human Problem Solving. Englewood Cliffs, NJ: Prentice Hall, 1972.

72

Diamond A. Developmental progression in human infants and infant monkeys, and the
neural bases of inhibitory control of reaching, in Diamond A (ed): The Development and
Neural Bases of Higher Cognitive Functions. New York: NY Academy of Science Press, 1989.

73

Dempster FN. The rise and fall of the inhibitory mechanism: Toward a unified theory of
cognitive development and aging. Dev Rev 12:45-75, 1992.

74

Roberts RJ; Hager LD & Heron C. Prefrontal cognitive processes: Working memory and
inhibition in the antisaccade task. J Exp Psychol Gen 123:374393,1994.

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patient groups at anti-saccade tasks75. [MDL would not be able to cooperate with this test.]
This gives support for the view that frontal and/or basal ganglia dysfunction is present in
neurological patients with pathology in these brain regions.

Supervisory Attentional System According to Shallice 76,77,78 the frontal lobes

instantiate a supervisory attentional system (SAS). Although this system is not needed for
routine action, which is controlled by learned associations between stimuli in the
environment and possible action, it serves to override these associations when stimuli or
goals are novel. Thus, frontal damaged patients, in whom the SAS is damaged, are no
longer able to exert goal-directed control over their actions but simply respond to stimuli.
This theory accords well with much of the observed behaviour of frontal-damaged patients.
For instance, it predicts that they should behave more normally in familiar situations than in
unfamiliar ones. It also accords with the slow learning evidenced by many patients in the
WCST, as their behaviour seems very much like the slow learning of an associative module
combined with the tendency of more familiar, routinely made responses to emerge even
when inappropriate.
It is well established that in adults who have had normal development of social behaviour,
damage to certain sectors of prefrontal cortex produces a severe impairment of decisionmaking and disrupts social behaviour, although the patients so affected preserve
intellectual abilities and maintain factual knowledge of social conventions and moral rules.
79, 80, 81, 82, 83, 84

75

The anti-saccade task

In the laboratory, behavioural paradigms have been
developed to study the ability of the brain to respond flexibly to our environment. The antisaccade task has become one of the most popular tasks because it contains a manipulation
of stimulusresponse compatibility that decouples stimulus encoding and response
preparation. In this task, the participant is instructed that, after presentation of a peripheral
target, they must look away to its mirror position. Correct performance on this task requires
two steps. The subject must first suppress the automatic response to look at the target (prosaccade) and then transform the location of the stimulus into a voluntary motor command to
look away from the target (anti-saccade). Performance on the anti-saccade task can be
contrasted with performance on the pro-saccade task in which the location of the sensory
stimulus and the goal of the saccade are compatible, requiring a direct sensorymotor
transformation. In the anti-saccade task, stimulus location and saccade goal are
decoupled; the direct response must be suppressed and the stimulus vector must be inverted
into the saccade vector.

76

Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B 298:199-209, 1982.

77

Shallice T. From Neuropsychology to Mental Structure. Cambridge, England: Cambridge

University Press, 1988.

78

Shallice T. & Burgess P. Higher-order cognitive impairments and frontal lobe lesions in man, in
Levin HS, Eisenberg HM, Benton AL (eds): Frontal Lobe Function and Dysfunction. New York:
Oxford University Press, 1991.

79

Damasio, A. R., Tranel, D. & Damasio, H. in Frontal Lobe Function and Dysfunction (eds. Levin,
H. S., Eisenberg, H. M. & Benton, A. L.) 217229 (Oxford Univ. Press, New York, 1991).

80

Damasio, A. R. Descartes' Error. (Grosset/Putnam, New York, 1994).

81

Damasio, A. R. The somatic marker hypothesis and the possible functions of the prefrontal
cortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 351, 14131420 (1996). MEDLINE

82

Grafman, J. in Structure and Functions of the Human Prefrontal Cortex (eds. Grafman, J.,
Holyoak, K. J. & Boller, F.) 337368 (1995).

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Little is known for certain, however, about the consequences of comparable damage
occurring before the maturation of the relevant neural and cognitive systems, namely in
infancy, because such cases are exceedingly rare. Information about the early onset
condition is vital to the elucidation of how social and moral competencies develop from a
neurobiological standpoint.
A number of questions have arisen in this regard. First, would early-onset lesions lead to the
appearance of persistent defects comparable to those seen in adult-onset lesions, or
would further development and brain plasticity reduce or cancel the effects of the lesions
and prevent the appearance of the defects? Second, assuming early-onset lesions cause
a comparable defect, would there be a dissociation between disrupted social behaviour
and preserved factual social knowledge, as seen in the adult-onset condition, or would the
acquisition of social knowledge at factual level be compromised as well? 85 Anderson et
al found that the cognitive and behavioural profiles resulting from early prefrontal damage
resembled, in several respects, the profiles resulting from adult-onset damage. However,
unlike adult-onset patients, early-onset patients could not retrieve complex social
knowledge at the factual level, and may never have acquired such knowledge. The case
of MDL might add some relevant information to the answer to those questions.

___________________________________

THE NEUROSCIENCE OF BEHAVIOUR:

AN INTRODUCTION
Brain injury is an active disease process with a variety of lifelong consequences, unique to
each person. In order to understand the problems in a damaged brain it helps to have
knowledge of how the normal brain works. Information is passed to various parts of the
brain not only from its intrinsic parts but also from all other areas of the body (the periphery).
Assuming that the nerve supply to these peripheral areas is in good order there will be
connections between the parts of the brain which makes it the central command
structure.
The complexity of the brain adds difficulty to our understanding of how the brain develops,
matures and functions. Both structural and molecular components define brain functional
connectivity, and its alteration may result in developmental, behavioural and social
deficits.86 Furthermore, changes in the brain during the development of a person can also
provide information about when and where the diseased brain loses functional
connectivity.87 Jeffrey Neul proposes that studying the functional networks in people with
autism and other neurodevelopmental disorders, and correlating changes with functional

83

Shallice T. & Burgess, P. W. Deficits in strategy application following frontal lobe damage in
man. Brain 114, 727741 (1991). MEDLINE

84

Stuss, D. T. & Benson, D. F. The Frontal Lobes (Raven, New York, 1986).

85

Anderson, SW; Bechara, A; Damasio, H; Tranel, D. & Damasio, AR. Impairment of social and
moral behavior related to early damage in human prefrontal cortex. Nature Neuroscience;
November 1999 Volume 2 Number 11 pp 1032 1037

86

Atrens, D. & Curthoys, I. The Neurosciences of Behaviour. Academic Press; Australia, 1982.

87

Ting, JT & Feng, G. Found in Translation. Nature Medicine; Vol 17, No. 11; Nov. 2011.

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connectivity in animal models of these diseases, will uncover the mechanisms of normal
and abnormal development and suggest possible treatment strategies.88

Neurons and Neurotransmitters

The pathways along which messages

are sent are called neurons. A neuron has three main structural features, a cell-body or
soma, an axon and a number of dendrites. Dendrites are branch-like extensions of the cellbody, the number and arrangement of which vary enormously from neuron to neuron.
Generally, the function of dendrites is to carry information to the cell-body. Most receptors
and neurons have a special tubular extension of the cell-body the axon which, in
general, carries information away from the cell-body. Axons vary considerably in both the
number of branches or collaterals they make, and in their length.
The space between two nerve cells is called the synaptic gap. This gap is extremely narrow
and it prevents a pre-synaptic action potential from jumping between the two cells.
Instead, the action potential causes the nerve terminals to release certain chemicals which
diffuse rapidly across the gap where they can then alter the membrane permeability of the
post-synaptic cell. Thus we see that transmission of information within cells is an electrical
process, whereas transmission of information between cells is a chemical process.
Therefore, information transmission in the nervous system is, in effect, an electro-chemical
process.
Every sensation, perception or thought, and every physiological or behavioural response
depends on micro-chemical events. Dramatic changes in perception and behaviour
resulting from the modulation by drugs of neurotransmitter activity is one of the most
powerful, exciting and potentially dangerous discoveries man has ever made. A key to
understanding this rapidly expanding area, psycho-pharmacology, lies in the
understanding of the life cycle or metabolism of neurotransmitters.
Most neurotransmitters are either amino acids or are synthesized from amino acids.
Although some amino acids may be synthesized in the brain, it appears that the majority
are obtained from the breakdown of food proteins. Thus dietary factors can potentially
influence behaviour by regulating the availability of these precursors of neurotransmitters.
However, this should not be misinterpreted as supporting brain diets or psycho-dietetics.
Under most conditions, precursor availability is a relatively minor factor in the regulation of
neurotransmitter metabolism.
Amino acids are transported by the blood stream from the gastro-intestinal tract to the
brain where they are extracted by energy-dependent uptake mechanisms. Once released
into the synaptic gap, the action of the various neurotransmitters is rapidly terminated by
chemical and physiological means. Chemical termination is achieved by enzymes which
transform the neurotransmitters into inactive (or at least less active) products called
metabolites. The metabolites may in turn be broken down and eventually excreted from
the body. Consequently, measuring the levels of selected transmitter metabolites in the
blood, cerebrospinal fluid, urine, saliva and so on provides an index of the activity of a
particular transmitter system in the brain. Because of the ease with which blood and urine
samples can be taken, the analysis of metabolites in these fluids is a widely used clinical
and experimental index of brain function. However this is an indirect measure and may be
confounded by many extraneous variables.

88

Neul, JL. The mystery of developing connections. Nature Medicine; Vol 17, No. 11; Nov. 2011.

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Physiological termination of neurotransmitter action involves the re-uptake of the transmitter
into the pre-synaptic terminal. It may be thought of as a neuro-chemical recycling process,
in which the un-metabolized transmitter is repackaged and released again.
The relative importance of enzymatic versus re-uptake inactivation varies according to the
particular neurotransmitter system. For example, acetylcholine is inactivated by an enzyme
(acetylcholinesterase), whereas noradrenalin is primarily inactivated by re-uptake. The
enzymes monoamine oxidase (MAO) and catechol-o-methyl transferase serve a relatively
minor role in the inactivation of noradrenalin.
If either of these inactivation mechanisms malfunctions, serious disturbances in neural and,
consequently, physiological and behavioural processes can occur. For example, the
inactivation of the enzyme acetylcholinesterase at the neuromuscular junction results in a
surplus of acetylcholine and the over-activation of the muscle. It is in this manner that
nerve gases and snake venoms exert their toxic effects. By preventing transmitter
breakdown, they cause sustained muscle activation which manifests itself as violent and
uncontrollable muscle spasms that may result in death. Insecticides of the
organophosphate variety block transmitter breakdown in insect nervous systems and, in
high doses, are similarly toxic in humans. There are a variety of abnormalities in transmitter
metabolism that have been associated with phenomena as diverse as migraine
headaches and schizophrenia.
The exact biological basis of the development of functional connectivity is still an open
question. Strictly anatomical developmental changes are clearly important for dispersed
brain regions to form functional connections. However, there is additional complexity that
arises in neural circuits, as many functional pathways do not have direct monosynaptic
structural connections but rather are generated across multiple synaptic connections.
Additionally, functional networks can be reversibly altered by non-structural mechanisms.
For example, altering neuro-modulatory neurotransmitters such as dopamine89 or
serotonin90 can modulate functional connectivity in disease states. Thus, although
anatomical changes are clearly important in the formation of functional networks,
additional direct monosynaptic structural connections are generated across multiple
synaptic connections.
A major challenge in neuroscience has been to develop methods to assay and bridge
information between different levels of circuit organization. Although considerable
advances have furthered our understanding of how molecular, cellular, and electrical
processes within a cell relate to the functioning of a local neural circuit, we are just now
beginning to have tools capable of relating local to global changes in functional
connectivity and, ultimately, to behaviour. Perhaps combining these experimental
techniques with rs-fcMRI in animal models and relating this to human rs-fcMRI may help to
bridge these organizational levels to better understand brain development during both
health and disease. (Neul, Idem, 2011)

_______

89

Kelly C, et al. L-dopa modulates functional connectivity in striatal cognitive and motor
networks: A double-blind, placebo-controlled study. J Neurosci 29:73647378; 2009.

90

Anand, A; Li, Y; Wang, Y; Wu, J; Gao, S; Lubna Bukhari, B; Vincent P Mathews, VP; Kalnin, A &
Mark J Lowe, MJ. Antidepressant Effect on Connectivity of the Mood-Regulating Circuit: An
fMRI Study. Neuropsychopharmacology (2005) 30, 13341344, 27 April 2005.

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LOCALIZATION OF BRAIN LESIONS AND

DEVELOPMENTAL FUNCTIONS
Modern research (post-injury and also, mainly post-childhood) has
contributed greatly to the understanding of MDLs brain damage
and its consequences.
However, this needs to be referenced to factors that can be
identified as worthwhile contributors to improving her care and
establishing a purposeful lifestyle that does not compromise the
abilities to which she can reasonably aspire.
MDLs self-confidence arises from her successful achievements; the
less she is able to do, the fewer achievements she gains and the
lower her confidence becomes this is a self-fuelling regression.
She then relies on perseveration with soft toys and magazine
pictures. There needs to be a constant drive to improve her
abilities and this should progress to more macro actions than
jigsaws and threading beads. That said, these fingers/mindrelated activities are important and they should be used well and
judiciously.

Brain Damage
Brain injury caused by head trauma or stroke affects all brain
cells, including neurons; glial cells such as astrocytes, microglia, and oligodendrocytes;
blood vessel cells; and cells that produce and recycle cerebrospinal fluid (CSF), which line
the brains ventricles. In addition to causing direct cell damage and cell loss, brain injuries
disrupt blood flow and the blood-brain barrier (a barrier that allows only selective molecules
to pass from the bloodstream and come in contact with neurons and astroglial cells). Brain
injuries also interfere with the production, distribution, and reabsorption of CSF and cause
changes in the metabolism and function of cells not only in close proximity to the dying
tissue but also in more remote brain regions functionally and anatomically connected with
the injured area. Advances in diagnostic medicine, with the exception of certain cases
with mild or questionable cognitive impairment, have changed the typical referral question
to the neuropsychologist from one that attempts to determine if the patient has neurologic
disease or not. 91
In traumatic brain injury the brain may be injured in a specific location or the injury may be
diffused to many different parts of the brain. It is this indefinite nature of brain injury that
makes treatment unique for each individual patient. In the past twenty years, a great deal
has been learned about brain function, and we learn more every day. We can make
guesses about the nature of the problems an individual may have from knowing the
location of a lesion. Diagnostic procedures such as CT scans and MRI's can also provide
information about a brain injury. Rehabilitation specialists can also learn about an injury by
observing the day to day activities of the patient. All the activities we perform each day,
whether physical or mental, are directed by different parts of our brains. 92

91

Pekna, Marcela & Pekna, Milos. The Neurobiology of Brain Injury. Cerebrum, July 2012

92

Lehr, RP. Brain Function. Centre for Neuro-Skills. Neuroskills.com

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In most cases, the presence of brain damage has been clinically established and often
verified radiologically. However, the behavioural repercussions of brain damage vary with
the nature, extent, location, and duration of the lesion; with the age, sex, physical
condition, and psychosocial background and status of the patient; and with individual
neuro-anatomical and physiological differences.
Not only does the pattern of neuropsychological deficits differ with different lesion
characteristics and locations, but two persons with similar pathology and lesion sites may
have distinctly different neuropsychological profiles. 93,94,95 Cognitive outcome varies
according to the severity of the initial injury but there is found to be a variation in outcomes
amongst patients who have similar injuries. McAllister et al have suggested that this
difference might be due to modulation of the neural response by the individuals genes
and cite brain-derived neuro-trophic factor as a possible influence. 96
In contrast, patients with damage at different sites may present similar deficits97 . Thus,
although brain damage may be useful as an organizing concept for a broad range of
behavioural disorders, when dealing with individual patients the concept of brain damage
only becomes meaningful in terms of specific behavioural dysfunctions and their
implications regarding underlying brain pathology.98
Neurons continuously receive, process, and integrate information from the whole body,
including the brain, and send out signals to other neurons and cells in the periphery.
Neurons do not work in isolation; they form intricate circuitry, the function of which is directly
or indirectly influenced by all other cellular components of the brain tissue. Brain injury
affects neuronal circuitry by causing the death of neurons and glial cells and destroying
connections between them. This includes the cellular extensions (dendrites and axons)
through which neurons receive and emit signals by means of molecules called
neurotransmitters. Brain injury often leads to excessive accumulation of neurotransmitters in
the brain tissue, in particular glutamate, which can over-stimulate neurons and cause
neuronal death. (Pekna & Pekna, Idem)

Hemispheric cerebral dominance

The most important change in our conception

of the differences between the two cerebral hemispheres was initiated by the studies of
Hcaen99,100 and Zangwill101 and their co-workers which demonstrated conclusively that

93

De Bleser, R. Localisation of aphasia: Science or fiction. In G. Denes et al. (Eds.), Perspectives

on cognitive neuropsychology. Hove, UK: Erlbaum; 1988.

94

Howard, D. Language in the human brain. In M.D. Rugg (Ed.), Cognitive neuroscience.
Cambridge, MA: MIT Press; 1997.

95

Luria, A.R. Traumatic aphasia. The Hague: Mouton; 1970.

96

McAllister, TW; Tyler, AL; Flashman, LA; Rhodes, CH; McDonald, BC; Saykin, AJ; Tosteson, TD;
Tsongalis, GJ & Moore, JH. Polymorphisms in the Brain-Derived Neurotrophic Factor Gene
Influence Memory and Processing Speed One Month after Brain Injury. Journal of
Neurotrauma.

97

Naeser, M.A., Palumbo, C.L., Helm-Estabrooks, N., et al. Severe non-fluency in aphasia: Role
of the medial subcallosal fasciculus plus other white matter pathways in recovery of spontaneous speech. Brain, 112, 1-38; 1989.

98

Lezak, MD; Howieson, DB; Loring, DW. Neuropsyhcological Assessment. OUP, New York; 2004.

99

Hcaen, H., Ajuriaguerra, J. & Massonet, J. Les troubles visuoconstructifs par lesion parietooccipitale droite. Encephale 40,122-179; 1951.

100

Hcaen, H., Penfield, W., Bertand, C. & Malmo. R. The syndrome of apractagnosia due to
lesions of the minor hemisphere. Arch. Neurol. Psychiat. 75,400-434; 1956.

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patients with right-hemisphere disease show a very high frequency of specific visuoperceptual, visuo-spatial and visuo-constructional defects. Thus, the scattered findings of
earlier investigators were confirmed. In effect these studies, indicating that the right
hemisphere also possessed distinctive functional properties in the mediation of behaviour,
invalidated the doctrine of exclusive left hemisphere dominance and put in its place the
more egalitarian concept of asymmetry of hemispheric function.
The Hcaen-Zangwill initiative had a number of consequences. Its implications led to a
widespread exploration of the role that the right hemisphere might be playing in the
mediation of various aspects of mentation102. The result was that a remarkably diverse
array of capacities and attributes, far beyond the visuo-perceptual and visuoconstructional abilities described by Hcaen and Zangwill, were ascribed to operations in
the right hemisphere.
A list of these is shown in the Table One. As will be seen, in addition to sensory and motor
functions, the inventory includes attentional processes, levels of awareness, and affective
reactivity. It was obvious that a simple verbal vs. non-verbal dichotomy could not account
for these presumed differences in hemispheric specialization, and a number of other
cognitive dimensions were proposed, as shown in Table Two. Taken singly, none of these
was more adequate than the verbal/non-verbal dichotomy and finally the suggestion was
made that a multi-dimensional criterion might be the answer.

Table One:

Performances mediated by the right hemisphere

Vision
Discrimination of configurations (e.g. complex shapes)
Spatial orientation (e.g. route finding, directions, geography)
Recognition of familiar faces, unfamiliar faces, facial expression
Stereopsis 103
Mental rotation
Audition
Sound localization
Discrimination of pitch, loudness, timbre
Perception of emotional oral speech
Identification of persons by voice

101

McFie, J., Piercy, M.P. & Zangwill, O.L. Visual-spatial agnosia associated with lesions of the
right cerebral hemisphere. Brain 73,167-190; 1950.

102

Mentation The process of thinking

103

Stereopsis the perception of three-dimensional shape from any source of depth.

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Understanding of metaphoric speech
Somesthesis 104
Object and form perception
Perception of spatial stimuli (e.g. direction of lines drawn on skin)
Motor
Simple reaction time
Music: instrumental performance
Singing
Prosody in speech
Motor persistence

General
Arousal and attention
Preparatory set 105
Awareness of hemispace 106
Mood (euphoria/dysphoria107)

Table Two:

Left hemisphere/right hemisphere dichotomies

Verbal vs. non-verbal

Serial vs. parallel

104

Somesthesis the faculty of bodily perception.

105

Diversity in behavioral responses to sensory stimuli has been attributed to variations in

preparatory set.

106

Hemispatial neglect, also called hemiagnosia, hemineglect, unilateral neglect, spatial

neglect, unilateral visual inattention, hemi-inattention or neglect syndrome is a
neuropsychological condition in which, after damage to one hemisphere of the brain, a
deficit in attention to and awareness of one side of space is observed. It is defined by the
inability for a person to process and perceive stimuli on one side of the body or environment
that is not due to a lack of sensation.

107

Dysphoria disquiet or restlessness.

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Analytic vs. holistic
Controlled vs. creative
Logical vs. pictorial
Propositional vs. appositional 108
Rational vs. intuitive
Social vs. physical
However, it also became evident that the specialization of the right hemisphere for any
function was not nearly as sharp as was the specialization of the left hemisphere for
language. The studies of Conrad109 and Russell & Espir110 on right-handed soldiers who had
been rendered aphasic by penetrating wounds apparently confined to a single
hemisphere confirmed what had long been assumed, namely, that crossed aphasia (i.e.
produced by a right hemisphere lesion in a right-handed patient) was a rare occurrence.
In Conrad's study the observed frequency was 6 per cent and in the better controlled study
of Russell & Espir it was 1.8 per cent. But when the same analysis was applied to disabilities
associated with lesions of the right hemisphere, the findings were rather different. Studies
by Arrigoni & De Renzi111 and Benton112 found that the frequency of crossed
constructional apraxia in right-handed patients with left hemisphere lesions was 32 per cent
and 28 per cent, respectively. Similarly, Benton & Van Allen113 , investigating impairment in
facial recognition in patients with unilateral disease, found that 23 per cent had left
hemisphere lesions. 114
These observations showed that, although there was indeed asymmetry of hemispheric
function, this asymmetry was itself asymmetric, so to speak, with a much more clear
specialization of function in the left hemisphere than in the right. Later studies of normal
subjects added other dimensions to the topic. Employment of the dichotic listening
procedure and of tachistoscopic visual half-field stimulation115 disclosed considerable

108

The cognitive differences between the left and right hemispheres have been characterized
as propositional vs. appositional.

109

Conrad, K. Ueber aphasischer Sprachstoerungen bei Linkshaendern. Nervenarzt 20,148-154.

Damasio, A.R. (1992): Aphasia. New Eng. J. Med. 326,531-539; 1949.

110

Russell, W.R. & Espir, M.L.E. Traumatic aphasia. Oxford & London: Oxford University Press; 1961.

111

Arrigoni, G. & De Renzi, E. Constructional apraxia and hemispheric locus oflesion. Cortex 1,
170-197. Babinski, J. (1914): Contribution 11 l'etude des troubles mentaux dans l'hemipMgie
organique cerebrale (anosagnosie). Rev. Neural. 22,845-848; 1964.

112

Benton, AL. Constructional apraxia and the minor hemisphere. Confinia Neurologica 29,1-16;
1967.

113

Benton, A. L. & Van Allen, M. W. Impairment in facial recognition in patients with cerebral
disease. Cortex, 4, 344-358; 1968.

114

See also http://web-us.com/brain/LRBrain.html

115

Tachistoscopic visual half-field stimulation:

Uses an apparatus that projects a series of
images onto a screen at rapid speed to test visual perception, memory

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instability in their performances from one testing session to another and even within the
course of a single testing session116,117,118 .
Specific instructions and duration of stimulus exposure were also found to be significant
determinants of the degree of differential hemispheric participation in a performance like
facial recognition119 . These indications of flexibility in function and inter-hemispheric
communication in normal subjects could not help but raise doubts about the validity of
simple interpretations of the defective performances of patients with unilateral brain
disease.

THE ORGANIZATION OF MEMORY DURING DEVELOPMENTAL AGE

The hippocampus is a seahorse-shaped part of the brain, found in the inner folds of the
bottom middle section of the brain known as the mesial temporal lobe. It consists of two
parts; one on each side of the brain. It is about 1/100th of the size of the outer layer of the
brain (cerebral cortex). It consists of three layers, with characteristic pyramid-shaped cells.
Its main functions involve human learning and memory. The mesial temporal lobe is, as the
name suggests, located on the medial aspect of the temporal lobe. This area of the brain
includes five structures:

amygdala

hippocampus

uncus (The uncus is the most anterior portion of the medial parahippocampal
gyrus.)

dentate gyrus (The dentate gyrus is thought to contribute to the formation of new
episodic memories, the spontaneous exploration of novel environments, and other
functions.)

parahippocampal gyrus (The parahippocampal gyrus is an important and active

region of the brain's limbic system. Its main function involves memory creation and
recall of visual scenes.

The hippocampus is part of the limbic system, which includes parts of the brain associated
less with conscious thought but more with feeling and reacting. The limbic system also
includes the amygdala. These structures help control different bodily functions, such as the
endocrine system including what is commonly known as the "fight or flight" reaction which is
a response to a triggering of the autonomic nervous system.
Social communication involves influencing what other people think and feel about
themselves. Theory of mind (connotative) refers to communicative interactions involving

116

Pizzarniglio, L., DePascali, C. & Vignati, A. Stability of dichotic listening test. Cortex 10, 203-205.
Rieger, e. (1909): Ueber Apparate in dem Him. Arbeiten aus der Psychiatrischen Klinik
Wuerzburg 5, 176-192; 1974.

117

Blumstein, S., Goodglass, H. & Tartter, V. The reliability of ear advantage. Brain Lang. 2,226236. Boller, F. (1973): Destruction of Wernicke's area without language disturbance.
Neuropsychologia 11, 243-246; 1975.

118

Turkewitz, G. & Ross, P. Changes in visual field advantage for facial recognition. Cortex 19,
179-185; 1983.

119

Galper, E. & Costa, L. Hemispheric superiority for recognizing faces depends upon how they
are learned. Cortex 16, 21-38; 1980.

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one person trying to influence or understand the mental and emotional state of another,
paradigmatic examples of which are irony and empathy.

THEORY OF MIND AND BRAIN DAMAGE

Lack of a theory of mind has important knock-on effects upon emotions. The cerebellum is
linked to the hypothalamus, amygdala, hippocampus, anterior cingulate and prefrontal
cortex. 120,121,122,123,124 They make up our limbic system the part of the brain which
creates our emotions. During development this emotional processing needs to become
socialised and that needs the brain to associate with other people's responses, particularly
as shaped by their minds. What is the point of crying if we cannot connect with a meaning
for those tears and provide or receive a comfort? Why should we seek to enjoy doing
something with another if we cannot link this with the pleasure of their responses back to
us? Infants need these connections if they are to grow emotionally.
If the prefrontal cortex is damaged by toxins there may be nociceptive discharges125
evoked and these are conceivably involved in the affective rather than the sensorydiscriminative responses. Monosynaptic projections from the basolateral nucleus of the
amygdala to the prefrontal cortex are known to produce long-lasting synaptic plasticity126.
If the prefrontal cortex is damaged in a way that interferes with the synaptic plasticity then
there may be resulting abnormalities in the amygdala and the hippocampus and these
may mimic some aspects of autistic spectrum disorder and thus these may be associated
with loss of acquired motor, communication, and social skills. It has also been discovered
that injuries of this type may bring about cognitive abnormalities. Hippocampusdependent spatial memory, contextual fear memory, and social memory may also be
significantly impaired. 127

120

Heath, R., & Harper, J. Ascending projections of the cerebellar fastigial nucleus to the
hippocampus, amygdala, and other temporal lobe sites. Experimental Neurology, 45, 268287; 1974.

121

Haines, D., May, P., & Dietrichs, E. Neuronal connections between the cerebellar nuclei and
hypothalamus in Macaca Fascicularis: Cerebello-visceral circuits. Journal of comparative
neurology, 299, 106-122; 1990.

122

Supple, W. J. Hypothalamic modulation of Purkinje cell activity in the anterior cerebellar

vermis. NeuroReport, 4, 979-982; 1993.

123

Vilensky, J. A., & Van Hoesen, G. W. Corticopontine projections from the cingulate cortex in
the rhesus monkey. Brain Research, 205, 391-395; 1981.

124

Schmahmann, J. D. The cerebellum in autism: Clinical and anatomic perspectives. In M. L.

Bauman & T. L. Kemper, (Eds.), Neurobiology of autism, pp 195-226, Baltimore, ML: John
Hopkins University Press; 1994.

125

A tissue damaging event

126

The ability of the connection, or synapse, between two neurons to change in strength in
response to either use or disuse of transmission over synaptic pathways

127

Moretti, P.; Levenson, JM.; Battaglia, F.; Atkinson, R.; Teague,R.; Antalffy, B.; Armstrong, D.;
Arancio, O.; Sweatt, JD. & Huda Y. Zoghbi1, HY. Learning and Memory and Synaptic Plasticity
Are Impaired in a Mouse Model of Rett Syndrome. The Journal of Neuroscience, January 4,
2006 26(1):319 327 319

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A child will be socially blinded if it lacks the ability to see how its stimulation of others minds
makes return responses. People might be responding to their attempts to interest and
interact with them, but their brains would be indifferent to their returning behavioural
echoes. As a result they would be unable to use feedback to give them a sense of their
presence in the world. They will, as a result, stop seeking social responses, becoming to the
outside world, remote and unaffectionate. Thus cerebellar circuits and their links with the
rest of the brain which enable tracking are essential: it is they that give us our interface with
human life, and so let us emotionally grow up as social beings.
Denis et al studied theory of mind in children with traumatic brain injury (TBI) and age- and
gender-matched children with orthopaedic injuries (OI), using a new three-frame Jack and
Jill cartoon task that measured intentional thinking separate from contingent task demands.
In the key theory of mind trials, which required intentional thinking, Jack switched a black
ball from one hat to another of a different colour, but Jill did not witness the switch; in the
otherwise identical non-theory of mind trials, the switch was witnessed. Overall accuracy
was higher in children with OI than in those with TBI. Children with severe TBI showed a
larger decline in accuracy on theory of mind trials, suggesting a specific deficit in theory of
mind among children with severe TBI. Accuracy was significantly higher on trials following
errors than on trials following correct responses, suggesting that all groups monitored
performance and responded to errors with increased vigilance. TBI is associated with
poorer intentional processing in school-age children and adolescents relative to peers with
OI; furthermore, children with TBI are challenged specifically by intentional demands,
especially when their injury is severe.128
Bellerose et al have also studied Theory of Mind (ToM) in preschool children following mild
TBI. More recently they have followed this up in order to determine whether those findings
were the result of a brain-injury-specific effect or rather a general-injury effect and to
examine the long-term evolution of ToM skills following preschool mTBI, as well as to
investigate the links between ToM abilities and general social functioning. They found that,
there was a brain-injury-specific effect that persisted in the long-term following mTBI in
preschool children. 129
The hippocampus also plays another vital role in memory; it is where short-term memories
are turned into long-term memories, which are then stored elsewhere in the brain. While it
was once thought that new nerve cells only grew in embryos or young children, research
has now shown that nerve cells develop throughout adulthood. The hippocampus is one of
the few places in the brain where the new nerve cells can be generated.
The hippocampus helps humans process and retrieve two specific kinds of memories:
declarative memories and spatial relationships. Declarative memories are memories
related to facts and events. Learning how to memorize speeches or lines in a play is a good
example of declarative memories in action. Spatial relationship memories involve
pathways or routes, as when cab drivers learn routes through a city. Knowledge of brain

128

Dennis M, Simic N, Gerry Taylor H, Bigler ED, Rubin K, Vannatta K, Gerhardt CA, Stancin T,
Roncadin C & Yeates KO. Theory of mind in children with traumatic brain injury. J Int
Neuropsychol Soc. 2012 Sep;18(5):908-16.

129

Bellerose J ; Bernier A ; Beaudoin C ; Gravel J & Beauchamp MH. Long-Term Brain-InjurySpecific Effects Following Preschool Mild TBI: A Study of Theory of Mind. Neuropsychology.
2017 Jan 23. doi: 10.1037/neu0000341. [Epub ahead of print]

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functions has grown to the point where researchers can now say spatial relationship
memories are stored in the right hippocampus. 130
Temporo-mesial structures are critical for the organization of long term declarative
memories during developmental age. This means that the architecture of the anatomical
structures is established very early in life. Very early lesions can cause memory deficits of
different severity and typology and are age-related. These early lesions (particularly of the
hippocampus) irreversibly compromise the capacity to acquire complex modalities of
verbal and social communication and to organize a personal and unique cognitive map.
A study by Frye et al, has found an improvement in an important core autism spectrum
disorder (ASD) symptom, verbal communication, in non-syndromic ASD children receiving
high-dose folinic acid vs placebo, particularly in those participants who were positive for
folate receptor-autoantibodys. Improvement in a number of secondary outcomes was
observed as well, with no significant adverse events. The effect of folinic acid is consistent
with the therapeutic effect of early behavioural interventions. 131,132, 133
Dennis et al report how children with traumatic brain injury understand ironic criticism and
empathic praise, on a task requiring them to identify speaker belief and intention for direct
conative speech acts involving literal truth, and indirect speech acts involving either ironic
criticism or empathic praise. Deficits in understanding the social, conative function of
indirect speech acts like irony and empathy have widespread and deep implications for
social function in children with traumatic brain injury. 134
Later lesions cause amnesia of different severity, with impairment of episodic memory and
preservation of semantic memory if the lesion is localized to the hippocampus, or the
impairment of both types of memory in case of hippocampus and para-hippocampus
localization. More particularly, the temporo-mesial structures are critical for the development of
long-term declaratory memories. 135
Damage to the hippocampus or to some of its connections such as the fornix produces
deficits in learning about the places of objects and about the places where responses
should be made. For example, humans with damage to the hippocampal system or fornix
are impaired in object-place memory tasks in which not only the objects seen, but where

130

Ming GL & Song H. Adult Neurogenesis in the Mammalian Brain: Significant Answers and
Significant Questions. Neuron. 2011 May 26; 70(4): 687702. doi: 10.1016/j.neuron.2011.05.001

131

Frye, RE. et al Folinic acid improves verbal communication in children with autism and
language impairment: a randomized double-blind placebo-controlled trial. Molecular
Psychiatry 2016; doi: 10.1038/mp.2016.168.

132

Schreibman L. & Stahmer AC. A randomized trial comparison of the effects of verbal and
pictorial naturalistic communication strategies on spoken language for young children with
autism. J Autism Dev Disord 2014; 44: 12441251.

133

Wetherby, AM; Guthrie, W; Woods, J; Schatschneider, C; Holland, RD& Morgan L et al. Parentimplemented social intervention for toddlers with autism: an RCT. Pediatrics 2014; 134: 1084
1093.

134

Dennis M; Simic N; Agostino A; Taylor HG; Bigler ED; Rubin K; Vannatta K; Gerhardt CA;
Stancin T & Yeates KO. Irony and empathy in children with traumatic brain injury. J Int
Neuropsychol Soc. 2013 Jan 21:1-11.

135

Riva, D; Saletti, V; & Nichelli, F. The organization of memory in temporo-mesial structures in

developmental age. In, Riva, D; & Benton, A. Localization of Brain Lesions and
Developmental Functions. John Libby, London; 2000.

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they were seen, must be remembered. Further, neurotoxic lesions that selectively damage
the primate hippocampus impair spatial scene memory. Also, fornix lesions impair
conditional left-right discrimination learning, in which the visual appearance of an object
specifies whether a response is to be made to the left or the right. 136, 137
Evidence from Monti et al suggests that a history of head trauma is associated with memory
deficits later in life. The majority of previous research had focused on moderate-to-severe
traumatic brain injury (TBI), but recent evidence suggests that even a mild TBI (mTBI) can
interact with the aging process and produce reductions in memory performance. This study
examined the association of mTBI with memory and the brain by comparing young and
middle-aged adults who have had mTBI in their recent (several years ago) and remote
(several decades ago) past, respectively, with control subjects on a face-scene relational
memory paradigm while they underwent functional magnetic resonance imaging (fMRI).138
In observations of hippocampal volumes from high-resolution structural images Monti et al
have also shown that middle-aged adults with a head injury in their remote past had
impaired memory compared to gender, age, and education matched control
participants, consistent with previous results in the study of memory, aging, and TBI. Their
findings extended previous results by demonstrating that these individuals also had smaller
bilateral hippocampi, and had reduced neural activity during memory performance in
cortical regions important for memory retrieval. These results also indicate that a history of
mTBI may be one of the many factors that negatively influence cognitive and brain health
in aging. (Idem)
One way of relating the impairment of spatial processing to other aspects of hippocampal
function is to note that this spatial processing involves a snapshot type of memory, in which
one whole scene must be remembered. This memory may then be a special case of
episodic memory, which involves an arbitrary association of a particular set of events which
describe a past episode.139 Further, the non-spatial tasks impaired by damage to the
hippocampal system may be impaired because they are tasks in which a memory of a
particular episode or context rather than of a general rule is involved. Further, the deficit in
paired associate learning in humans may be especially evident when this involves arbitrary
associations between words.140
The evidence provided from a historical case known as HM and many others after him
made it possible to arrive at the definition of a memory system organized into short- and
long-term components. Long-term memory is sub-divided into implicit (or procedural) and
explicit (or declarative) memory.141,142 Procedural memory is at most only partially
conscious and consists of a collection of different skills; it is expressed by means of

136

Rolls, ET. Memory, Attention and Decision-Making. OUP; 2008.

137

Petrides, M. Deficits on conditional associative-learning tasks after frontal- and temporal-lobe

lesions in man. Neuropsychologia 23; 601-614.

138

Monti JM; Voss MW; Pence A; McAuley E; Kramer AF & Cohen NJ. History of mild traumatic
brain injury is associated with deficits in relational memory, reduced hippocampal volume,
and less neural activity later in life. Front Aging Neurosci. 2013 Aug 22;5:41 PMID 23986698.

139

Rolls, ET. The primate hippocampus and episodic memory; in, Dere, Huston & Easton (Eds)
Episodic Memory Research; Elsevier, Amsterdam, 2008.

140

Rolls, ET. Memory, Attention and Decision-Making. OUP; 2008.

141

Tulving, E. Episodic and semantic memory. In: Organization of memory, eds. E. Tulving & W.
Donaldson. New York: Academic Press, 1972.

142

Tulving, E. In: Elements of episodic memory. Oxford: Oxford University Press; 1983.

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activities, does not respond to the criterion of true/false; progressively increases with
experience, and generally represents a predisposition to behave in a particular way on the
basis of previous memories. On the contrary, declarative memory is conscious and
expressed by means of words, concepts and propositions; it is also expressed by means of
images and the recall of previously encountered facts and events.
Declarative memory is further sub-divided into semantic and episodic memory. Semantic
memory (See also p 38) represents our knowledge of the world beyond any context or
temporal parameters, is automatically expressed and lives in the present; episodic memory
is based on facts/events occurring in a precise temporal and spatial context in which the
fundamental reference point is the person remembering. Amnesia is therefore related to
the long-term declarative memory143 . Given the existence of different types of memory, it
follows that they are processed by different brain areas and based on different neuronal
circuits. 144
Short-term memory is probably processed by the inferior parietal lobe (although not
everybody agrees on this point); declaratory long-term memory is processed by the
temporo-mesial structures, in particular, the hippocampus and para-hippocampal regions,
whereas procedural memory seems to be processed by the striatum and the cerebellum.
Given that different brain areas process different components of the memory system, it
follows that these components may be independently deficient depending on the
damaged area. Short-term memory deficits can therefore exist in the presence of a
perfectly functioning long-term memory, and vice versa; a deficient declaratory memory in
the presence of an intact procedural memory, and vice versa; and a deficient semantic
memory in the presence of an integral episodic memory and vice-versa145,146 .
In Mishkin and Eichenbaum's model of the anatomy of the temporo-mesial structures, the
memory is seen as being very flexible and based on representations stored in the neocortex
in a highly precise and sophisticated manner. 147,148
Systematic studies of animal temporo-mesial structures have made it possible to validate
the model in an irrefutable manner.149,150,151 A rat's hippocampus is the site of spatial

143

Baddeley, A. The human memory (1982). Italian edn. La memoria umana. Bologna: II Mulino;
1984.

144

Gabrieli, J.D.E., Brewer, J.B., Desmond, J.E. & Glover, G.H. Separate neural bases of two
fundamental memory processes in the human medial temporal lobe. Science 276, 264-266;
1997.

145

Baddeley, A. The human memory (1982). Italian edn. La memoria umana. Bologna: II Mulino;
1984.

146

Ellis, W.A. & Young, A.W. Memory. In: Human cognitive neuropsychology. Hove, London,
Hillsdale; 1988.

147

Mishkin, M., Suzuki, W., Gadian, D.G. & Vargha-Khadem, F. Hierarchical organization of
cognitive memory. Phil. Trans. Roy. Soc. London (B) 352,1461-1467; 1997.

148

Eichenbaum, H. How does the brain organize memory? Science 277,330-332; 1997.

149

Mishkin, et al, Idem. 1997.

150

Suzuki, W.A & Amaral, D.G. Perirhinal and parahippocampal cortices orille macaque monkey:
cortical afferents. J. Compo Neurol. 350, 497-533; 1994.

151

Suzuki, W.A & Amaral, D.G. Topographic organization of the reciprocal connections between
monkey entorhinal cortex and the perirhinal and parahippocampal cortices. J. Neurosci. 14,
1856-1877; 1994.

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memory, but actually provides what is nothing less than a cognitive map of the entire
ecological space in which it is capable of navigating by using the procedures, moves and
anticipations of events that come from previous individual experiences. It has also been
found that primates have the possibility of taking advantage of a cognitive map of their
episodic experiences.
Kitamura et al have shown however, that whilst the hypothalamus is a key brain structure
for learning and memory. Recall of some associative and spatial memories initially
depends on the hippocampus, but that hippocampal dependency progressively decays
over time, a process that is associated with a gradual increase of neocortexdependency.152
It has been suggested that the quality of original memories also transforms from a precise
(i.e., detailed) form to a less precise (i.e., more schematic or generic) form with similar time
course. 153,154,155 The question arises of whether changes in the quality of the original
memories depend on the shift in brain regions on which the recall of these memories relies,
i.e., whether the hippocampus is always required for the precision of memories. This is an
important question for understanding physiological significances of the hippocampalcortical complementary memory systems.
In the study by Kitamura et al, found clear indication that the association with fear masks
the actual precision of place memory. Moreover, in contextual fear conditioning, the
experimental subjects (mice) showed the freezing responses even for unconditioned place
in recent memory test, whereas in the non-associative place recognition test mice did not
show any adaptation behaviour even for similar place in remote memory test. Therefore,
the conclusions of previous studies using contextual fear conditioning156,157,158 need to be
validated by non-associative protocol. Thus, they examined the contribution of
hippocampal function on the precision of remote place memory by non-associative place
recognition test. Fear Conditioning; see p 132
Using this procedure, they found that the place memory is precisely maintained for 28 days,
which may require -CaMKII-dependent plasticity in the cortex, and that the retrieval of
remote place memory (not recent memory) does not require hippocampal function. These
results indicate that the quality of a place memory does not correlate with the brain region
on which that memory depends. Moreover, they found that the inactivation of

152

Kitamura, T; Reiko Okubo-suzuki, R; Takashima, N; Murayama, A; Hino, T; Nishizono, H; Kida, S.

& Inokuchi, K. Hippocampal function is not required for the precision of remote place
memory. Molecular Brain 2012, 5:5 doi:10.1186/1756-6606-5-5

153

Nadel L, & Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal
complex. Curr Opin Neurobiol 1997, 7:217-227.

154

Moscovitch M; Nadel L; Winocur G; Gilboa A. & Rosenbaum RS. The cognitive neuroscience of
remote episodic, semantic and spatial memory. Curr Opin Neurobiol 2006, 16:179-190.

155

McKenzie S. & Eichenbaum H. Consolidation and reconsolidation: two lives of memories?

Neuron 2011, 71:224-233.

156

Winocur G; Moscovitch M. & Sekeres M. Memory consolidation or transformation: context

manipulation and hippocampal representations of memory. Nat Neurosci 2007, 10:555-557.

157

Wiltgen BJ; Zhou M; Cai Y; Balaji J; Karlsson MG; Parivash SN; Li W. & Silva AJ. The
hippocampus plays a selective role in the retrieval of detailed contextual memories. Curr Biol
2010, 20:1336-1344.

158

Wang SH; Teixeira CM; Wheeler AL & Frankland PW. The precision of remote context memories
does not require the hippocampus. NatNeurosci 2009, 12:253-255.

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hippocampal function does not inhibit the precision of remote place memory. These results
indicate that the hippocampal function is not required for the precision of remote place
memory. This is consistent with a human case study in which a patient with bilateral
extensive hippocampal damage showed intact memories for places learned long ago, but
not intact recent place memory159. Eight patients with bilateral hippocampal damage
were able to recall their remote autobiographical memories. 160 Thus, the quality of original
place memories is not determined by brain regions on which the memory depends.
Ablation of the anterior portion of the temporal lobe + amygdala + part of the hippocampus
or excision of the temporal cortex/neocortex (excluding the amygdala and hippocampus)
or selective ablation of the amygdala and hippocampus cause learning and delayed
recall deficits respectively relating to verbal or non-verbal stimuli (the latter being generally
less severe). The underlying pathogenic mechanism could be the disconnection of the
cortex from the hippocampus: although the neocortex is still capable of storing the
memories, it cannot pass them to the hippocampus and the para-hippocampal structures,
and so they cannot be recalled as such or rearranged161 .
These results show that the temporo-mesial structures also process long-term declarative
memory at developmental age. This not only means that the architecture of the
anatomical structures is established very early in life, but also that an early lesion affecting
these structures cannot be compensated for by the establishment of alternative pathways
and, furthermore, that the degree of impairment is age-related (i.e. it is greater in patients
who are affected at a younger age).
Very early lesions of (particularly) the hippocampus irreversibly compromise the possibility
of acquiring complex modalities of verbal and social communication, as well as the
possibility of organizing an absolutely personal cognitive map.162 Later lesions only cause
amnesias of various degrees of severity, with impairment of episodic; but the preservation
of semantic memory, if localized to the hippocampus; or the impairment of both in cases
that involve both the hippocampus and para-hippocampus.
These results not only confirm that dissociations between the various components of the
memory system are also possible at a very early developmental age, but also confirm the
structure of the circuit. The cortex/neocortex faithfully stores the information. The parahippocampal regions codify the information belonging to the same categories in a
contiguous manner, and are also capable of re-evoking simple connections with the
cortex/neocortex under the impulse of simple stimuli, particularly if they are contiguous and
mono modal. The hippocampus analyses different elements of various experiences and
stimuli, acquired in different spatio-temporal contexts and via a wide range of modalities
(sight, touch, smells, sounds, emotions, etc.), and is capable of relating them to each other
in a myriad of different combinations and in a totally flexible and inexhaustible manner.

159

Teng E & Squire LR. Memory for places learned long ago is intact after hippocampal damage.
Nature 1999, 400:675-677.

160

Bayley PJ; Hopkins RO & Squire LR. Successful recollection of remote autobiographical
memories by amnesic patients with medial temporal lobe lesions. Neuron 2003, 38:135-144.

161

Jones-Gotman, M; Zatorre, RJ; Olivier, A; Andermann, F; Cendes, F; Stauton, H; McMackin,

Dumpsy; Siegel, A.M. & Wieser, H.G. Learning and retention of words and designs following
excision from medial or lateral temporal-lobe structures. Neuropsychologia 35, 963-973; 1997.

162

Challoner, A. Abnormal Brain Structure & Autism

https://www.scribd.com/doc/9635846/Abnormal-Brain-Structure-and-Autism

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Studies of the temporo-mesial structures therefore not only highlight specific
neuropsychological deficits, but also provide an extremely interesting insight into the
pathologies typical of childhood development, such as infantile autism.
Schuetze et al have shown that morphological alterations in the thalamus, striatum and
pallidum are present in those with autism spectrum disorder.163 Lesion studies have shown
social deficits (a core symptom in autism spectrum disorder) resulting from injury to areas of
the orbitofrontal circuit. 164, 165 Schuetze et al also show findings which suggest that cellularlevel properties within the thalamus may contribute to these differences in connectivity.
Functionally, abnormalities in the pulvinar may have particular relevance to welldocumented differences in attention skills in autism spectrum disorder. 166
In the typical population, IQ has been associated with total brain volume 167 as well as
structure of cortical, white matter, and subcortical regions168,169 . Grazioplene et al also
suggest that any findings of morphological differences in pallidum, putamen and thalamus
should be considered relative to intellectual functioning (idem). This is important to
consider for any structural study of ASD; while intellectual disability is not among the
diagnostic criteria for ASD, it is an extremely common comorbidity.170
Schuetze et al (idem 2016) show very important confirmations that brain injuries are possible
causes of autism spectrum disorder.

Basal ganglia lesions Language and Neuropsychological Dysfunction

There is not much knowledge about the behavioural consequences of subcortical and
basal ganglia lesions during childhood. They are a group of grey matter nuclei located
deep in the cerebral hemispheres. These include, among others, the caudate nucleus, the
lenticular nucleus (with an outer part called the putamen and an inner part, the globus
pallidus) and a larger and more posterior nucleus, the thalamus. While the first two are

163

Schuetze, M.; Park, MTM; Cho, I Y; MacMaster, FP; Chakravarty, MM & Signe Bray, SL.
Morphological Alterations in the Thalamus, Striatum, and Pallidum in Autism Spectrum
Disorder. Neuropsychopharmacology (2016) 41, 26272637

164

Bechara A. Emotion, decision making and the orbitofrontal cortex. Cereb Cortex 10: 295307;
2000.

165

Hillis, AE. Inability to empathize: brain lesions that disrupt sharing and understanding anothers
emotions. Brain 137: 981997; 2014.

166

Allen, G. & Courchesne, E. Attention function and dysfunction in autism. Front Biosci 6: D105
D119; 2001.

167

McDaniel, M. Big-brained people are smarter: a metaanalysis of the relationship between in

vivo brain volume and intelligence. Intelligence 33: 337346; 2005.

168

Grazioplene, RG; Ryman, GS; Gray JR, Rustichini, A; Jung, RE; DeYoung, CG. Subcortical
intelligence: caudate volume predicts IQ in healthy adults. Hum Brain Mapp 36: 14071416;
2014.

169

Schumann, CM; Hamstra, J; Goodlin-Jones BL; Kwon, H; Reiss, AL & Amaral DG. Hippocampal
size positively correlates with verbal IQ in male children. Hippocampus 17: 486493; 2007.

170

Yeargin-Allsopp, M; Rice, C; Karapurkar, T; Doernberg, N; Boyle, C & Murphy, C. Prevalence

of autism in a US metropolitan area. JAMA 289: 4955; 2003.

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involved in motor functions, (they are part of the extra-pyramidal system171), the latter
receives all the sensory information travelling into the brain.
These subcortical structures are connected to each other and to the cerebral cortex in
multiple and complex ways but, in general, the fibres travel from the different parts of the
cortex to the striatum (name given both to the caudate and the putamen), from there
they project into the pallidus, from the pallidus they travel to the thalamus and from there
they go back to the cortex. These loops are called the cortico-striato-pallido-thalamocortical loops, which subserve multiple functions. Some of them have an activating or
modulatory role on the overlying cortex.
For many years the basal ganglia were thought to be responsible for motor functions only.
However, with the advent of brain imaging (CT and MRI scans) it became clear that deep
hemisphere lesions could interfere with behaviour. The first studies on this matter were
published in the early 1980s on adult patients with deep hemispheric stroke and focused on
language and hemispatial neglect.172,173,174 But soon other papers followed, describing
cases of memory, behavioural and emotional disturbances175,176. Animal experiments
corroborated the role of these structures in a variety of cognitive functions and
behaviour177.
The difficulty in establishing such clinico-anatomical correlations is not just due to the fact
that single lesions (particularly the vascular ones) tend to damage multiple areas. The
main methodological problem is that the symptoms caused by purely sub-cortical lesions
can result from different pathogenic mechanisms. The basal ganglia have a direct effect
on behaviour since they integrate cortico-subcortical neuronal networks subserving
language and other complex behaviours. But these structures may also have an indirect
effect upon cognitive functions, as they may produce a depression of the metabolic
activity of the overlying cortex, as has been demonstrated with the PET scan178 .
Aram & Eiselle179 divided their patients by an anterior/posterior anatomical axis. According
to these authors, anterior lesions tend to produce non-fluent types of speech and good
auditory comprehension. Posterior lesions, on the other hand, may cause comprehension

171

See: http://www.neurophysiology.ws/extrapyramidalsystem.htm

172

Watson, RT., Valenstein, E. & Heilman, KM. Thalamic neglect. Possible role of the medial
thalamus and nucleus reticularis in behaviour. Arch. Neurol. 38,501-506; 1981.

173

Damasio, A.R., Damasio, H., Rizzo, M., Varney, N. & Gersh, F. Aphasia with nonhemorrhagic
lesions in the basal ganglia and internal capsule. Arch. Neural. 39, 15-20; 1982.

174

Naeser, M.A., Alexander, M.P., Helm-Estabrooks, N., Levine, H., Laughlin, S.A. & Geschwind, N.
Aphasia with predominantly subcortical lesions sites. Description of three capsular/putaminal
aphasia syndromes. Arch. Neurol. 39,2-14; 1982.

175

Habib, M. & Poncet, M. Perte de l'elan vital, de l'interet et de l'affectivite (syndrome

athymhorrnique) au cours de lesions lacunaires des des corps stries. Rev. Neural. 144,571577;1988.

176

Mendez, M.F., Adams, N.I. & Lewandowski, KS. Neurobehavioural changes associated with
caudate lesions. Neurology 39, 349-354; 1989.

177

Divac, I. & Oberg, R.G.E. Subcortical mechanisms in cognition. In: Neuropsychological

disorders associated with subcortical lesions, eds. G. Vallar, S.F. Cappa & Claus-W. Wallesch,
pp. 42-60. Oxford: Oxford University Press; 1992.

178

Metter, E.J; Riege, W.H; Hanson, W.R; Jackson, CA; Kempler, D. & Lancker, D. Subcortical
structures in aphasia. An analysis based on (F-18) fluorodeoxyglucose, positron emission
tomography and computed tomography. Arch. Neurol. 45, 1229-1234; 1988.

179

Aram, D. & Eisele, J. Language development following subcortical lesions in children. Paper
presertted at the European Meeting of the International Neuropsychological Society,
Funchal, Portugal; 1993.

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disorders, fluent aphasia (conduction type) or no aphasia at all. In both locations there are
motor disorders of speech (dysarthria180 and hypophonia181), and both have a good
prognosis for total recovery (If the injury is sustained at a post-developmental age). On the
contrary, if the lesion involves simultaneously the anterior and the posterior subcortical
structures, then the defects are more severe and persistent. Several years after the lesion,
these patients remain dysfluent and obtain low scores in several language measures.

_______
Subcortical lesions and the right hemisphere

The data concerning

subcortical lesions of the right hemisphere in children are even sparser than for left
hemisphere lesions.
One known case is an 8-year-old-girl182 with a coagulation disorder (aplastic anaemia) who
developed a right thalamic haematoma. On the acute stage she was drowsy and had a
mild left hemiparesis but she recovered from this motor defect and was examined 1 month
later. At that time it was noticed she tended not to use her left upper limb unless she was
specifically requested. During simultaneous movements of both hands, she tended to
forget the left hand movements, a phenomenon called motor neglect. She also had a
marked visuo-spatial impairment, but no visuo-spatial neglect.
MDL does not use her left hand unless absolutely necessary and she has less control over
directed movements of her left leg than her right. Thus, she is capable of wiping her right
foot on the door mat in a normal fashion but she cannot do that with her left side.
Subcortical structures are specialized from an early age: there are right/left differences,
identical to the ones found in adults. One of the main differences of subcortical damage
between adults and children is the better outcome for immediate recovery in the latter.
However, long term effects can occur, especially when children were aphasic in the acute
stage (in particular, learning difficulties). The pathogenesis of symptoms observed in
association with subcortical damage probably involves direct mechanisms and indirect
effects upon the overlying cortex.
It will be seen then that MDLs brain damage, because of its very early incidence and its
diffuse nature, did not allow for recovery in the sense reported above.
In conclusion: motor and visual neglect and visuo-spatial disturbances can occur in
children following subcortical damage to the right hemisphere, just as in adults183 .
However, children tend to recover quickly. If they are not examined in the acute stage of
illness it is unlikely that these defects will be found. There seem to be no major long term
effects, although Aram & Ekelman184 reported that these patients tend to have a
performance IQ below verbal IQ, when compared to controls.

180

Dysarthria a motor speech disorder resulting from neurological injury and it is

characterized by poor articulation (cf. aphasia: a disorder of the content of speech). Any of
the speech subsystems (respiration, phonation, resonance, prosody, and articulation) can be
affected, leading to impairments in intelligibility, audibility, naturalness, and efficiency of
vocal communication.

181

Hypophonia a weak voice due to incoordination of the vocal muscles.

182

Ferro, J.M. & Martins, I.P. Some new aspects of neglect in children. Behav. Neurol. 3, 1-6; 1990.

183

Ferro, J.M., Kertesz, A. & Black, S.E. Subcortical neglect: quantitation, anatomy and recovery.
Neurology 37,1487-1492; 1987.

184

Aram, D.M. & Ekelman, B.L. Scholastic aptitude and achievement among children with
unilateral brain lesions. Neuropsychologia 26, 903-916; 1988.

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_______

CHILDHOOD APHASIC SYNDROMES AND THE LOCALIZATION OF LESIONS

The study of acquired childhood aphasia (ACA) has made significant progress in the past
20 years. From highlighting fundamental differences between childhood and adulthood
aphasia for more than a century, it has evolved since the late 1970s towards an
acknowledgement of fundamental similarities between both185 . Regarding the clinical
picture, it is clear that the traditional view asserting the universality of non-fluency in ACA is
no longer tenable. Other types of semiological186 pictures co-exist besides the classically
reported non-fluent type. They may even correspond to syndromes which infrequently
occur in adults. Moreover, neuro-radiological data support the current opinion that in
children, lesion location and clinical picture are interrelated in a similar manner as in
adults.187
In a comprehensive review of aphasic syndromes, Damasio188 defines aphasia as, a
disturbance of the comprehension and formulation of language caused by dysfunction in
specific brain regions. Adult aphasics, he continues, can no longer accurately convert
the sequences of non-verbal mental representations that constitute thought into the
symbols and grammatical organization that constitute language [p. 531].
The generation of mental representations corresponding to a sentence that is heard or
seen, is also defective in aphasia. Damasio (idem, 1992) further emphasizes that aphasia is
neither a disorder of perception (deafness, for instance, does not hinder language
comprehension through other channels than the auditory one) nor a motor speech disorder
(dysarthria, for instance, leaves language formulation intact).
Finally, aphasia is not a disorder of the basic thought processes such as those occurring in
schizophrenia. Aphasia can result from any neurological lesion that affects the cerebral
hemispheres, provided that language-related areas are involved; these include: vascular
diseases, traumatic head injuries, tumours, infectious diseases, degenerative or toxic
processes and convulsive disorders. These aphasic syndromes are defined by the anatomy
of the lesion rather than by the language characteristics, but different patterns of language
difficulties have also been described. 189

185

Woods, B.T. Acquired aphasia in children. In: Handbook of clinical neurology.

Neurabehavioural disorders, ed. J.A.M. Frederiks, vol. 46, pp. 147-157. Amsterdam: Elsevier
Science Publishers; 1985.

186

Semiology a science which studies the role of signs as part of social life.

187

Paquier, P; & van Dongen, H. Aphasic syndromes and localization of lesions in children. In,
Riva, D. & Benton, A. Localization of Brain Lesions and Developmental Functions. John Libby,
London; 2000.

188

Damasio, AR. Aphasia. N. Engl. J. Med. 326,531-539; 1992.

189

Kirshner, H.S. Classical aphasia syndromes. In: Handbook of neurological speech and
language disorders, ed. H.S. Kirshner, pp. 57-89. New York: Marcel Dekker; 1995.

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Type of aphasia Spontaneous speech

Auditory
Comprehension

Repetition

Site of lesion
(left hemisphere)

Global aphasia

Non-fluent, scant,
stereotyped
utterances

Impaired

Impaired

Large perisylvian or separate

anterior and posterior damage

Brocas aphasia

Non-fluent, poorly
articulated,
dysprosodic,
agrammatic

Largely
preserved

Impaired

Frontal (inferior and posterior)

Largely
preserved

Largely
preserved

Anterior or superior to Brocas

area (ACA-ACM watershed
area)

Non-fluent,
decreased speech
Transcortical
initiation, effortful,
motor aphasia perseverative, stutterlike, poorly
articulated
Mixed
transcortical
aphasia

Non-fluent, scant,
stereotyped
utterances, echolalic

Impaired

Largely
preserved

Massive hemispheric damage

with sparing of perisylvian area

Wernickes
aphasia

Fluent, abundant,
well-articulated,
melodic, paraphasic,
paragrammatic*

Impaired

Impaired

Temporal (superior and

posterior)

Transcortical
sensory aphasia

Fluent, paraphasic,
well-articulated,
melodic, echolalic

Impaired

Largely
preserved

Posterior or inferior to Wernickes

area (ACM- ACP watershed
area)

Conduction
aphasia

Fluent, phonemic
paraphasias, wellarticulated, melodic,
conduites
dapproche 190

Largely
preserved

Impaired

Fluent, empty,
circumlocutory , wellAnomie aphasia articulated, wordfinding pauses,
melodic

Largely
preserved

Largely
preserved

Supramarginal gyrus, insula,

arcuate fasciculus,

No specific localization

Table Three Main aphasia syndromes according to traditional asphasiology

(Damasio, 1992 & Kirshner, 1995)

190

Conduite d'approche refers to the tendency, most evident in conduction aphasics, to

make repeated attempts at a word (e.g., for pretzel, "trep . . . tretzle . . . trethle . . . tredfles . . .
ki") that do not necessarily result in closer approximations to the target.

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ACA = arteria cerebri anterior; ACM = arteria cerebri media; ACP = arteria cerebri posterior. *When
fluent speech becomes completely incomprehensible because of excessive errors, the aphasia is
termed jargon aphasia.

The shaded rows show the likely types of aphasia that affect MDL. However, MDLs present
medication regime does affect the neurology of her mouth and she cannot control
salivation and has some problems with chewing and therefore swallowing. Her speech is
affected and not only because she does not open her mouth very far when talking and this
causes her to speak through teeth that are almost together. From past experience it is
found that when the medication is considerably reduced or no longer prescribed, these
symptoms disappear.
Stuttering Following Acquired Brain Damage
The identification of causative lesions in
TBI/(ABI) is difficult due to the fact that diffuse axonal injury is typically superimposed on
multiple focal lesions. Communication problems resulting from acquired brain damage are
most frequently manifested as motor speech disorders such as dysarthria, syndromes of
aphasia, and impairments of pragmatics. When stuttering occurs in association with
neuropathology, precise characterization and explanation of observed behaviors is often
difficult. Among the clinical challenges presented by acquired stuttering are the problem of
distinguishing this form of dysfluency from those associated with dysarthria and aphasia,
and identifying the neuropathological condition(s) and brain lesion site(s) giving rise to this
speech disorder. 191
It is significant that MDLs aphasia is worse when she is heavily medicated. As
communication is such an important aspect of MDLs care, there does need to be a more
intelligent approach made towards this supposed treatment.
MDLs speech has deteriorated since 2004 in that she now shows para-grammatism, i.e.
errors in the use of grammatical rules, resulting in incorrect verb tenses. For instance
instead of saying, he bought, she now might say, he buyed.
Delineation of acquired childhood aphasia
From the preceding it should not be
assumed that in adults the use of the term aphasia implies that language had already
been acquired prior to lesion onset. In children, on the contrary, the term has been used in
reference to a number of language impairments attributable to both developmental and
acquired disorders. Thus, congenital, developmental and acquired aphasia have been
distinguished. According to Vargha-Khadem et al192 , congenital aphasia is a language
disorder caused by early and extensive cerebral lesions in the thalamo-cortical projection
system. Due to such demonstrable structural lesions, children with congenital aphasia fail
to develop normal language functions.193
Woods194, developmental aphasia (also called developmental dysphasia or specific

191

Lundgren, K; Helm-Estabrooks, N; & Klein, R. Stuttering Following Acquired Brain Damage: A

Review of the Literature. J Neurolinguistics. 2010 Sep 1; 23(5): 447-454. doi:
10.1016/i.ineurolinq.2009.08.008

192

Vargha-Khadem, F., Watters, G.V. & O'Gorman, AM. Development of speech and language
following bilateral frontal lesions. Brain Lang. 25, 167-183; 1985.

193

Landau, W.M., Goldstein, R. & Kleffner, F.R. Congenital aphasia: a clinicopathologic study.
Neurology 10,915-921; 1960.

194

Woods, B.T. Developmental dysphasia. In: Handbook of clinical neurology. Neurabehavioural

disorders, ed. J.A.M. Frederiks, vol. 46, pp. 139-145. Amsterdam: Elsevier Science Publishers;
1985.

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language impairment) refers to, a level of language function that is significantly below
age norms, and has always been so (i.e. it has not been arrested at, nor has it declined
from an earlier level) and is not adequately accounted for by general mental retardation,
peripheral sensory or motor defects, severe emotional disturbance, or major environmental
deprivation. [p.139] Aram195 emphasizes that a frank neurological basis is not apparent in
developmental aphasia. Both congenital and developmental aphasia share the common
feature that the pathological process which prevents the normal development of language
is already present before language skills begin to emerge.

_______

COGNITIVE DEFICIT AFTER CLOSED HEAD INJURY IN CHILDREN

Development of the human prefrontal cortex has been elucidated in neuro-anatomic
studies which have shown that the density of synaptic contacts peaks by age 11 years.196
Consistent with the developmental changes in synaptogenesis, positron emission
tomography has indicated that the glucose metabolic rate in frontal cortex increases with
age, reaching a peak by age 9 years197.
Confirmatory observations concerning the heterogeneity of functional maturation of subregions of the frontal lobes in humans are limited, particularly in view of the rarity of discrete
lesions confined to one of these areas in children. Although studies of children sustaining
discrete prefrontal lesions are sparse, there is minimal evidence for apparent sparing of
function analogous to Goldman's observations in infant monkeys subjected to dorso-lateral
lesions.198,199
On the contrary, case reports have suggested that early bi-frontal lesions can interfere with
cognitive growth particularly in learning to appreciate the perspective of others and in both
moral and social development200,201. However, developmental studies have raised the
possibility that various cognitive capacities subserved by the prefrontal region are
heterogeneous in respect of their rate of functional maturation.
Using a task analogous to the delayed response, Diamond & Goldman-Rakic202 found that

195

Aram, D.M. Acquired aphasia in children. In: Acquired aphasia, ed. M.T. Sarno, pp. 425--453.
Orlando: Academic Press; 1991.

196

Huttenlocher, P.R. Synaptic density in human frontal cortex: developmental changes and
effects of aging. Brain Res. 163, 195-205; 1979.

197

Chugani, H.T., Phelps, M.E. & Mazziotta, J.C. Positron emission tomography study of human
brain functional development. Ann. Neurol. 22,487-497; 1987.

198

Goldman, P.S. Functional recovery after lesions of the nervous systems. 3. Developmental
processes in neural plasticity. Recovery of function after CNS lesions ininfant monkeys.
Neurosci. Res. Progr. Bull. 12, 217-222; 1974.

199

Goldman, P.S. & Alexander, G.E. Maturation of prefrontal cortex in the monkey revealed by
focal reversible cryogenic depression. Nature 267, 613-615; 1977.

200

Price, B.H., Daffner, KR, Stowe, RM. & Mesulam, M.M. The comportmental learning disabilities
of early frontal lobe damage. Brain 113,1383-1393; 1990.

201

Williams, D. & Mateer, C.A. Developmental impact of fronta11obe injury in middle childhood.
Brain Cognition 20,196204; 1992.

202

Diamond, A & Goldman-Rakic, P.S. Comparison of human infants and rhesus monkeys on
Piaget's A-not-B task: evidence for dependence on dorsolateral prefrontal cortex. Exp. Brain
Res. 74, 24-40; 1989.

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human infants between 6 and 12 months began to reach for a location where an object
was previously hidden. This finding, which brought into question the view that the prefrontal
region becomes functionally mature late in childhood (e.g. at about 10 years), has been
interpreted as evidence for the heterogeneous developmental trajectories of the diverse
functions subserved by the prefrontal region.
Executive function (EF)
The term refers to the distinct, but related cognitive abilities
which depend primarily on a network or system comprised by the prefrontal area and its
major connections. Although this definition (or its variants) is widely accepted, there is no
consensus concerning the specific cognitive abilities which comprise EFs. To build
consensus on this aspect of cognitive development, the National Institute of Child Health
and Development in the United States sponsored a workshop in 1994 which focused on EFs
in children. The workshop proceedings reflected the diversity of EFs and our rudimentary
understanding of interrelationships. It was also clear that there is variation in the purported
relationship of development to the maturation of various sub-regions of the prefrontal
region.203 While acknowledging these limitations, the workshop participants reached
consensus on the following EFs:
Flexibility in problem solving
This refers to the capacity for shifting response strategy
according to changes in the environment.
Temporal organization of behaviour Planning
This EF refers to the capacity for setting
goals and maintaining an action sequence in working memory.
Resource allocation
This EF refers to the computational capacity of the
brain for manipulation or transformation of information such as performing concurrent tasks
which involve divided attention.
Inhibition
In proposing inhibition as an EF, the workshop
participants referred to the capacity for switching from initiation to termination of a
response at the appropriate time. (This seems to correspond to some aspects of
perseveration.)
Self-regulation
This EF refers to the capacity for self-monitoring,
including cognitive performance such as utilizing strategies to enhance memory or study
skills and the capacity to monitor one's behaviour in relation to external constraints or
according to an internal representation which guides behaviour.
Working memory

See many references but esp. p146

_______

LANGUAGE IN CHILDREN WITH EARLY BRAIN DAMAGE

Although specific features characterize the acquisition of particular languages, researchers
have identified a set of milestones that children pass through as they grapple with learning
their native tongue. Overall, the findings suggest that initially, at least, both hemispheres

203

Levin, HS. & Chapman, SB. Contribution of frontal lobe lesions to cognitive deficit after closed
head injury in children. In, Riva, D; & Benton, A. Localization of Brain Lesions and
Developmental Functions. John Libby, London; 2000.

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are implicated in initiating the language acquisition process, and that rather than being
localized to the left hemisphere, as is true for the vast majority of adults, language as it is
being acquired is a rather broadly distributed function.
In the realm of language, Lenneberg (1967) found that children with early onset strokes do
not suffer the same irreversible damage as adults with homologous lesions. Together these
findings raised the possibility that children's brains, unlike those of adults, are flexible and
reflect a wider potential for assuming diverse behavioural functions. According to the
strongest view of this hypothesis of equipotentiality, any area of the brain could assume
responsibility for any behavioural function.
Lenneberg also suggested that the plasticity, or flexibility, responsible for this broad
potential decreased substantially by adolescence when the brain had lateralized, and
different cortical areas had assumed responsibility for specific behavioural functions.
Our brains enable us to perceive and interact with the outer world. Synaptic connections
between neurons can be adjusted to respond flexibly to changes in the environment, for
example when we learn. In addition, plasticity mechanisms play important roles during
early development, even before we are born, to prepare the neuronal circuitry for
processing sensory information when we open our eyes.
The demands for synaptic plasticity keep changing during the course of a lifetime. At the
first developmental stage of life, neuronal networks are being built in the brain in order to
prepare itself for dealing with the outside world after birth (enabling perceptions and the
programming of innate behaviour). To accomplish this, synaptic contacts are being
shaped in the absence of sensory input. In the next phase of life, the infant has to absorb
and process a great deal of new information in a short time (parents, family, language,
cultural behaviour), which demands high levels of synaptic plasticity. At the mature stage
the need for synaptic plasticity becomes gradually less urgent: a picture of the outside
world is made that only incidentally requires adaptation.204 It is very clear, that synaptic
plasticity mechanisms are important for the establishment of the neuronal circuitry.
Therefore, disruptions of developmental plasticity mechanisms have long-lasting
consequences for cognition and behavior. 205, 206, 207, 208
Developmental disorders and conditions such as autism can be caused genetically209 but
also through physical, hormonal or pharmacological impact during gestation or birth, and
through stressful events during birth or early childhood210. Therefore, the mapping of active

204

Lohmann, C & Kessels, HW. The Developmental Stages of Synaptic Plasticity J Physiol. 2013
Oct 21. [Epub ahead of print]

205

Zoghbi HY (2003). Postnatal Neuro-developmental Disorders: Meeting at the Synapse?

Science 302, 826-830.

206

Castren E, Elgersma Y, Maffei L, & Hagerman R (2012). Treatment of neurodevelopmental

disorders in adulthood. J Neurosci 32, 14074-14079.

207

Bhakar AL, D+len G+, & Bear MF (2012). The Pathophysiology of Fragile X (and What It
Teaches Us about Synapses). Annu Rev Neurosci 35, 417-443.

208

Sudhof TC (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature
455, 903-911.

209

Vorstman JA & Ophoff RA (2013). Genetic causes of developmental disorders. Curr Opin
Neurol 26, 128-136.

210

Insel TR & Fernald RD (2004). How the brain processes social information: searching for the
social brain. Annu Rev Neurosci 27, 697-722.

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plasticity mechanisms during the phases of development may provide insights into the
specific causes of developmental disorders. Further research integrating molecular,
physiological and behavioral aspects will provide a more complete map of synaptic
plasticity mechanisms during the different phases of brain development and may inform us
at what stage the brain is particularly sensitive to errors in mechanisms of synaptic plasticity
and how interventions may prevent cognitive deficits. (Lohmann et al)
In the ensuing years, additional studies in children with brain damage have noted subtle yet
persistent language deficits in children with early brain damage. Reviews have been
written by a number of researchers, including Hcaen211, Riva & Cazzaniga212, VarghaKhadem213 , Aram214,215 and Eisele & Aram.216,217
While all of these studies have contributed to our understanding of language functions in
children with neurological dysfunction, many have included children who incurred
damage at different ages, and these studies have come to differing conclusions regarding
the nature and role of the left hemisphere in language development. The goal over the
last twenty years has been to understand the development of brain-language relations
from the beginning of life by following the course of language development in children with
early unilateral focal brain damage. All of the children in this group suffered their cerebral
insult before six months of age, that is, pre-linguistically. By prospectively chronicling their
language development from infancy to adolescence, we can begin to address the
following basic questions:
1.

Localization of function
To what degree is language specified early on? Do behavioural patterns
correlate with site of brain damage? Are they comparable to those of
adults with homologous injuries?

2.

Neuroplasticity
Do behavioural deficits persist or is there recovery of function over time?

211

Hcaen, H. Acquired aphasia in children and the ontogenesis of hemispheric functional

specialization. Brain Lang. 3, 114-134; 1976.

212

Riva, D. & Cazzaniga, L. Late effects of unilateral brain lesions sustained before and after age
one. Neuropsychologia 24, 423-428; 1986.

213

Vargha-Khadem, F. & Polkey, C.E. A review of cognitive outcome after hemi-decortication in

humans. In: Recovery from brain damage: Advances in experimental medicine and biology,
eds. ED. Rosen & D.A. Johnson, 325, pp. 137-171. New York: Plenum Press; 1992.

214

Aram, D. Language sequelae of unilateral brain lesions in children. In: Language,

communication and the brain, ed. F. Pluin, pp. 171-197. New York: Raven Press; 1988.

215

Aram, D. Review of language development in children with focal brain injury. Paper
presented to the Venice Conference on Developmental Neuropsychology, Venice (San
Servolo). (Published in Italian in: Neuropsicologia in eta evolutiva, eds. D. Riva, A. Benton & H.
Levin. Milan: Franco Angeli; 1991.

216

Eisele, J. & Aram, D. Comprehension and imitation of syntax following early hemisphere
damage. Brain Lang. 46, 212-231; 1994.

217

Eisele, J. & Aram, D. Lexical and grammatical development in children witH early hemisphere
damage: a cross-sectional view from birth to adolescence. In: Handbook of child language,
eds. P. Fletcher & B. MacWhinney. Oxford: Basil Blackwell; 1995.

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Does the deficit express itself differentially over time?

3.

The nature of the language acquisition process

How flexible is the language acquisition process itself? Is the process fairly
rigid or are there many ways to approach learning a language?

All of the children were delayed in onset of language regardless of whether the injury was
RHD or LHD. The children at 10-17 months who had right posterior damage were more
delayed in comprehension than those with other focal lesions. Toddlers, 19-31 months with
either L or R frontal damage were more delayed in production but this was transient. Those
aged 20-44 months with left temporal damage had more delays in the production of
vocabularies and produced shorter utterances. MDL developed a good vocabulary so that
seems to confirm her RHB damage.
Interesting though this research is, all of the children involved had focal injury and not the
diffuse damage sustained by MDL. However, we can interpolate and gain some
comparisons that are useful in relating MDLs damage to her ability.

Narratives

Once children are producing sentences and are well along in

mastering the basic morphological structures of their language, linguistic development
involves developing more sophisticated discourse skills and using particular syntactic
structures with increasing frequency and effectiveness.
Beginning at about age three and a half to four years, we see an increasing ability to
recruit particular linguistic structures for specific discourse purposes, e.g. to provide clearer
directions, relate more coherent stories, to tell better jokes. In light of this developmental
transition, researchers have used narratives to investigate multiple aspects of language and
discourse in pre-school and school-age children who are developing typically.
According to the adult model, we would expect a child with LHD to have problems with
morphology and syntax whereas those aspects of language would be spared in children
with RHD. In contrast, those with RHD would be expected to make fewer inferences, and
show problems with discourse coherence.
This research into narratives shows clearly that MDLs diffuse brain damage makes her
neurological functioning worse than that experienced by the focal injury group.
As a child, MDL always told very short stories without much imagination and again that is a
worse effect than that shown by focal inured children. This difference increases
dramatically as focally injured children reach 7-10 years and clearly shows that MDL has
diffuse damage to areas of cognition. She still makes tense-making errors, e.g. singed
rather than sang though she has made more of these errors since she was put onto the
present medication regime in 2004.
She has also, in this period, begun to make pronominal errors, for example, she may say
him when referring to a female and her when referring to a male. Strangely, these
mistakes are not consistent.
MDL does not employ complex syntax. She would say boy went to sleep; dog ran away;
rather than, while the dog was sleeping, the dog ran away. She has also got beyond using
the connective, and, and does not use because, since or when for example. However,
as a child she often used to ask, why?

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In any case, research shows that those with focal RHD only catch up later in school years.
One can only speculate as to whether MDLs failure to catch-up is due to the diffuse nature
of her brain damage, or to the lack of social contact with normal peers.
The research regarding the issue of neuro-plasticity shows the fairly rapid acquisition of the
morpho-syntax of English in the children with early brain damage regardless of lesion site
and that is strong evidence of the flexibility of the developing brain. In those morphosyntactic structures examined, it was found that for the mandatory grammatical functions,
the children in the focal lesion group were initially delayed, but they eventually performed
within the normal range.
These findings for this particular group of research projects with children who have early
focal brain damage have shown that, overall, children with brain damage are delayed in
the acquisition of language, regardless of side of lesion, but eventually do go on to acquire
the lexicon and grammar and be competent speakers of English.
It is clear that just as different aspects of language develop at different points in time so,
too, do the deficits change over time. In sum, language development continues in the
face of early unilateral brain damage, and although recruiting alternative neural means,
the children with early focal brain damage follow a similar, but delayed, behavioural path
to their typically developing counterparts. Additionally the data suggest that the brain
areas suited to acquire language may be more broadly distributed than those necessary to
maintain language functioning once it has been acquired.

Non-verbal learning disabilities

218

Researchers view the significant

disruption of right hemispheral systems in children (and, in some cases, adults) to be a
sufficient condition for the appearance of the syndrome of non-verbal learning disabilities
(NLD). At the same time, it is clear that aetiologies which involve direct disruption of right
hemispheral systems are not necessary for the exhibition of the syndrome. 219
Various learning disability phenotypes have been ascribed to the right hemisphere (RH)
dysfunction and sometimes packaged together as RH learning disability, often based on a
simplistic equation of left hemisphere (LH) with verbal and RH with nonverbal functioning.
Conversely, the RH has been credited with specific roles in some ostensibly LH-based verbal
learning disabilities220. These attributions are speculative. However, Minshew regards Nonverbal Learning Disability as being restricted to verbal individuals with IQs above 70. 221
By definition, learning disability excludes underlying structural brain damage. Therefore,
external validation by means of a consistently localized lesion site is not available.
Neuropsychological analysis may point to underlying structural brain damage and to an
underlying processing deficit of known localizing significance. But even if one ventures to
equate the localizing values of comparable acquired and developmental deficits, there

218

Kinsbourne, M. Nonverbal Learning Disability. In Feinberg, T E & Farah, M J. Behavioural

Neurology and Neuropsychology. McGraw-Hill, New York, 1997

219

Rourke, BP. Non-verbal learning disabilities: development of the syndrome and the model. .
In, Riva, D; & Benton, A. Localization of Brain Lesions and Developmental Functions. John
Libby, London; 2000.

220

Bakker D & Licht R. Learning to read: Changing horses in mid-stream, in Pavlidis GT, Fisher DF
(eds): Dyslexia: Its Neuropsychology and Treatment. New York: Wiley, 1986, pp 87-96.

221

Minshew, NJ. Pervasive Developmental Disorders: Autism and Similar Disorders. In Feinberg, T E
& Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997

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remains little demonstrated correspondence between the functional specializations of the
hemispheres and patterns of academic achievement.
Characteristics and dynamics of the NLD syndrome
The principal clinical
manifestations (content) and dynamics of the NLD syndrome, identified through a process
of intensive clinical examination, are as follows:
(1) Bilateral tactile-perceptual deficits, usually more marked on the left side of the
body. Evidence of simple tactile imperception and suppression tends to subside
with age, but problems in dealing with complex tactile input tend to persist.
(2) Bilateral psychomotor coordination deficiencies, often more marked on the left
side of the body. Relatively simple motor skills, such as finger tapping and static
steadiness, tend to normalize with advancing years. Complex psychomotor skills,
especially when required within a novel framework, tend to worsen relative to agebased norms.
(3) Outstanding deficiencies in visual-spatial-organizational abilities. Simple visual
discrimination, especially for material that is verbalizable, usually approaches
normal levels with age. Complex visual-spatial-organizational skills, especially when
required within a novel framework, tend to worsen relative to age-based norms.
(4) Extreme difficulty in adapting to novel and otherwise complex situations. An
overreliance on prosaic, rote (and, in consequence, inappropriate) behaviours in
such situations. Capacity to deal with novel experiences usually remains poor, or
even worsens, with advancing age.
(5) Marked deficits in non-verbal problem-solving, concept-information, hypothesistesting, and the capacity to benefit from positive and negative informational
feedback in novel or otherwise complex situations. Included are significant
difficulties in dealing with cause-effect relationships and marked deficiencies in the
appreciation of incongruities (e.g. age-appropriate sensitivity to humour). Such
deficiencies tend to persist, and even worsen, with advancing age.
(6) Very distorted sense of time. This is reflected in poor estimation of elapsed time
during common activities, and poor estimation of time of day. (This deficit may not
appear spontaneously; it usually requires a very direct attempt to elicit it.)
(7) Very well-developed rote verbal capacities, including extremely well-developed
rote verbal memory skills. 'Memory' for complex verbal material is usually very poor,
probably as a result of poor initial comprehension of such material.
(8) Much verbosity of a repetitive, straightforward, rote nature. Content disorders of
language and very poor psycholinguistic pragmatics. Misspellings are almost
exclusively of the phonetically accurate variety. Little or no speech prosody, except
on an imitative basis. Excessive reliance upon language as a principal means for
social relating, information gathering, and relief from anxiety.
(9) Outstanding relative deficiencies in mechanical arithmetic as compared to
proficiencies in reading (word-recognition) and spelling. Comprehension of, as
opposed to rote memory for, complex text may continue to be very poor with advancing age.
(10) Significant deficits in social perception, social judgement, and social interaction
skills.

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At a very elementary level, MDL might be seen as someone with NLD. However, on a closer
and longer examination, it will be seen that this superficial assessment would be wrong as
she shows only some of the characteristics of NLD and in others she shows a far greater
disability.
The model that is used to identify the principal or primary dimensions of NLD syndrome are
deficits in visual-perceptual-organizational abilities, complex psychomotor skills, and tactile
perception, in addition to difficulties in dealing with novelty. Primary assets include
proficiency in most rote verbal and some simple motor and psychomotor skills. 222
Confirmation of these dimensions as primary arises from the results of several studies.223,224
The primary neuropsychological deficits experienced by the child with NLD are seen as
having to do with aspects of tactile and visual perception, complex psychomotor skills, and
the capacity to deal adaptively with novel material. Such deficits would be expected to
eventuate in disordered tactile and visual attention and stunted exploratory behaviour; in
turn, problems in memory for material delivered through the tactile and visual modalities as
well as deficits in concept-formation and problem-solving would be expected to ensue.
This set of deficits would be expected to eventuate in particular linguistic deficiencies.
(Rourke, 2000, idem)
The academic and psychosocial/adaptive deficiencies are the sequelae of these
neuropsychological deficits. It is especially important to note that this set of
neuropsychological deficits is expected to lead, in a necessary way, to a particular
configuration of problems in psychosocial/adaptive behaviour both within and without the
academic situation. (Rourke, 2000, idem)
Growing evidence indicates that multiple types of brain injury, including traumatic brain
injury, are dynamic conditions that continue to change years after onset. For a subset of
individuals who incur these injuries, decline occurs over time and is likely due to progressive
neurodegenerative processes, comorbid conditions, aging, behavioural choices, and/or
psychosocial factors. Deterioration, whether directly or indirectly associated with the
original brain injury, necessitates a clinical approach as a chronic health condition,
including identification of risk and protective factors, protocols for early identification,
evidence-based preventive and ameliorative treatment, and training in selfmanagement.225 It is important therefore for those with an early-life brain injury that it can
be assessed and researched by neurologists or neuropsychologists in order to provide a
proper management approach.
One example of possible treatment is with omega-3 polyunsaturated fatty acids (PUFAs).
These are compounds that have a structural role in the nervous system and are essential for
neuro-development. It has been shown that there is therapeutic potential in neurotrauma
with the use of docosahexaenoic acid and eicosapentaenoic acid. Omega-3 capsules

222

Rourke, B.P. Nonverbal learning disabilities: the syndrome and the model. New York: Guilford
Press; 1989.

223

Casey, J.E., Rourke, B.P. & Picard, E.M. Syndrome of nonverballearning disabilities: age
differences in neuropsychological, academic, and socioemotional functioning. Dev.
Psychopathol. 3,329-345; 1991.

224

Harnadek, M.C.S. & Rourke, B.P. Principal identifying features of the syndrome of nonverbal
learning disabilities in children. J. Learning Disabilities 27,144-154; 1994.

225

Corrigan JD & Hammond FM. Traumatic brain injury as a chronic health condition. Arch Phys
Med Rehabil. 2013 Jun; 94(6):1199-201

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were supplied to MDL for several years, along with other Vitamins and mineral supplements
but they were all withdrawn by a locum psychiatrist whilst Dr Farquhar was away.
Michael-Titus et al suggest that traumatic brain injury (TBI) and spinal cord injury (SCI) can
lead to major disability and have a significant socioeconomic cost and that there is an
unmet need for acute neuro-protection and for treatments that promote neuroregeneration. Their research shows that acute administration of omega-3 PUFAs after injury
and dietary exposure before or after injury improve neurological outcomes in experimental
SCI and TBI. The mechanisms involved include decreased neuro-inflammation and
oxidative stress, neurotrophic support, and activation of cell survival pathways. However,
this review raises questions that must be addressed before successful clinical translation.226
Harper suggests that, people with learning disabilities are at increased risk of low bone
mineral density, osteopenia, osteoporosis and fractures, compared to the general
population, mainly due to higher levels of obesity or undernutrition, reduced weightbearing exercise, and polypharmacy, including anti-epileptic and antipsychotic
medications. Healthy lifestyles that reduce obesity and ensure adequate levels of vitamin
D, calcium, protein, and a variety of vegetables, can protect people from developing
musculoskeletal diseases and support bone health. 227
In traumatic brain injury, oxidation and inammation have been linked to poorer cognitive
outcomes. Theadom and colleagues have investigated the effects of Enzogenol on loss of
cognitive functioning following traumatic brain injury. Enzogenol is a avonoid-rich extract
from Pinus radiata bark with antioxidant and anti-inammatory properties that has been
shown to improve working memory in healthy adults. 228
The investigators found that Enzogenol was safe and well tolerated. Trend and breakpoint
analyses showed a significant reduction in cognitive failures after 6 weeks. Improvements in
the frequency of self-reported cognitive failures were found to stabilize shortly after the halfway period of the study. Overall, Enzogenol supplementation was found to be safe and
well tolerated in people after mild TBI, and may improve cognitive functioning in this patient
population. (Idem)
MDL has only some of the assets normally found in NLD but most of the deficits. It has been
found on examination of the brains of some of those assessed as having NLD, that there can
be significant tissue destruction within the right cerebral hemisphere.
It seems that in MDLs case, the lack of ability in many, if not all, of those associated with
NLD will have come to her by means of post-natal damage to particular areas of her brain
that are connected to the functions that are lost or disabled. This is confirmed in the work of
Ewing Cobbs et al and Fletcher Levin in their work on traumatic brain injury.229,230

226

Michael-Titus, AT & Priestley JV. Omega-3 fatty acids and traumatic neurological injury: from
neuroprotection to neuroplasticity? Trends Neurosci. 2014 Jan;37(1):30-8. doi:
10.1016/j.tins.2013.10.005.

227

Harper, L. Optimal nutrition for bone health in people with a learning disability. Learning
Disability Practice 2017 20: 1, 31-35.

228

Theadom A; Mahon S; Barker-Collo S; McPherson K; Rush E; Vandal AC & Feigin VL.

Enzogenol for cognitive functioning in traumatic brain injury. Eur J Neurol. 2013 Aug;
20(8):1135-44.

229

Ewing-Cobbs, L., Fletcher, J. M. & Levin, H.S. Traumatic brain injury. In: Syndrome of nonverbal
learning disabilities: neurodevelopmental manifestations, ed. B.P. Rourke, pp. 433-459. New
York: Guilford Press; 1995.

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_____________________

The Neuropsychology of Brain Damage

as it relates to MDL
Using the Lesion Method to locate brain damage231
The lesion method aims at establishing a correlation between a circumscribed region of
brain damage, a lesion and a pattern of alteration in some aspect of an experimentally
controlled cognitive or behavioural performance. The brain-damaged region is
conceptualized as part of a large-scale network of cortical and sub-cortical sites that
operate in concert, by virtue of their interlocking connectivity, to produce a particular
function.
The lesions may have been produced by neurologic disease alone or incurred in the
process of treating it (e.g., a surgical procedure). They may be small or large and may be
studied in vivo or at post mortem. The indispensable requirements are that lesions be
stable, well demarcated, and referable to a neuro-anatomic unit.
The lesion approach provided the first method in what was to become neuroscience. In
the very least, it dates to Morgagni's demonstration of an association between unilateral
brain disease and contra-lateral sensory and motor disabilities. Bouillaud's and Broca's
finding of a correlation between speech and focal damage to the frontal lobe are
reasonable signposts to mark the modern era of lesion studies.
It is now accepted that the classically discovered links between certain brain regions of the
cerebral cortex and signs of neuropsychological dysfunction have been validated and
they remain a staple of clinical neurology, and allow for relatively accurate predictions of
localization of damage from neurologic signs. That is, more often than not, the presence of
certain neuropsychological defects indicates to the clinical expert that there is dysfunction
in a specific brain area. These valid links, however, should not be taken to mean that the
functions disturbed by the lesion were inscribed in the tissue that the lesion destroyed. The
complex psychological functions, which usually constitute the target of neuropsychological
studies in humans, are not localizable at that level. The new technique permits a direct
identification of gyri and sulci, comparable to what can be achieved at the autopsy table
in a post mortem brain after the meninges have been removed.232
Thompson et al have devised, implemented, and tested a technique for creating a
comprehensive probabilistic atlas of the human cerebral cortex, based on highdimensional fluid transformations. The goal of the atlas is to detect and quantify subtle and

230

Fletcher, J.M. & Levin, H. Neurobehavioral effects of brain injury in children. In: Handbook of
paediatric psychology, ed. D.K Routh, pp. 258-295. New York: Guilford Press; 1988.

231

Damasio, H. & Damasio, AR. The Lesion Method in Behavioural Neurology and
Neuropsychology. In Feinberg, T E & Farah, M J. Behavioural Neurology and
Neuropsychology. McGraw-Hill, New York, 1997.

232

Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New

York, 1997.

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distributed patterns of deviation from normal cortical anatomy, in a 3D brain image from
any given subject. The method that is used takes a 3D MR image of a new subject and a
high-resolution surface representation of the cerebral cortex is automatically extracted.
The algorithm then calculates a set of high-dimensional volumetric maps, fluidly deforming
this surface into structural correspondence with other cortical surfaces, selected one by
one from an anatomic image database. The family of volumetric warps so constructed
encodes statistical properties of local anatomical variation across the cortical surface.
Additional strategies are developed to fluidly deform the sulcal patterns of different
subjects into structural correspondence. A probability space of random transformations,
based on the theory of anisotropic Gaussian random fields, is then used to encode
information on complex variations in gyral and sulcal topography from one individual to
another. 233
The neural architectures revealed by neuro-anatomy and neuro-physiology and the
cognitive architectures revealed by experimental neuropsychology suggest that singlecentre functions, single-purpose pathways, and unidirectional cascades of information
process are unrealistic. Moreover, the residual performance that follows focal brain insults,
and the ensuing patterns of recovery, suggest that knowledge must be widely distributed,
at multiple neural levels, and complex psychological functions must emerge from the
cooperation of multiple components of integrated networks.
Two key developments made human lesion studies rewarding again. First, lesion studies in
non-human primates brought major advances to the understanding of the neural basis of
vision and memory, as demonstrated, among others, by Mishkin and colleagues. Second,
the advent of CT and MRI scans began to permit human lesion studies in vivo. It is apparent
now that the lesion method is indispensable to cognitive neuroscience, especially when it
comes to human studies. The new lesion method is not concerned with localizing functions, nor is it a contest for localizing lesions. It is a means to test, at systems level,
hypotheses regarding both neural structure and cognitive processes. What investigators
from Dejerine to Geschwind gleaned from single cases can now be replicated
systematically in a suitable group of subjects. Hypotheses old and new, including some
advanced by the pioneer neuropsychologists, can be tested experimentally.
In using this method of locating lesions in MDLs brain it should always be remembered that
her brain was injured at a very early stage and its later development could not therefore be
normal. In other words we are not dealing with a mature brain that has subsequently been
damaged.
______

233

Thompson, P M.; MacDonald, D; Mega, M S.; Holmes, C J.; Evans, A C &; Toga, A W. Detection
and Mapping of Abnormal Brain Structure with a Probabilistic Atlas of Cortical Surfaces.
Journal of Computer Assisted Tomography: July/August 1997 - Volume 21 - Issue 4 - pp 567581.

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Problems of an Adverse Living Environment

There are two distinct aspects to MDLs brain functioning:
1. The original damage caused by the vaccination (this appears to be largely to the
right-side of the brain and probably the connections to and from the amygdala,
hippocampus and hypothalamus).
2. The subsequent damage/alteration that has been brought about by environmental
issues such as stress 234,235,236,237,238,239,240,241 anxiety242,243,244 and
medication245,246,247,248,249,250,251,252,253.

234

http://www.fi.edu/learn/brain/stress.html#how

235

Ulrich-Lai,Y M. & Herman, J P. Neural regulation of endocrine and autonomic stress responses.
Nature Reviews Neuroscience 10, 397-409 (2009)

236

Arnsten, A F T. Stress signalling pathways that impair prefrontal cortex structure and function.
Nature Reviews Neuroscience 10, 410-422 (2009)

237

Roozendaal, B; McEwen, B S & Chattarji, S. Stress, memory and the amygdala. Nature
Reviews Neuroscience 10, 423-433 (2009)

238

Lupien, S J; McEwen, B S; Gunnar, M R & Heim, C. Effects of stress throughout the lifespan on
the brain, behaviour and cognition. Nature Reviews Neuroscience 10, 434-445 (2009)

239

Feder, A; Nestler, E J & Charney, D S. Psychobiology and molecular genetics of resilience.

Nature Reviews Neuroscience 10, 446-457 (2009)

240

Jols, M & Baram, T Z. The neuro-symphony of stress. Nature Reviews Neuroscience 10, 459466 (2009)

241

Soliman A, Udemgba C, Fan I, Xu X, Miler L, Rusjan P, Houle S, Wilson AA, Pruessner J, Ou XM,
Meyer JH. Convergent Effects of Acute Stress and Glucocorticoid Exposure upon MAO-A in
Humans. J Neurosci. 2012 Nov 28;32(48):17120-17127.

242

Soo, C & Tate, R. Psychological treatment for anxiety in people with traumatic brain injury
(Review). The Cochrane Collaboration and published in The Cochrane Library; 2009, Issue 3

243

Vasa RA, Grados M, Slomine B, Herskovits EH, Thompson RE, Salorio C, Christensen J, Wursta C,
Riddle MA, Gerring JP. Neuroimaging correlates of anxiety after paediatric traumatic brain
injury. Biol Psychiatry. 2004 Feb 1; 55(3):208-16.

244

Hiott DW & Labbate L. Anxiety disorders associated with traumatic brain injuries.
NeuroRehabilitation. 2002; 17(4):345-55.

245

Dorph-Petersen KA, Pierri JN, et al. The Influence of Chronic Exposure to Antipsychotic
Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and
Olanzapine in Macaque Monkeys. Neuropsychopharmacology 9 March 2005

246

Christensen, E. Neuropathological investigations of 28 brains from patients with dyskinesia.

Acta Psychiatrica Scandinavica, 46,14-23, 1970

247

Baribeau, J. Tardive dyskinesia and associated cognitive disorders: a convergent

neuropsycological and neurophysiological approach. Brain and Cognition 23, 40-55, 1993.

248

Paulsen, J S. Neuropsychological impairment in tardive dyskinesia. Neurospsychology 8, 227241. 1994.

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It has long been accepted that psychotropic drugs can bring about tardive dyskinesia254
and akathisia255. Snchez et al advise that antipsychotics induce significant side effects,
including neurological, behavioural and metabolic side effects. 256 These symptoms can
become a larger problem because of the danger that the brain will be damaged by the
intrusion of the medication over a long period of time. So, the pathological process or
processes that underlie the development of tardive dyskinesia are not just neurochemical in
nature, but affect brain structure. Compared with those without tardive dyskinesia, patients
with tardive dyskinesia show a pattern of volume reductions in predominantly subcortical
regions, including the basal ganglia and the thalamus. Within the basal ganglia, volume
reductions are seen in the caudate nucleus, to a lesser extent in the putamen, and only
marginally in the globus pallidus. The patients with tardive dyskinesia, but not those without,
show significant volume reductions in the basal ganglia compared with the healthy controls
but both groups had smaller volumes than controls in other affected areas. 257
Patients who are chronically treated with antipsychotic drugs show changes in brain
structure. There is strong support for this view from Chege et al who, using resonance
imaging findings, have found that there is Iincreasing evidence to suggest that
antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral
cortex. They used automated analysis techniques to map the regions that show maximal
impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat
cortex. Guided by these imaging findings, they undertook a focused postmortem
investigation with stereology. [My emphasis]
Their results showed decreases in the volume and thickness of the anterior cingulate cortex
(ACC) after chronic APD treatment, regardless of the APD administered. Postmortem
analysis confirmed these volumetric findings and demonstrated that chronic APD treatment

249

Sachdev, P. Negative symptoms, cognitive dysfunction, tardive akathisia and tardive

dyskinesia. Acta Psychiatr Scand. 93, 451-459. 1996.

250

Madsen, A. Neuroleptics in progressive structural brain abnormalities in psychiatric illness. The

Lancet, 352, 784-785. Sept. 5, 1998.

251

Tsai, G. Markers of glutamergic neurotransmission and oxidative stress associated with tardive
dyskinesia. American Journal of Psychiatry, 155, 1207-1213. 1998.

252

Wade, JB; Lehmann, L; Hart, R; Linden, D; Novak, T & Hamer R. Cognitive Changes Associated
with Tardive Dyskinesia. Neuropsychiatry, Neuropsychology and Behavioural Neurology;
Vol.1; No 3; pp217-227; 1989.

Yang SY; Liao YT; Liu HC; Chen WJ; Chen CC; & Kuo CJ. Antipsychotic drugs mood
stabilizers and risk of pneumonia in bipolar disorder: a nationwide case-control study. J Clin
Psychiatry. 2013 Jan; 74(1):e79-86. doi: 10.4088/JCP.12m07938.
253

Tardive dyskinesia was first named and classified in 1964. By the early 1960s,
symptoms associated with tardive dyskinesia were apparent in approximately 30 percent of
psychiatric patients treated with antipsychotic medications, linking the development of the
condition to these drugs.
254

255

In very general terms, akathisia is a movement disorder and it is characterized by unpleasant

sensations of inner restlessness that manifests itself with an inability to sit still or remain
motionless. It can be a side effect of medications.

256

Snchez, JPB & Ellenbroek, BA. Preclinical Effects of Antipsychotic Drugs. Behavioral
Neurosciences pp 1-16 Series ISSN 1866-3370; 30 June 2016

257

Sarr, S. et al. Structural brain changes associated with tardive dyskinesia in schizophrenia.
BJPsych. July 2013 203:51-57; doi:10.1192/bjp.bp.112.114538.

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had no effect on the total number of neurons or S100+ astrocytes in the ACC but that in
contrast there was an increase in the density of these cells.
This study demonstrates region-specific structural effects of chronic APD treatment on the
rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these
changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss
of neuropil.258 This study highlights the power of this approach to link magnetic resonance
imaging findings to their histopathological origins. The results show such changes after only
eight weeks of treatment and MDL has been treated continuously with olanzapine for
many years.259
A more recent study by Semon, JP. Has shown the effects of chronic exposure to the
antipsychotic olanzapine on metabolism and hormones. By administering olanzapine to
mice over a period of four weeks and controlling their diet, he was able to show at which
doses and diets olanzapine had the strongest interaction. While the 10 and 60% diets
showed no significant weight gain associated with olanzapine, the 30 and 45% diets did
show an interaction. The 30% fat diet is within the bounds of what is considered healthy for
humans, so the results have significant meaning. Further testing may shed light on whether
the olanzapine-diet interaction is present at the lower bounds of healthy fat consumption
(20% of daily calories). 260
Straus et al have found that the use of antipsychotics is also associated with an increased
risk of sudden cardiac death. They concluded from their research that the use of these
medications in a general population is associated with sudden cardiac death even at a
low dose for conditions other than schizophrenia. It was the highest risk amongst recent
users but also remained elevated during long-term use. 261
The case-control study used the Integrated Primary Care Information (IPCI) project, a
longitudinal observational database with complete medical records from 150 general
practitioners, to identify all deaths between January 1, 1995, and April 1, 2001. Cases of
sudden cardiac death were classified by time between onset of cardiovascular symptoms
and death, and matched with up to 10 random controls based on age, sex, date of
sudden death, and practice. Exposure to antipsychotic medications at the index date was
categorized as current use, past use, or non-use. Of 554 cases of sudden cardiac death,
334 cases were witnessed.
Pasternak et al have also found a number of serious cardiovascular safety concerns related
to the use of atypical antipsychotics, compared with no use. Most of their cohort were

258

In neuroanatomy, a neuropil, which is sometimes referred to as a neuropile, is a region

between neuronal cell bodies in the gray matter of the brain and spinal cord (i.e. the central
nervous system). It consists of a dense tangle of axon terminals, dendrites and glial cell
processes. It is where synaptic connections are formed between branches of axons and
dendrites.

259

Chege, W; Natesan, S.; Modo, M.; Cooper, JD.; Williams, SCR. & Kapur, S. Reduced Cortical
Volume and Elevated Astrocyte Density in Rats Chronically Treated with Antipsychotic
DrugsLinking Magnetic Resonance Imaging Findings to Cellular Pathology. Biol. Psych.
published online 21 October 2013 doi:10.1016/j.biopsych.2013.09.012.

260

Semon, J P. Effects of Chronic Exposure to the Antipsychotic Olanzapine on Metabolism and

Hormones: Is There an Interaction with Dietary Fat Levels?" Indiana University of Pennsylvania;
Theses and Dissertations. Paper 1397; 2016.

261

Straus, SMJM; Gysle, SB; Dieleman, JP; van der Lei, J; t Jong, GW; Kingma, JH; Sturkenboom,
MCJM; Stricker, BHC. Antipsychotics and the Risk of Sudden Cardiac Death. Arch Intern
Med; Vol 164, June 28, 2004.

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from studies of older patients. They aimed to compare the risk of cardiovascular events
between the three most commonly used atypical antipsychotics in young and middleaged adults: olanzapine, oral quetiapine and oral or intramuscular risperidone. 262
The primary outcome searched was any major cardiovascular event (composite of
cardiovascular mortality, acute coronary syndrome, or ischemic stroke) within 1 year
following treatment initiation. Cox regression was used to estimate hazard ratios while on
current antipsychotic monotherapy in the outpatient setting, adjusting for an outcomespecific disease risk score.
They concluded that among young and middle-aged outpatients, the risk of acute major
cardiovascular events was similar with use of olanzapine, quetiapine, and risperidone.
Although moderate relative differences could not be ruled out, any differences were small
in absolute terms.
There is also a risk, particularly in older adults, of the condition of hyponatremia263, 264
becoming established following the prescribing of psychotropic drugs and this may be
associated with increased morbidity and mortality. 265, 266
Kim et al have reviewed the risks associated with the use of antipsychotic medications.
They have concluded that second-generation antipsychotics (SGAs) are powerful
pharmacologic tools when used to treat a wide array of psychiatric conditions. They also
comment that their use is not just limited to psychosis but may also extend to mania,
depression, anxiety and even autism spectrum disorders. To treat these conditions,
most SGAs are dosed daily and used chronically. Evidence to date suggests that the risk of
tardive dyskinesia is probably lower with SGAs as compared to first-generation
antipsychotics, but tardive dyskinesia will still occur with SGAs, and this was seen in the
cases that they reviewed. Prospective, large-scale studies involving antipsychotic-nave
patients exposed to SGAs would show the true risk and incidence of SGA-induced EEG
dyskinesia. 267
Amann et al studied the effects of the atypical antipsychotics quetiapine and olanzapine,
and the typical antipsychotic haloperidol on EEG patterns retrospectively in 81 patients
under stable monotherapy with either drug (quetiapine: n=22, olanzapine: n=37,
haloperidol: n=22). These three subgroups were compared with a control group of healthy

262

Pasternak B; Svanstrm H; Ranthe MF; Melbye M & Hviid A. Atypical Antipsychotics

Olanzapine, Quetiapine, Risperidone and Risk of Acute Major Cardiovascular Events in Young
and Middle-Aged Adults: A Nationwide Register-Based Cohort Study in Denmark. CNS
Drugs. 2014 Jun 4.

263

A serum electrolyte disorder.

264

Barclay, L & Nainggolan, L. New European Guidelines Address Hyponatremia Management.

Medscape Medical News. Available at http://www.medscape.com/viewarticle/821130.
Accessed: March 1, 2014.

265

Gandhi, S. Risk of Hyponatremia in Older Adults Receiving Psychotropic Drug Treatment.

(2016). Electronic Thesis and Dissertation Repository. Paper 4131. Western University, London,
Ontario, 2016.

266

Gandhi, S. et al Second-Generation Antidepressants and Hyponatremia Risk: A PopulationBased Cohort Study of Older Adults. American Journal of Kidney Diseases.
http://dx.doi.org/10.1053/j.ajkd.2016.08.020

267

Kim, J; MacMaster, E & Schwartz, TL. Tardive dyskinesia in patients treated with atypical
antipsychotics: case series and brief review of etiologic and treatment considerations. Drugs
in Context 2014; 3: 212259; doi: 10.7573/dic.212259.

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subjects (n=30) which were matched regarding sex and age. Diagnoses of patients were
schizophrenia (DSM-IV 295.xx, n=61), brief psychotic disorder (DSM-IV 298.8, n=9),
schizoaffective disorder (DSM-IV 295.70, n=8) and delusional disorder (DSM-IV 297.1, n=3).
There were no statistically significant differences regarding demographic characteristics
between the groups.
Digital EEG recordings were retrieved from a database and visually assessed by two
independent investigators, and one blinded regarding medication. One patient from the
quetiapine group (5%), 13 olanzapine patients (35%), five of the haloperidol patients (23%)
and two subjects of the control group (7%) had an abnormal EEG.
Epileptiform activity was observed in four patients (11%) of the olanzapine group, and none
in the others. EEG abnormalities were statistically significantly increased with dose in the
olanzapine group, in contrast to patients treated with haloperidol, quetiapine or healthy
subjects. They concluded that EEG abnormalities seemed to occur rarely in patients treated
with quetiapine comparable to the control group, but significantly more often with
haloperidol and olanzapine, possibly due to different receptor profiles of these
substances.268
Wichniak et al investigated whether EEG slowing during olanzapine treatment was related
to therapy outcome and sleepiness in patients with schizophrenia. Olanzapine was found
to induce slowing of EEG activity in the majority of patients, but their background EEG
activity remained mostly unchanged. In patients at high olanzapine doses (10 mg/day) the
paroxysmal slow wave activity was found in as many as 25% of cases, while sharp waves
were found in 32% of patients. The EEG slowing during olanzapine treatment was not
related to the treatment outcome. Moreover, no direct relationships were found between
the presence of sleepiness in EEG recordings, treatment outcome and type as well as dose
of medication used. These ndings suggest that the relationship between EEG slowing and
treatment outcome during olanzapine treatment is not as strong as that during clozapine
treatment or ECT. They suggest that further investigation of this aspect is needed using more
complex study designs. In addition they also propose that EEGs should be performed both
before and during antipsychotic medication when the patients state is stabilized. 269
A later study by Deaner et al undertook a naturalistic observational study into EEG
alterations in patients under olanzapine treatment with a special regard to olanzapine dose
and plasma concentration. They suggest that EEG control recordings should be mandatory
during olanzapine treatment. Twenty-two in-patients of a psychiatric university ward were
involved and all of them had a normal alpha-EEG before drug therapy, and did not suffer
from brain-organic dysfunctions, as verified by clinical examination and cMRI scans.
EEG and olanzapine plasma levels were determined under steady-state conditions
(between 18 and 22 days after begin of treatment). In 9 patients (40.9%), pathological EEG
changes (one with spike-waves) consecutive to olanzapine treatment were observed. The
dose of olanzapine was significantly higher in patients with changes of the EEG than in
patients without changes. In patients with EEG changes, the blood plasma concentration
of olanzapine tended to be higher also. The sensitivity of olanzapine dosage to predict EEG
changes was 66.7%. EEG abnormalities during olanzapine treatment are common. And are

268

Amann BL; Pogarell O; Mergl R; Juckel G; Grunze H; Mulert C & Hegerl U. EEG abnormalities
associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and
healthy subjects. Hum Psychopharmacol. 2003 Dec;18(8):641-6.

269

Wichniak A; Szafranski T; Wierzbicka A; Waliniowska E & Jernajczyk W.

Electroencephalogram slowing, sleepiness and treatment response in patients with
schizophrenia during olanzapine treatment. J Psychopharmacol. 2006 Jan; 20(1):80-5.

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significantly dose dependent. Thus, EEG control recordings should be mandatory during
olanzapine treatment with special emphasis on dosages exceeding 20 mg per day,
although keeping in mind that EEGs have only a limited predictive power regarding future
epileptic seizures. 270
The underlying cause of akathisia is still far from clear. There appears to be dopamine
receptor blockade in the mesocortical dopamine system. PET studies show D2 receptor
occupancy in the striatum plays a role and noradrenergic and serotonergic systems also
appear to be involved. Antipsychotics with potent 5HT receptor antagonism show a lower
incidence of akathisia and some 5HT2 antagonists e.g. cyproheptadine, have therapeutic
efficacy. There is a possible association between low iron status and akathisia in patients
with restless legs syndrome. There have been a number of subtypes of akathisia proposed,
although a lack of consensus in the use of the terms is evident. Most authors refer to acute,
tardive (arising at least six months after the continuous use of the medication), chronic,
withdrawal and pseudoakathisia. 271 The Barnes Akathisia Scale is the most widely used
rating scale for akathisia. This scale includes objective and subjective items such as the
level of the patient's restlessness.
Mills has suggested that even when child psychiatrists can agree about the boundary
between healthy and disordered moods and behaviors in children, misdiagnosis remains a
problem and goes on to say that there are children who need treatment who are not
getting it and children who do not need treatment who are. 272 A further question is, should
children have the right to a psychotropic medication-free childhood?
This idea is also put forward by Parens & Johnston 273 who ask:

Are children being overmedicated?

Is normal childhood behaviour being medicalized?

What is the long-term safety of psychotropic drugs?

How effective and safe is it to use those drugs that have only been tested in adults?

What is needed is a policy that allows children to thrive and one that tries to find the
ultimate wellbeing so that there is a possibility of the child being as much a complete and
rational human being as he can be helped to be. This can often be achieved by placing
the child in the right environment, one that can hopefully be cultivated without any
institutional placement and preferable without being removed from home and family.
Kane et al, in an updated review focusing on second-generation antipsychotics (SGAs),
found that in seventy-seven trials akathisia was observed with the use of all the SGAs. The
akathisia incidence reported in bipolar disorder trials was generally higher compared with

270

Degner D; Nitsche MA; Bias F; Rther E & Reulbach U. EEG alterations during treatment with
olanzapine. Eur Arch Psychiatry Clin Neurosci. 2011 Oct; 261(7):483-8.

271

Nelson, DE. Akathisia - A Brief Review. SMJ; 2001; 46: 133-134.

272

Mills, C. Psychotropic Childhoods Global Mental Health and Pharmaceutical Children. Article
first published online: Children & Society; 9 DEC 2013; DOI: 10.1111/chso.12062; John Wiley &
Sons Ltd and National Children's Bureau, 2013.

273

Parens, E. & Johnston, J. Mental Health in children and Adolescents. In, From Birth to Death
and Bench to Clinic: The Hastings Center Bioethics Briefing Book for Journalists, Policymakers,
and Campaigns, ed. Mary Crowley (Garrison, NY: the Hastings center, 2008), Chapter 22; 101106.

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schizophrenia trials. The incidence reported for first-generation antipsychotics was
consistently higher than that reported for SGAs, regardless of the patient population
studied. They concluded that akathisia remains a concern with the use of SGAs; and that
more accurate and standardized evaluations are required for a better understanding of
the nature and incidence of akathisia.274
There have been increasing numbers of reports concerning diabetes, ketoacidosis,
hyperglycaemia and lipid dysregulation in patients treated with second-generation (or
atypical) antipsychotics have raised concerns about a possible association between these
metabolic effects and treatment with these medications. 275
He et al have reported that treatment with second generation antipsychotics (SGAs),
notably olanzapine and clozapine, causes severe obesity side effects. They identified
antagonism of histamine H1 receptors as a main cause of SGA-induced obesity, but the
molecular mechanisms associated with this antagonism in different stages of SGA-induced
weight gain remain unclear.
They explored the potential role of hypothalamic histamine H1 receptors in different stages
of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced
antagonism of these receptors. Their data have demonstrated the importance of
hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking
hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a
well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor
antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase signalling to
rapidly increase caloric intake and result in weight gain. During long-term SGA treatment,
hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting
the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral
medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking
of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by
decreasing lipolysis but increasing lipogenesis in white adipose tissue.
They suggest that antagonism of hypothalamic H1 receptors by SGAs may timedependently affect the hypothalamus-brainstem circuits to cause weight gain by
stimulating appetite and fat accumulation but reducing energy expenditure. The H1
receptor and its downstream signalling molecules could be valuable targets for the design
of new compounds for treating SGA-induced weight gain/obesity.276
These findings have been confirmed in 2014 by Goswami et al; their research has shown
that atypical antipsychotic agents produce significant disturbances in blood glucose and
lipid profile levels. Olanzapine treatment is associated with high risk of abnormal metabolic
changes. They draw attention to the need for prescribers to be aware about detailed
pharmacological information medications and that the prescribing of atypical
antipsychotics should be considered after assessment and the taking of the patients history

Kane JM; Fleischhacker WW; Hansen L, Perlis R; Pikalov A 3rd & Assuno-Talbott S.
Akathisia an updated review focusing on second-generation antipsychotics. J Clin
Psychiatry. 2009 Apr 21.
274

Newcomer JW. Second-generation (atypical) antipsychotics and metabolic

effects: a comprehensive literature review. CNS Drugs. 2005; 19 Suppl 1:1-93.

275

276

He M; Deng C & Huang XF. The role of hypothalamic H1 receptor antagonism in

antipsychotic-induced weight gain. CNS Drugs. 2013 Jun; 27(6):423-34. doi: 10.1007/s40263013-0062-1.

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including personal and family, general and laboratory parameter measurement. Atypical
antipsychotics should be avoided in high risk patients like those who suffer from obesity,
insulin resistance, hypertension and hyperlipidaemia. Thus prescription of antipsychotic
agents must be based on patients metabolic parameters and they should be measured
during the course of treatment. 277
Second generation antipsychotics (SGAs) are widely prescribed to treat various disorders,
most notably schizophrenia and bipolar disorder; however, SGAs can cause abnormal
glucose metabolism that can lead to insulin-resistance and type 2 diabetes mellitus sideeffects by largely unknown mechanisms. Weston-Green et al have explored the potential
candidature of the acetylcholine (ACh) muscarinic M3 receptor (M3R) as a prime
mechanistic and possible therapeutic target of interest in SGA-induced insulin
dysregulation.
OBrien et al have studied the off-label prescribing of psychotropic medication. The study
examined rates of psychotropic prescriptions for various on- and off-label uses in 2005 and
2013 in the context of changes in labelled indications. Expanded labelling was associated
with increased use of antidepressants for anxiety; antipsychotics for depression, bipolar
disorder, autism (and related disorders); and anxiolytics for anxiety disorders. They
concluded that labelling plays an important but imperfect role in influencing how providers
select medications. However, labelled indications often lag the science, and prescribing
patterns should be tracked to inform the need for more education, research, and labelling
changes. 278
Studies have identified that SGA binding affinity to the M3R is a predictor of diabetes risk;
indeed, olanzapine and clozapine, SGAs with the highest clinical incidence of diabetes
side-effects, are potent M3R antagonists. Pancreatic M3Rs regulate the glucose-stimulated
cholinergic pathway of insulin secretion; their activation on -cells stimulates insulin
secretion, while M3R blockade decreases insulin secretion. Genetic modification of M3Rs
causes robust alterations in insulin levels and glucose tolerance in mice. Olanzapine alters
M3R density in discrete nuclei of the hypothalamus and caudal brainstem, regions that
regulate glucose homeostasis and insulin secretion through vagal innervation of the
pancreas. Furthermore, studies have demonstrated a dynamic sensitivity of hypothalamic
and brainstem M3Rs to altered glucometabolic status of the body. Therefore, the M3R is in a
prime position to influence glucose homeostasis through direct effects on pancreatic -cells
and by potentially altering signaling in the hypothalamus and brainstem. SGA-induced
insulin dysregulation may be partly due to blockade of central and peripheral M3Rs,
causing an initial disruption to insulin secretion and glucose homeostasis that can
progressively lead to insulin resistance and diabetes during chronic treatment. 279
One of the drugs that has been prescribed for MDL over a long period of time is olanzapine.
Olanzapine works by blocking the receptors in the brain on which dopamine acts. It
increases the concentrations of the dopamine metabolites DOPAC and HVA in striatum

277

Goswami, NN; Gandhi, AM: Patel, PP & Dikshit, RK. An evaluation of the metabolic effects of
antipsychotic medications in patients suffering from psychiatric illness. Journal of Applied
Pharmaceutical Science Vol. 4 (04), pp. 014-019, April, 2014. Available online at
http://www.japsonline.com DOI: 10.7324/JAPS.2014.40403 ISSN 2231-3354

278

OBrien, PL; Cummings, N; & Mark, TL. Off-Label Prescribing of Psychotropic Medication, 2005
2013: An Examination of Potential Influences. Psychiatric Services, November 9, 2015;
Published online: January 17, 2017.

279

Weston-Green, K; Huang, X; & Deng, C. Second Generation Antipsychotic-Induced Type 2

Diabetes: A Role for the Muscarinic M3 Receptor. CNS Drugs; October 2013.

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and nucleus accumbens. In addition it antagonizes the pergolide-induced decrease of
striatal DOPA concentrations in rats treated with gammabutyrolactone and NSD1015 and
increased striatal 3-methoxytyramine concentrations in nomifensine-treated rats (but not
after gammabutyrolactone administration), suggesting that olanzapine blocks terminal and
somatodendritic autoreceptors on dopamine neurons. These findings provide evidence
that olanzapine antagonizes dopamine, serotonin, -adrenergic and muscarinic receptors
in vivo, consistent with its high affinity for these receptor sites in vitro.280 There are therefore
cognitive impairments that can be observed in cases where there is disturbed dopamine
transmission as a result of antipsychotic drug treatment.281 Veselinovi et al show in their
findings that modulation of dopaminergic systems affects primarily the speed of information
processing, attention and learning. This would seem to be a contrary support mechanism
for those with learning disability and should not be prescribed unless they advantages
outweigh the disadvantages.
This situation can easily be made worse if olanzapine is prescribed as part of an
antipsychotic polypharmacy. (APP) Pre-clinical studies underpinning neurobiological
hypotheses in APP are lacking. Evidence supporting the efficacy of APP is limited with
modest beneficial clinical relevance. APP is associated with several serious adverse effects
and increased health costs. In the absence of more convincing pre-clinical support and
clinical evidence, van Bennekom et al advise adherence to existing guidelines and limiting
combinations of antipsychotics (in consideration with other pharmacotherapeutic, somatic
and psychotherapeutic options) to patients with clozapine-refractory psychosis in wellevaluated individual trials that might need 10 weeks or more.282 There is much evidence
that olanzapine gives rise to Extrapyramidal symptoms. Hill et al put the risk at about 910%283; this was confirmed by Woerner et al. 284
It is interesting to note that patients do not always have the same perceptions about the
risks of using drugs as healthcare professionals. In a study of 400 health-care professionals
(278 general practitioners, 76 pharmacists, and 46 pharmaco-vigilance professionals) and
153 non-professionals, the healthcare professionals ranked anticoagulants and antiinflammatory drugs as carrying the highest risk in a list of 13 categories; psychotropic drugs

Bymaster, FP; Hemrick-Luecke, SK; Perry, KW; & Fuller, RW. Neurochemical evidence
for antagonism by olanzapine of dopamine, serotonin, 1-adrenergic and muscarinic
receptors in vivo in rats. Psychopharmacology; Volume 124, Numbers 1-2, 87-94, DOI:
10.1007/BF02245608.
280

281
Veselinovi, T; Schorn, H; Vernaleken, IB; Hiemke, C; Zernig, G; Gur, R; & Grnder,G.
Effects of antipsychotic treatment on cognition in healthy subjects. J Psychopharmacol
April 2013 vol. 27 no. 4 374-385.

van Bennekom, MWHL; Gijsman, HJ; & Zitman, FG. Antipsychotic polypharmacy in
psychotic disorders: a critical review of neurobiology, efficacy, tolerability and cost
effectiveness. J Psychopharmacol April 2013 vol. 27 no. 4 327-336.

282

Hill AL; Sun B; & McDonnell DP. Incidences of Extrapyramidal Symptoms in Patients
with Schizophrenia after Treatment With Long-Acting-Injection (Depot) or Oral Formulations
of Olanzapine. Clin Schizophr Relat Psychoses. 2013 Feb 21:1-23.

283

Woerner, MG; U Correll, CU; Alvir, JMJ; Greenwald, B; Delman, H; & Kane, JM.
Incidence of Tardive Dyskinesia with Risperidone or Olanzapine in the Elderly: Results from a
2-Year, Prospective Study in Antipsychotic-Nave Patients. Neuropsychopharmacology
(2011) 36, 17381746.
284

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(sleeping pills and tranquillisers) were next. In contrast, the non-professionals ranked the
psychotropic drugs (sleeping pills, tranquillisers, and antidepressants) highest.285
(See Fear Conditioning - p 132 and Sleep - p 143)
MDLs pattern of deterioration has developed markedly since 2004 and it will require the
diminution of medication and an improvement in MDLs social environment before it can be
seen if there are prospects of recovery.
She has been seriously affected by ill-thought-out changes to her home life and by
interference to her life in general by those who have no knowledge of the effects that such
changes can have. Environmental security and familiarity are very important stabilising
components in the life of someone with MDLs type of brain injury. Cognition, learning and
the retrieval of learned memories are degraded dramatically by removing them to strange
situations; particularly if this also involves a change of carers and others who are important
persons in their lives.
In clinical neuro-psychology, the environmental context in which learning occurs can be a
very important factor that affects retrieval in humans and other animals and much debate
has centred on whether the brain is more likely to degenerate following adverse
environmental changes. Placing the subject back into the same context in which the
original learning occurred can greatly facilitate retrieval. The very well-known effects of
context in the human memory literature can arise in a very simple way.
An implication of this explanation is that context effects will be especially important at late
stages of memory or information processing systems in the brain for the information from a
wide range of modalities will be mixed; some of that information could reflect the context
in which the learning takes place. One part of the brain where such effects may be strong
is the hippocampus, which is implicated in the memory of recent episodes, and which
receives inputs derived from most of the cortical information processing streams, including
those involved in space286.
There is a popular belief that an active mental life may delay the cognitive deterioration
associated with normal aging. Animal studies also support the concept that environment
can influence brain development 287. It is therefore of considerable importance to MDL that
her environment supports all of her potential activities and that nothing is done that subverts
that aim.
It is to the carers advantage to know how to keep MDL happy and to gain her confidence.
A good carer will become a communication exchange wherein she will understand MDLs
unspoken demeanour and she will find the ways to explain things to MDL so that there is an
avoidance of confrontation. MDL has had to learn some self-protection strategies over the
years and most of these involve closing down rather than opening up. Carers have to find
ways of letting MDL find peace with herself because only through that will she become
settled in her environment. When she is at peace she will be quiet and unobtrusive, getting

285

Talbot, J. & Aronson, JK. (Eds) Stephens Detection and Evaluation of Adverse Drug
Reactions: Principles and Practice, Sixth Edition. [In Process to be published 2012] John
Wiley & Sons, Ltd.

286

Rolls, ET. Memory, Attention and Decision-making: A unifying computational neuroscience

approach. OUP; Oxford; 2008 (pp 568-569)

287

Ostrosky-Sols, F. Can Literacy Change Brain Anatomy? International Journal of Psychology,

Psychology Press; June 2004; ISBN: 978-1-84169-968-4

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on with her own activities. It is only when she becomes anxious and uncertain that she
takes refuge in perseveration.

_______

SEMANTIC MEMORY IMPAIRMENTS

The term semantic memory refers to our general knowledge of the objects, people, and
events of the world288. The facts that Paris is the capital of France, birds have feathers, and
a desk is a piece of furniture, are examples of semantic memory. More particular
knowledge, tied to an individual's personal experience, is considered episodic memory
rather than semantic memory. Examples of the episodic memory include the facts that
you bought this book at a certain store or ate a certain food for breakfast this morning.
Neurologic disease and damage can affect semantic memory disproportionately.
Semantic memory is at least partially dissociable from other forms of memory, language,
and cognition, generally as a result of degenerative diseases. It appears to depend on the
temporal cortex, with some degree of lateralization to the left being suggested.289
The information about episodic events recalled from the hippocampus is seen to be used
to help form semantic memories. For example, remembering many particular journeys
could help to build a geographic cognitive map in the neocortex. The hippocampus and
neocortex would thus be complementary memory systems, with the hippocampus being
used for rapid, on the fly, unstructured storage of information involving activity potentially
arriving from many areas of the neocortex; while the neocortex would gradually build and
adjust, on the basis of much accumulating information, the semantic representation.290
In some cases it appears that knowledge from certain semantic categories is
disproportionately impaired, suggesting that the neural bases of semantic memory are
subdivided by semantic category. Category-specific semantic memory impairments are
sometimes confused with category-specific impairments in name retrieval and visual
recognition. The face-specificity of prosopagnosia (see, p 87) affects visual recognition
only. In contrast, category-specific semantic memory impairments are manifest in all tasks
that require knowledge of the object, whether they involve vision, language, or other
modalities of stimulus and response. The most common category-specific semantic
memory impairment affects knowledge of living things.
Yim et al in studying the relationship between facial affect recognition and cognitive
functioning after traumatic brain injury, concluded that: impairment in several cognitive
processes may contribute to facial affect recognition deficits in TBI, in particular non-verbal
memory, working memory and speed of processing. Furthermore, executive
functioning may not be a critical factor in facial affect recognition, but would
most likely be important in deciding what to do once facial affect is perceived. 291 (See

288

Tulving E. Episodic and semantic memory. In, Tulving E, Donaldon W (eds): Organization of
Memory. New York: Academic Press, 1972.

289

Farah, MJ & Grossman, M. Semantic Memory Impairments. In Feinberg, T E & Farah, M J.

Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

290

Rolls, ET. Memory, Attention and Decision-Making. OUP; 2008.

291

Yim J; Babbage DR; Zupan B, Neumann D & Willer B. The relationship between facial affect
recognition and cognitive functioning after traumatic brain injury. Research Reports -Brain
Injury 27(10):1155 (2013) PMID 23895556.

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page 51 for factors that might be introduced in order to try and improve cognitive
functioning.)
The first report of impaired knowledge of living things was made by Warrington and
Shallice292, who described three patients who had survived herpes encephalitis. Although
the patients were impaired across the board at tasks such as picture naming and defining
words, they were dramatically worse when the pictures or words represented animals and
plants than when they represented artefacts. In subsequent years numerous other reports
appeared of similar cases, generally suffering damage to temporal cortex from herpes
encephalitis, closed head injury or, less frequently, cerebro-vascular or degenerative
disease. Category-specific disorders of semantic memory are distinct from the disorders
related to amnesia, despite the implication of temporal brain regions in both.
Building on the hypothesis of Allport293, that semantic memory is subdivided into different
sensori-motor modalities (e.g., visual knowledge, tactile knowledge, and motor knowledge;
Warrington and Shallice (1984, idem) proposed a different kind of alternative explanation
for category-specific knowledge deficits. They suggested that living and non-living things
may differ from one another in their reliance on knowledge from different sensori-motor
modalities, with living things being known predominantly by their visual and other sensory
attributes.
Impaired knowledge of living things could result from an impairment of visual knowledge.
Similarly, non-living things might be known predominantly by their function, an abstract
form of motoric representation, and impaired knowledge of non-living things could result
from an impairment of functional knowledge. This interpretation has the advantage of
parsimony, in that it invokes a type of organization already known to exist in the brainmodality-specific organization rather than invoking an organization based on semantic
categories such as aliveness.
The idea that certain brain regions are specialized for representing knowledge about living
things has naturally aroused some scepticism and prompted a search for alternative
explanations of apparently impaired knowledge of living things. The simplest alternative
explanation is that the impairment is an artefact of the greater difficulty of retrieving
knowledge about living things. It has been suggested that when difficulty is equated across
living and non-living test items, the selectivity of the semantic memory impairment
disappears. 294,295 However, the selectivity has also been shown to be reliable in two cases
when multiple measures of difficulty are accounted for296.

_______

292

Warrington EK& Shallice T. Category specific semantic impairments. Brain 107:829-854, 1984.

293

Allport DA. Distributed memory, modular subsystems and dysphasia, in Newman S, Epstein R
(eds): Current Perspectives in Dysphasia. Edinburgh: Churchill Livingstone, 1985.

294

Funnell E & Sheridan J. Categories of knowledge? Unfamiliar aspects of Jiving and non-living
things. Cogn Neuropsychol9:135-154, 1992.

295

Stewart F; Parkin AJ & Hunkin NM. Naming impairments following recovery from herpes
simplex encephalitis: Category specific? Q J Exp Psychol 44A:261-284, 1992.

296

Farah MJ; McMullen PA & Meyer MM. Can recognition of living things be selectively
impaired? Neuropsychologia 29:185-193, 1991.

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Elements of Language and Communication

As a result of the fundamental discoveries of Broca and Wernicke that focal lesions in the
left hemisphere cause spectacular deficits in the verbal aspects of language, clinical
studies of human communication have, for the most part, focused on the aphasias. These
studies led to the (then) widely held belief that language is a dominant function of the left
hemisphere, with the right hemisphere being relegated to a minor or non-dominant role
in language and behaviour.
Brocas aphasia arises from a lesion in areas on the left hemisphere and leads to non-fluent
speech, agrammatism, paraphasias, anomia, and poor repetition. Lesions anterior,
superior, and deep to (but sparing) the Broca area produce abnormal syntax and
grammar but repetition and automatic language are preserved. This disorder is known as
transcortical motor aphasia and uninhibited echolalia is common. Memory disturbances
only develop with lesion extension into the septal nucleus of the basal forebrain.
Appreciation of verbal humour is most impaired in right frontal polar pathology297. (See also
page 32) MDL has shown regular episodes of echolalia but these disappear when she is
functioning at her best. It is also interesting that during conversations when she makes a
comment your reply must use the words that she has used or she will repeat what she has
said.
Over the last three decades, however, considerable evidence has accrued to support the
thesis that communication functions are distributed between the hemispheres298. The left is
primarily concerned with processing the verbal, syntactic, and other language-related
functions such as pantomime, pragmatics, denotation, and the linguistic and dialectal
aspects of prosody299, while the right is primarily concerned with processing affective
prosody, gestures, and certain word-related functions such as connotation, thematic
inference, and comprehension of non-literal phrases and complex linguistic relations.
In addition, both focal cerebral blood flow and positron emission tomography scanning
studies have established an active role for the right hemisphere in language. The most
intensively analyzed right hemispheric function has been affective prosody and gestures.
(Which MDL lacks.)
Language and communication are characterized by four major constituents: the lexicon
(vocabulary), syntax (grammar), prosody, and kinesics. The segment is the smallest
articulated feature of a language, which, in nontechnical terms, is most closely allied with
the syllable. Segments, therefore, might be thought of as the primary building blocks for
creating the words that form the lexicon. Words, in turn, are concatenated into

297

Price, BH; Daffner KR; Stowe RM & Mesulam, MM. The comportmental learning disabilities of
early frontal lobe damage. Brain: a journal of neurology, Vol. 113 (Pt 5) (October 1990), pp.
1383-1393.

298

Ross, ED. The Aprosodias. . In Feinberg, T E & Farah, M J. Behavioural Neurology and
Neuropsychology. McGraw-Hill, New York, 1997.

299

PROSODY is a non-verbal or supra-segmental feature of language that conveys various levels

of information to the listener, including linguistic, affective (attitudinal and emotional),
dialectical, and idiosyncratic data. The acoustical features underlying prosody include pitch,
intonation, melody, cadence, loudness, timbre, tempo, stress, accent, and pauses. Although
the pre-eminence of the propositional aspects of language is well accepted, developmental
studies have established that the earliest building blocks of language are prosodicintonational rather than verbal-segmental features. As children acquire the verbal-segmental
features of language, prosodic phenomena eventually become embedded and carried by
the articulatory line.

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grammatical relationships to form phrases, sentences, and discourse. It is the segmentally
related or verbal-propositional features of language that are primarily disrupted by focal
left-brain injury, thus causing aphasic syndromes. Kinesics refers to the limb, body, and
facial movements associated with language and communication. (Ross, 1997, idem)
Disturbances in the production and comprehension of pantomimal kinesics have been
firmly linked to left brain damage. All studies to date have found that disorders of
pantomime are almost always due to LBD, resulting in aphasic disturbance.
In case that should tempt one to consider that relationship to MDLs brain damage and may
be puzzled by why MDLs behaviour seems paradoxical in those respects, it should be
remembered that some of her lacks in prosody and kinesics may have arisen because of
the very early time in her life when her brain damage occurred and the fact that she did not
have the opportunity to learn these important characteristics of language because she
lacked the usual interaction with normal children of comparable age. Indeed it is salutary
to recognise that when such interaction did take place, through very limited opportunities,
other children sensed her difference and, unconsciously perhaps, her communicative
immaturity and conducted their communication with her in a selective and elementary
manner in much the same way that adults do with toddlers.
Another confounding factor though is that as a child she would sit by her mother as she
played the piano and sing songs that she read from the music sheet having picked up the
tune by ear. It should also be added that MDL was introduced to the sound of music both
instrumental and voice from a very early age; indeed from before her brain damage
occurred. It is only since 2004 that MDLs response to music has changed. Quite often now
she does not want to listen to music or song. Music that at one time entertained her and
which she enjoyed listening to now frequently produces tears. It is interesting to wonder
why.
Adolphs and others tell us that in humans, the emotional reactions that can be triggered by
stimuli also play a role in complex aesthetic judgements. Building on lesion studies that
have shown dissociations between identifying melodies or recognizing emotion from
music300, a recent functional imaging study found that highly emotional music, which
resulted in shivers down the spine in the listener, activated a set of para-limbic structures
including the ventral striatum, amygdala, and orbitofrontal cortex301. Just how to
categorize the emotion triggered by such stimuli remains a challenging issue, as it appears
distinct from mere happiness302.
Gestural kinesics has not been well studied neurologically until fairly recently, although
occasionally clinical researchers have mentioned that gestural activity may be preserved in
aphasic patients.303,304 The first paper to specifically address the possible relationship of
gestures to right brain damage and loss of affective prosody was published in 1979 by Ross

300

Peretz I. Brain specialization for music. New evidence from congenital amusia. Ann N Y Acad
Sci 2001, 930:153-165.

301

Blood AJ & Zatorre RJ. Intensely pleasurable responses to music correlate with activity in brain
regions implicated in reward and emotion. Proc Natl Acad Sci USA 2001, 98:11818-11823.

302

Adolphs, R. Neural systems for recognizing emotion. Current Opinion in Neurobiology 2002;
Apr; 12(2): 169-77.

303

Critchley M. The Language of Gesture. London: Edward Arnold, 1939.

304

Hughlings-Jackson J. On affections of speech from diseases of the brain. Brain 38:106-174,

1915.

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and Mesulam305. They observed that lesions of the right frontal operculum may cause
complete loss of spontaneous gestural activity in the non-paralyzed right face and limbs
without any disturbance in praxis. The suggestion was made, therefore, that the gestural
behaviour as opposed to pantomime was a dominant function of the right hemisphere.
Since then a number of studies have lent further support to this hypothesis by showing that
the right hemisphere is specialized not only for producing gestures but also for comprehending their meaning. (Ross, 1997, idem) MDL does not use gestures to convey
meaning nor does she seem to understand any that are made by others.
Gesture can be as affected as language in cases of autism because all the
communicative skills are diminished. When evaluating the problems found in autism there
are studies showing that language and gesture may be mediated by common neural
systems.306 Language and gesture milestones advance together in typical children growing
up. It has been shown that there is a close correlation between the first word production
and what is called "gestural naming," usually in the 12 to 18 month age group.307 In studies
of young autistic children, word production does not begin until recognitory gestures have
appeared.308
Further evidence for language-gesture links in early development comes from a study of
handedness, which shows a right-hand bias in typical children before they begin to speak;
the right-handed bias is greatest for gestures with communicative or symbolic content.309
In infants, linguistic knowledge is not thought to be innate and is not localized in a clear and
compact place in the brain, but the infant brain is not a tabula rasa either: it is already
highly differentiated at birth, and certain regions are biased from the beginning toward
modes of information processing that are particularly useful for language. (Coleman, Idem,
2005) However, if there is a developmental problem, the infant brain is thought to be highly
plastic, which permits alternative brain plans for language to emerge if the standard
situation does not hold.310 Since social interaction with another human being affects
speech learning, children with autism are at risk especially if they prefer non-speech signals
to "motherese."
Some mute individuals with autism clearly have an oral dyspraxia; they have hypomobile,
atrophic tongues, suggestive of cranial nerve involvement. But the neural networks that
control speech are difficult to evaluate in mute patients with autism. Perhaps one reason
there is so little consistent work is that the circuits underlying vocal control are extremely
complex. They consist of essentially three components: laryngeal activity, supralaryngeal
(articulatory) activity, and respiratory movements.311

305

Ross ED & Mesulam MM. Dominant language functions of the right hemisphere? Prosody and
emotional gesturing. Arch NeuroI36:144-148, 1979.

306

Bates E. & Dick F. Language, gesture and the developing brain. Developmental Psychobiology 40:293-31: 2002.

307

Coleman, M. Other Neurological Signs & Symptoms in Autism. In, The Neurology of Autism.
Mary Coleman [Ed.]. New York, OUP; 2005

308

Happe F. & Frith U. The neuropsychology of autism. Brain 119:1377-1400; 1996.

309

Bates E; O'Connell B; Vaid J; Sledge P & Oakes L. Language and hand preference in early
development. Developmental Neuropsychology 2:1-5; 1986.

310

Bates E. Language and the infant brain. Journal of Communication Disorders 32:195205; 1999.

311

Jurgens U. Neural pathways underlying vocal control. Neuroscience Biobehavioral Review

26:235-258; 2002.

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Voluntary control of vocalization, in contrast to involuntary vocal reactions such as shouts of
pain, require the forebrain to be intact. The motor neurons controlling vocalization are
located in nuclei of the pons, medulla, and ventral horn of the spinal cord and need
facilitation and coordination by many additional nuclei ranging from the supplementary
motor area of the frontal lobe all the way down to the cerebellum. (Coleman, Idem, 2005)
MDL has abnormal reaction to painful events and there isnt normally a shout that can be
interpreted as a verbal one. There may be a grunt or series of grunts or, at worst a pretend,
momentary cry.
Although Hughlings-Jackson suggested over a hundred years ago that the right hemisphere
may have a dominant role in emotional communication, the first clinical study of affective
prosody was published in 1975 by Heilman and co-workers312. They assessed the ability of
patients with right and left hemispheric strokes in the posterior sylvian distribution to
recognize the affective content of verbally neutral statements that were spoken with
various emotional intonations. Right brain-damaged patients were markedly impaired on
the task as compared with normals and mildly aphasic left-brain-damaged patients. In a
follow-up study, Tucker and colleagues 313 found that right but not left-brain-damaged
patients also had great difficulty in inserting affective variation into verbally neutral
sentences on request and on a repetition task.
In 1979, Ross and Mesulam (idem) described two patients with infarctions of the right
anterior supra-sylvian region verified by computed tomography. Neither patient was
aphasic or apraxic, but both complained bitterly of their almost total inability to insert
affective variation into their speech and gestural behaviour. Neither patient seemed to
have difficulty in perceiving affective displays in others, and both insisted that they could
feel and experience emotions inwardly.
Based on these patients and the previous publications by Heilman and associates it was
hypothesized that:
1. the right hemisphere was dominant for organizing the affective-prosodic
components of language and gestural behaviour and,
2. the functional/anatomic organization of affective language in the right hemisphere
was analogous to the organization of propositional language in the left hemisphere.
(Ross, 1997, idem)
An issue not resolved however, was whether the prosodic deficits from right brain damage
also involved the linguistic aspects of prosody. Subsequent studies have looked more
carefully at this issue in both right- and left brain-damaged patients. The composite data
indicate that the linguistic features of prosody may be impaired by either right or left brain
damage but that the affective components seem to be disrupted exclusively by right brain
damage. (Ross, 1997, idem)
MDL has no spontaneous gestural activity; there is a loss of affective prosody in her speech
and she does not produce gestures and probably has difficulty comprehending their
meaning in most cases.

312

Heilman KM; Scholes R & Watson RT. Auditoryaffective agnosia: Disturbed comprehension of
affective speech. J Neurol Neurosurg Psychiatry 38:69-72,1975.

313

Tucker DM; Watson RT & Heilman KM. Discrimination and evocation of affectively intoned
speech in patients with right parietal disease. Neurology 27:947-950, 1977.

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All prosodic systems and not just affective prosody are modulated by the right brain.
Acquired aprosodias in children314 and developmental disorders of affective prosody
associated with aberrant psychosocial development resulting from early right brain damage315,316,317 have been reported that are comparable with the syndromes of acquired
aphasia in children and developmental dyslexia. However, although others have shown
disturbances in the production and comprehension of affective prosody in LBD, it is still
generally maintained that it is the dominant function of the right brain.
Ross and colleagues (Idem) added to this affirmation by assessing affective prosody in a
series of right-brain-damaged and left-brain-damaged patients using a quantitative testing
paradigm in which the verbal-articulatory demands were progressively reduced by using
token sentences in which various emotions are carried by words, a repeated monosyllable
("ba ba ba ba ba ba"), and an asyllabic articulation ("aaaaaahhhhhhh"). In the left-braindamaged patients, reducing the verbal-articulatory load caused statistically robust
improvement in their ability to comprehend and produce affective prosody on a repetition
task, whereas no improvement occurred in the right-brain-damaged patients. These
findings, therefore, sustain the hypothesis that affective prosody is both a dominant and a
lateralized function of the right hemisphere and lend strong support to research by Blonder
and co-workers (1991, idem) and Bowers and associates (1993, idem) & 318 suggesting loss
of affective-communicative representations caused by right brain damage as the
theoretical basis for the aprosodias, similar to loss of verbal-syntactic representations
caused by left brain damage as the theoretical basis for the aphasias 319.
The aprosodias represent disturbances of graded emotional behaviour encompassing both
affective prosody and gestures. These behaviours are organized predominantly at the level
of the neocortex as part of the language-related systems of communication. (Ross, 1997,
idem)

Aspects of Aphasia & Agraphia that affect MDL

Aphasia

is a condition characterized by either partial or total loss of the ability to

communicate verbally or by using written words. A person with aphasia may have difficulty
speaking, reading, writing, recognizing the names of objects, or understanding what other
people have said. Aphasia is caused by a brain injury, as may occur during a traumatic
accident or when the brain is deprived of oxygen during a stroke. It may also be caused
by a brain tumour, a disease such as Alzheimer's, or an infection like encephalitis (as in
MDLs case). Aphasia may be temporary or permanent. Aphasia does not include speech
impediments caused by loss of muscle control. [Verbal/Speech apraxia is a speech

314

Bell WL; Davis DL; Morgan-Fisher A & Ross ED. Acquired aprosodias in children. J Child Neurol
5:19-26, 1989.

315

Weintraub S & Mesulam MM. Developmental learning disabilities of the right hemisphere:
Emotional, interpersonal, and cognitive components. Arch NeuroI40:463-468, 1983.

316

Manaoch DS; Sandson TA & Weintraub S. The developmental social-emotional processing

disorder is associated with right hemisphere abnormalities. Neuropsychiatr Neuropsychol
Behav Neurol 8:99-105, 1995.

317

Voeller KKS. Right hemisphere deficit syndrome in children. Am J PsychoI143:1004-1009, 1986.

318

Bowers D; Bauer RM & Heilman KM. The nonverbal affect lexicon: Theoretical perspectives
from neuropsychological studies of affect perception. Neuropsychology 7:433-444, 1993.

319

Ross ED; Stark RD & Yenkosky JP. Lateralization of affective prosody in brain and the callosal
integration of hemispheric language functions. Brain Lang. 1997; 56:27-54.

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disturbance in which language comprehension and muscle control are retained, but the
memory of how to use the muscles to form words is not.]
Language comprehension is a complex process that involves the analysis of the acoustic
and phonologic properties of input as well as the recognition of syntactic and lexical
elements. 320 This rapid parallel processing of input and matching it to linguistic precepts is a
dominantly left hemispheric function, although the right hemisphere has been shown to
recognize words and syntax to a certain degree. 321,322 Wernicke has postulated that the
auditory association area plays a monitoring role in language output and that its damage
results in paraphasic, faulty speech.
In the past 20 years, fresh interest has come to clinical aphasia research from two
directions: modern neuro-imaging and cognitive neurosciences. Together, they have
additionally provided tools to carry out aphasia-related language experiments in normal
brains. Furthermore, old questions such as cerebral laterality, the influence of handedness,
the effects of gender and bilingualism on aphasia, and the mechanisms of recovery have
been re-explored. 323
The description of syndromes of aphasia arose out of much the same motivation as the
identification of other clinical neurologic syndromes; the need to identify clinically useful
associations between specific clusters of signs and the likely anatomy of the lesion
producing them. The most clinically transparent signs of aphasia have generally been
taken to be independent signs of brain damage. Thus, syndromes have been constructed
out of reduced language output as well as impaired comprehension, repetition, and
naming. Disorders of written language have been divided into additional syndromes only
as reading and writing have been impaired beyond spoken language impairments. Using
three independent signs will generate eight syndromes, assuming naming to be impaired in
all aphasics. (Alexander idem)
The series of MDLs preserved handwriting and typing examples show a clear deterioration
in her writing since 2004. These problems include not only her ability to write words and
sentences but also to do so in straight lines that are evenly written on the page. She cannot
now draw a straight line or draw a simple shape of an object that has been placed next to
her writing paper. Her attempts at drawing presently consists of continuous spiralling circles
whatever it is that she has been invited to draw.
She has not been able to use her typewriter since 2004 because of the effects of her
experiences since that time. When she was able to do so, her typing was efficient.
However, over time she appeared to lose the ability to start a new line appropriately. Prior
to that she could copy type very well, and would correct her spelling mistakes by using the
back-key, putting a forward slash through the incorrect letter and then typing the correct
one.
MDL learned to type at her first school from the age of about five. She had her own
typewriter both at school and at home where she was always happy to entertain herself

320

Liebermann AM; Cooper FS; Shankweiler DR & Staddert-Kennedy M. Perception of the speech
code. Psychol Rev 74:431-461,1967.

321

Zaidel E. Auditory vocabulary of the right hemisphere following brain bisection or

hemidecortication. Cortex 12:191-211, 1976.

322

Moscovitch M. Right hemisphere language. Top Lang Disord 1:41-61, 1981

323

Alexander, M P. Aphasia: Clinical and Anatomic Aspects. In Feinberg, T E & Farah, M J.

Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

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copy-typing from books and magazines. She could also make up very simple stories (one
or two line) and type them as she did so.
This ability that has been lost (hopefully temporarily) shows the amount of deterioration over
the last few years.

Some areas of aphasia that have affected MDL are:

Reduced language output
Impaired comprehension
Repetition
Naming
Also, disorders of written language where reading and writing have been impaired beyond
the spoken language impairments.
She also seems to have apraxic agraphia she cannot achieve oral spelling.
For the 10 percent of the population that is left-handed and for the approximately 2 to 5
percent of the right-handed population that becomes aphasic after a right-brain lesion
(crossed aphasia), some modifications of the clinical rules are required. (MDL is righthanded and has a right brain lesion.)
For left-handers, the phenomenology of aphasia is complicated by the very issue of lefthandedness. More than right-handers, all left-handers are not created equal; they vary
greatly in degree and nature of hemispheric specialization for language. For both
populations the phenomenology is further complicated by irregularities in lateral
dominance for other typically lateralized functions, such as praxis 324 and some aspects of
visuo-spatial function.

Brocas Aphasia
Many of the aspects of this condition fit MDLs reduced
communication skills. In Broca's aphasia, language output is non-fluent that is, it is
reduced in phrase length and grammatical complexity. This reduction can range from no
recognizable output or repeated meaningless utterances to short, truncated phrases using
only the most meaning-laden words (substantives). There is usually considerable hesitation
and delay in production. Speech quality is impaired. Articulation is poor (dysarthria325).
Melodic line is disrupted (dysprosody 326), partly due to dysarthria but often more than just
secondary to it. Volume is usually reduced at first (hypophonia). With time, speech takes
on hyperkinetic (dystonic and spastic) qualities. Language comprehension is adequate
although rarely normal. Response to word recognition tasks, simple commands, and
routine conversation is generally good. Response to multistep commands and complex
syntactical requests is generally poor. Repetition is poor, although often better than
speech. Relational words (functors articles, conjunctions, modifiers, etc.) may be
produced in repetition, but they are exceedingly uncommon in spontaneous speech.

324

Praxis is the process by which a theory, lesson, or skill is enacted, practised, embodied, or
realized. It may also refer to the act of engaging, applying, exercising, realizing, or practising
ideas.

325

Dysarthria is a speech disturbance caused by lack of control over the muscles used in
speaking, perhaps due to nerve damage, but also it can be caused by the effects of some
psychotropic medications.

326

Dysprosydy is a change in voice quality that gives rise to a foreign-accent syndrome.

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Written language parallels the spoken, although some patients, while never regaining useful
speech, develop writing that is telegraphic. Naming is usually poor, but it may be
surprisingly good in chronic patients. All types of errors can occur, although semantic errors
are most typical for substantive words. 327 Objects are frequently named better than are
actions.
Broca's aphasia is commonly accompanied by: bucco-facial apraxia328, and ideomotor
apraxia329 of the left arm (or both arms in the non-paretic case). MDL has failings in these
areas. Many patients have fractional syndromes of Broca's aphasia. Because all of these
fractional disorders are still taxonomically closer to Broca's aphasia than to any of the other
seven classic diagnoses, many aphasia systems will classify them all as Broca's aphasia.330
Broca's aphasia has been associated with lesions from several structures outside Broca's
area. Involvement of only Broca's area is usually followed by good recovery331. Recovered
Broca's aphasics often regain their fluency and syntax, but articulatory and prosodic
aspects of language may remain affected and the clinical condition widely known as
verbal apraxia continues. 332 (But these relate to late onset injury)
Kertesz et al evaluated lesion location in Broca's aphasics who were divided at the median
for poor and good recovery. In both groups, certain structures showed significant
involvement (more than 50 percent). These were the inferior frontal gyrus, especially the
pars opercularis and triangularis, and the insula. The difference between patients with
persisting Broca's aphasia and those who show good recovery was most prominent in the
involvement of the pre-central, post-central, and supra-marginal gyri in the cases of poor
recovery. The sub-cortical regions showed significant differences in the involvement of the
putamen and the caudate, which was twice as frequent in the persistent cases. 333
In analyzing reports of Broca's aphasia, it is crucial to understand the taxonomic rules of the
report's assessment tool. If all fractional cases are considered Broca's aphasia, the clinicoanatomic correlations will seem imprecise. This is an example of the difficulty inherent in
building syndromes with polytypic qualities. Analysis of the clinico-anatomic relationships
within these fractional cases may be much more informative than lumping them all
together on the basis of some overlap with the full syndrome. (Alexander idem)

Transcortical Aphasia

There is a possibility of MDL having this condition but

there is a need for further investigation as the literature seems to be based entirely on a

327

Ardila A. & Rosselli M. Language deviations in aphasia: A frequency analysis. Brain Lang
44:165-180, 1993.

328

Bucco-facial or orofacial apraxia. Difficulty carrying out movements of the face on demand.
For example, an inability to lick one's lips or whistle.

329

Ideomotor Apraxia is a neurological disorder characterized by the inability to correctly

imitate hand gestures and voluntarily pantomime tool use, e.g. pretend to brush one's hair.

330

Mazzocchi F. & Vignolo LA. Localisation of lesions in aphasia: Clinical-CT scan correlations in
stroke patients. Cortex 15:627-654, 1979.

331

Mohr JP. Broca's area and Broca's aphasia, in Whitaker H, Whitaker HA (eds): Studies in Neurolinguistics. New York, Academic Press, 1976, vol 1, pp 201-235.

332

Kertesz A. Aphasia and Associated Disorders: Taxonomy, Localization and Recovery. New
York, Grune & Stratton, 1979.

333

Kertesz, A. What do we learn from recovery from aphasia? In Waxman, SG (ed). Advances of
Neurol ogy. Functional Recovery in Neurological Disease. New York, Raven Press, 1988, vol 47 ,
pp 277 -292.

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subject population that had normal brain development prior to a trauma.
The syndrome includes the possibility of associated motor deficits depending upon the site
of the lesion. Those with cortical or sub-cortical lesions seem to have a fundamental deficit
in generative language tasks, i.e. they lack capacity to generate complex syntax when
asked an open-ended question. They do not have timely access to the range of syntax
needed to answer the question.
Patients with transcortical sensory aphasia who have semantic jargon usually have far more
posterior lesions, usually in the watershed area between the middle cerebral and posterior
cerebral circulation. 334 These patients are distinguished by preserved repetition.
Sometimes the term semantic aphasia is applied to patients with similar behaviour.
Recovery is usually rapid unless the syndrome evolves from a more severe lesion initially
producing Wernicke's aphasia. Mixed transcortical aphasia has features of both the motor
and sensory symptoms and tends to have a poor prognosis, with non-fluency persisting and
not all comprehension returning, depending on the aetiology. It occurs relatively
uncommonly and the recovery patterns have not been described extensively (Kertesz
idem).
Most of Alexanders research was based on information from the investigation of stroke
patients but there are some parallels to be drawn in MDLs case and those of Brocas and
Transcortical Aphasia are the ones that seem most relevant to her behaviour. The only
reference to encephalitis is to do with that following herpes simplex and that is not helpful in
understanding MDLs case.
It is important to remember that in MDLs case:
1. Her age at which her brain damage occurred
2. That her linguistic ability has been much better than it is now and this may well be
due to the effects of further brain damage.
3. That her present linguistic ability is affected by a lack of concentration and
sometimes it seems by tiredness.
It must be remembered that we all perform better in ideal circumstances even in the
things in which we show proficiency. In this context MDL has suffered the trauma of an
instantaneous removal from her homes; transferred in her environment to places that are
strange; to be cared for by people she did not know. Those conditions are bad enough
and will challenge even someone who knows the reasons. Imagine the psychological
effect on someone who does not understand why and who cannot ask why because asking
requires rationality and an understanding of other people and their motives. MDL has
neither of these attributes and she continues to suffer from the loss of her cultural milieu.

Recovery After Aphasia

Kertesz writes on Recovery after Aphasia335 but this

relies on subject research with those who already had normal linguistic capability before

334

Kertesz A; Sheppard A & MacKenzie RA. Localization in transcortical sensory aphasia. Arch
Neurol 39:475-478, 1982.

335

Kertesz, A. Recovery after Aphasia. In Feinberg, T E & Farah, M J. Behavioural Neurology and
Neuropsychology. McGraw-Hill, New York, 1997.

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trauma or other causative incidents. Wernicke336 postulated that much of the recovery
from aphasic symptoms is affected by right hemispheric compensation. This of course
could not apply in MDLs case. Subsequently, Henschen337 restated this principle, which
was named Henschen's principle. Von Monakow338 formulated his diaschisis theory on
observations with aphasics and on the analogy of spinal shock, which was well established
by physiologists. He even said: The temporary nature is one of the most important
characteristics of aphasia. Diaschisis is an active process by which acute brain damage
deprives the surrounding or functionally connected areas from a trophic influence initially
causing a more severe deficit than would be expected from the loss of the affected area
alone. The deprived areas recover by acquiring re-innervation from the original source or a
neuron or become active after adapting to the state of partial denervation. (Kertesz idem)
Animal experiments and clinical observations suggested that silent areas or structures, not
usually involved in the functions that were lost due to a specific structure damaged, take
over the function or account for the compensation. This was called vicariation or vicarious
functioning by Fritsch and Hitzig339, who observed the recovery of hemiplegia in dogs after
removing the motor cortex.
The CNS is considered as a dynamically organized network capable of substitution and
change of function rather than as permanently determined distinct centres. Functional
plasticity is quite extensive and reorganization of cerebral networks is evident from converging sources. Nevertheless, there is a finite amount of cortex subserving certain functions, so
that, when damaged in humans, permanent deficits result.
There is a prevalent view among speech and rehabilitation specialists showing that younger
patients recover better, but the issue of age as a factor in recovery is more complex than it
appears on the surface. Age is a major variable in recovery if one takes into consideration
the superior recovery rates of immature individuals. This is called the Kennard principle,
after a series of experiments in animals indicating much better recovery in the young. 340
Recovery means a return wholly or in part to a previous state.
For MDL, this would be a return to her abilities at the age of nine or ten years at which point
in her life, she was most capable.
It is widely accepted that the goal of aphasia rehabilitation is to maximize functional
communication skills. There is less agreement on the optimal route to that goal. Speechlanguage pathologists are exposed to a broad range of approaches and are expected to
make informed decisions about the best treatment for an individual patient based on a
number of factors (e.g., aetiology, severity, type of aphasia, and so on). They are trained
to view aphasia as a complex cognitive/linguistic/communication disorder requiring
intervention that addresses the social as well as the linguistic needs of the client 341, 342 in

336

Wernicke C. Die neueren Arbeiten ber Aphasie. Fortschr Med 4:371-377,1886

337

Henschen SE. Klinische und anatomische eitrage zur Pathologie des Gehirns. Stockholm,
Nordiska Bokhandel, vols 5-7,1920-1922.

338

von Monakow C. Die Lokalisation im Grosshirn und der Abbau der Funktionen durch corticale
Herde. Wiesbaden, Bergmann, 1914.

339

Fritsch GT & Hitzig E. ber die elektrische Erregbarkeit des Grosshirns. Archiv Anat Physiol 300332,1870.

340

Kennard MA. Age and other factors in motor recovery from precentral lesions in monkeys. Am
J PhysioI115:138-146,1936.

341

Chapey R. An introduction to language intervention strategies in adult aphasia, in Chapey R

(ed): Language Intervention Strategies in Adult Aphasia, 2d ed. Baltimore, MD: Williams &

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addition to working with patients in a variety of settings (acute care hospitals, rehabilitation
units, home care, and outpatient facilities) throughout the phases of recovery.
Differences aside, speech-language pathologists typically perform three basic functions:
assessment, treatment, and outcome evaluation. The initial assessment is critical for
establishing the diagnosis of aphasia and differentiating it from other neuro-pathologies
such as dementia and dysarthria, communicating with other professionals and the patient's
family, setting goals, and developing a treatment plan. Following a program of treatment,
an outcome evaluation is performed to determine how well the goals have been met.
Each of these three functions (assessment, treatment, and outcome evaluation) is carried
out at several levels of analysis. It should be remembered that these consideration refer
primarily to adult stroke patients, but there is some relevance for MDL.
When a child sustains brain damage, the plasticity of the brain probably allows for almost
complete compensation by the homologous hemisphere, whether it is related to a hemispherectomy in a young child 343 or childhood aphasia due to other aetiologies. 344 In
addition to the plasticity, however, one should also consider that children have different
aetiologies, such as infection and trauma, causing a different aphasia from that of
strokes.345
Multiple lesions confound the pattern of recovery. Several small lesions produce an
accumulating deficit, the sum of which is less than the deficit caused by a single large
lesion. This has been observed clinically by Dax 346 in the description of recovery from
motor aphasia. From the point of view of localization, more complex behaviours are likely
to have widespread input and will be affected by lesions in many areas. (Kertesz idem)
The added lesion effect 347 has been studied physiologically in animals and is a model to
explain why slowly growing tumours cause so much less deficit than the functional loss of a
sudden large lesion. Accumulating lesions avoid the diaschisis effect of a single large
lesion. There is often a critical stage when the amount of deficit becomes irreversible.
MDLs injury was said to be sporadic and one must therefore accept that she had multiple
lesions.
Traumatic aphasia usually recovers well unless it is related to penetrating head injury.

348,349.

Wilkins, 1986, pp 2-11.

342

Wepman J. Aphasia therapy: Some "relative" comments and some purely personal
prejudices, in Sarno M (ed): Aphasia-Selected Readings. New York: Appleton-Century-Crofts,
1972.

343

Basser LS. Hemiplegia of early onset and the faculty of speech with special reference to the
effects of hemispherectomy. Brain 85:427-460, 1962.

344

Martins IP & Ferro JM. Recovery of acquired aphasia in children. Aphasiology 6:431-438, 1992.

345

Woods BT & Teuber HL. Changing patterns of childhood aphasia. Ann Neurol 3:273-280, 1978.

346

Dax M. Lesions de la moitie gauche de l'encephale coincidant avec l'oubli des signes de la
pensee (lu a Montpellier en 1836). Gaz Hebd Med Chir 2:259262,1865.

347

Ades HW & Raab DH. Recovery of motor function after two-stage extirpation of area 4 in
monkeys. J Neurophysiol 9:55-60, 1946.

348

Kertesz A. & McCabe P. Recovery patterns and prognosis in aphasia. Brain 100:1-18, 1977.

349

Ludlow C; Rosenberg J & Fair C, et al: Brain lesions associated with nonfluent aphasia fifteen
years following penetrating head injury. Brain 109:55-80, 1986.

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Persisting dysarthria350 is common in severe trauma, and this often disrupts communication
to such a degree that the extent of posttraumatic aphasia is difficult to determine.
It is said that most recovery occurs in the first 2 to 3 months. Recovery curves show an
exponential decrease in the 3- to 6-month interval, a 6- to 12- month interval reaching a
plateau after 1 year. 351, 352 However, studies have shown some further recovery after one
year, even though some of these were only a few patients who improved with treatment. It
is impossible to relate these studies to MDL as there wasnt any diagnosis made of brain
injury until some four years after the event. Comparisons with intra-cerebral haemorrhages
are also of no help as these often tend to displace tissues rather than to destroy them, in
certain parts of the haemorrhage at any rate. Major haemorrhages, on the other hand,
are quite destructive, and the patients are less likely to survive because of the intraventricular extension or oedema.
These studies that have considered the factors in recovery are researched with patients
who have had late onset symptoms; thus none of these are applicable to MDLs case. That
said, and as previously noted, MDL made some recovery from her encephalitis at five
months of age but successive life-event traumas have caused a comparable regression to
that which might have accompanied a new mal-event for someone who suffered a late
onset injury.
Of course we do not know either which areas of her brain were immediately damaged by
the vaccination or which areas were affected consequently. Neither do we know how
much recovery there was initially, nor how much damage accrued later and whether it was
serial damage nor therefore do we know the sequence. In terms of behaviour however,
we know that she acquired a substantial advantage from her education at Pictor House
where she attended from 1964 to 1969. We know that when she was forced to leave that
school on the grounds of catchment area only, she regressed scholastically and
emotionally and her deterioration after recovery can be seen to date from that time.

Agraphia:

is traditionally defined as an acquired disorder of writing, although current

usage also includes disorders of spelling353. Breakdown in writing may occur at any level of
production, including the paragraph and sentence level. However, agraphia has typically
been studied at the word level. At this level, dysfunction may be the result of either
linguistic or motor disturbances. These disturbances may either be unique to the writing or
spelling systems (pure agraphia) or more generalized, with associated neuropsychological
dysfunction.
Typically, the agraphia is described as being similar to the aphasias354. Therefore, the nonfluent agraphias consist of sparse output with effortful processing and agrammatism, while
the fluent agraphias consist of normal output, easy production, and normal sentence
length. The non-fluent agraphias are usually associated with clumsy calligraphy and the

350

Dysarthria Poor articulation (diction).

351

Poeck K; Huber W & Willmes K. Outcome of intensive language treatment in aphasia. J

Speech Hear Disord 54:471-479, 1989.

352

Broida H. Language therapy effects in long term aphasia. Arch Phys Med Rehabil58:248-253,
1977.

353

Roeltgen, DP. Agraphia. In Feinberg, T E & Farah, M J. Behavioural Neurology and

Neuropsychology. McGraw-Hill, New York, 1997.

354

Benson DF & Cummings JL. Agraphia, in Vinken PJ; Bruyn GW; Klawans HL & Frederiks JAM
(eds): Clinical Neuropsychology. New York: Elsevier, 1985, vol 45, pp 457-472.

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fluent agraphias with well-formed letters (Benson et al, idem). However, some studies 355
have described patients with Broca's aphasia and noted that their agraphia more closely
resembled the agraphia of patients with Wernicke's aphasia than the agraphias of other
patients with Broca's aphasia. This reflects the dissociation of aphasia and agraphia first
described by Ogle. 356

Agraphia and Confusion

The sum of MDLs brain damage easily includes
confusion at certain times. This isnt delusional confusion nor, of course, the confusion of
dementia. It is the confusion that accompanies attempts to unfathom uncertainties when
the brain does not have the connections or, is unable to use them, in order to make sense
of communication from other people or to interpret environmental situations. This is at its
worse when those who are caring for MDL do not understand her disability or how it affects
her. MDL senses this uncertainty in others and yet she does not have the communicational
abilities to inform the carer how or why they are not connecting with her.
Patients with acute confusional states frequently have agraphia 357. Chedru and
Geschwind found agraphia in 33 of 34 cases of acute confusion. Their patients had
disruption of linguistic performance with spelling and syntactical disturbances. They also
had motor impairment and spatial impairment with poorly formed and improperly placed
letters.

Semantic Agraphia

Semantic agraphia is due to a disruption of semantic

influence on spelling output358. Patients with this disorder have trouble incorporating
meaning into spelling and writing.359,360 The error made by these patients is most commonly
that of homophone confusions, such as writing knight when asked to write night, as in The
moon can best be seen at night. Lesion sites associated with semantic agraphia include
those regions typically associated with trans-cortical aphasias with impaired
comprehension.361,362
To have a clear view of the complicated semantics of language that most of us develop
without too much trouble but which creates difficulties for those with semantic aphasia see:
http://ocw.nctu.edu.tw/course/syntax/W3III.pdf
____________

355

Roeltgen DP & Heilman KM. Review of agraphia and proposal for an anatomically-based
neuropsychological model of writing. Appl Psycho ling 6:205230,1985.

356

Ogle JW. Aphasia and agraphia. Report of the Medical Research Counsel of St. George's
Hospital (London) 2:83-122, 1867.

357

Chedru F. & Geschwind N. Writing disturbances in acute confusional states.

Neuropsychologica 10: 343-354, 1972.

358

Rothi LJG; Roeltgen DP & Kooistra CA. Isolated lexical agraphia in a right-handed patient with
a posterior lesion of the right cerebral hemisphere. Brain Lang 30:181-190,1987.

359

Patterson K. Lexical but nonsemantic spelling? Cogn Neuropsychol 3:341-367, 1986.

360

Rapcsak SZ & Rubens AB. Disruption of semantic influence on writing following a left
prefrontal lesion. Brain Lang 38:334-344, 1990.

361

Roeltgen DP & Rapcsak SZ. Acquired disorders of writing and spelling, in Blanken G, Dittmann
J, Grimm H (eds): Linguistic Disorders and Pathologies: An International Handbook. Berlin: De
Gruyter, 1993, pp 262-278.

362

Hatfield FM. & Patterson KE. Phonological spelling. Q J Exp PsychoI 35A:451-468, 1983.

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TABLE FOUR
Agraphia & Aphasia: their connections
1.

NON-FLUENT AGRAPHIA
A)

B)
2.

Agraphia and Broca's aphasia 363,364

i)

Poor grapheme production

ii)

Agrammatism

Agraphia and trans-cortical motor aphasia 365

FLUENT AGRAPHIA
A)

Agraphia and conduction aphasia (Marcie et al, Idem)

B)

Agraphia and Wernicke's aphasia (Marcie et al, Idem & Kaplan et al, idem)

C)

Agraphia and anomia (Benson et al, idem)

____________

Agraphia and Praxic or Spatial Disturbances

Apraxic agraphia is
described as difficulty in writing letters, writing spontaneously, and writing to dictation
366,367,368,369 . Copying or oral spelling are usually less impaired. Patients affected by this
syndrome are usually able to type or use anagram letters. The lesions causing apraxic
agraphia are usually in the parietal lobe, especially the superior parietal lobule19 opposite
the preferred hand (dominant parietal lobe). In contrast, lesions in the parietal lobe
ipsilateral370 to the preferred hand (non-dominant parietal lobe) are traditionally associated
with spatial agraphia. Patients with this disorder typically duplicate strokes and have spatial
disturbances in their writing. This includes trouble writing on a horizontal line and writing only
on the right side of the paper. It is frequently associated with the neglect syndrome. 371

363

Marcie P & Hecaen H. Agraphia, in Heilman KM, Valenstein E. (eds): Clinical

Neuropsychology. New York: Oxford University Press, 1979, pp 92-127.

364

Kaplan E & Goodglass H. Aphasia-related disorders, in Sarno MT (ed): Acquired Aphasia. New
York: Academic Press, 1981, pp 303-325.

365

Rubens AB. Transcortical motor aphasia, in Whitaker H, Whitaker HA (eds): Studies in Neurolinguistics. New York: Academic Press, 1976, vol 1, pp 293-303.

366

Roeltgen DP. Agraphia, in Heilman KM, Valenstein E (eds): Clinical Neuropsychology. 3d ed.
New York: Oxford University Press, 1993, pp 63-89.

367

Marcie P & Hecaen H. 1979, idem

368

Hecaen H. & Albert ML. Human Neuropsychology. New York: Wiley, 1978.

369

Leischner A. The agraphias, in Vinken PJ, Bruyn GW (eds): Disorders of Speech, Perception
and Symbolic Behavior. Amsterdam: North-Holland, 1969, pp 141-180.

370

IPSILATERAL
Being on the same side of the body as the brain injury; the converse is
CONTRALATERAL.

371

Roeltgen, DP. Agraphia. In Feinberg, T E & Farah, M J. Behavioural Neurology and

Neuropsychology. McGraw-Hill, New York, 1997.

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With spatial agraphia, there may also be letter omissions or additions within orthographic
groupings (e.g., syllables or morphologic units).

Acalculia

Acalculia is defined as an impairment of the ability to calculate. It is

used interchangeably with the term dyscalculia, although some authors have suggested
reserving the term acalculia for a complete inability to calculate and using the term
dyscalculia in cases where some ability to calculate remains. Here, the use the term
acalculia refers to both forms of impairment.
Acalculia is a frequently appearing deficit following damage to the left posterior region of
the brain, but it can occur following damage to other brain regions. It is a significant
functional deficit for patients, since it may restrict their ability to engage in financial
activities. It is also an opportunity for clinical researchers interested in the organization of
cognitive architectures, response execution, lexical-semantic stores, and the cooperation
between fact-based and analogue-scaled cognitive processes to study these processes
within the context of a relatively narrow domain of knowledge.
The condition is a common developmental disorder and is a frequent concomitant of
acute and progressive left posterior hemispheric lesions in children and adults. It can affect
a patients ability to balance a cheque book, make change, use a temperature gauge,
etc. Clinically, it is important as it allows for the assessment of number processing and
calculation.
Studying number processing and calculation in acalculic patients can also show the
cognitive architecture and computational demands of a relatively encapsulated cognitive
function by revealing patterns of spared and impaired abilities across individual patients.
Given that numbers and calculation represent a relatively closed information processing
system with a limited number of rules and symbols, it makes for an ideal domain of study.
(Rhawn, idem)
There are a number of general classification schemes for describing forms of acalculia,
which have divided acalculia into three broad types; 372
Type 1 is a secondary form of acalculia due to deficits in verbal processing.
Type 2 is also a secondary form of acalculia and is due to deficits in visuo-spatial
processing.
Type 3 is the primary form of acalculia; which is independent of (but may coexist
with) any other cognitive deficit.
A primary acalculia has been described in individual cases and made up approximately 6
percent of acalculic patients with right-hemispheric lesions and 23 percent of acalculic
patients with left-hemispheric lesions. 373
Acalculia is often associated with other cognitive impairment by virtue of the location of

372

Levin HS; Goldstein FC & Spiers P A. Acalculia, in Heilman K, Valenstein E (eds): Clinical
Neuropsychology. New York, Oxford University Press, 1993, pp 91-118.

373

Grafman, J. & Rickard, T. Acalculia. In Feinberg, T E & Farah, M J. Behavioural Neurology

and Neuropsychology. McGraw-Hill, New York, 1997.

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the lesions that cause primary acalculia and because of the relationship of the domainspecific calculation procedures to other cognitive processes.
Finger agnosia (See below p. 89), agraphia, and right-left discrimination are frequently
observed together with acalculia following left posterior cortical lesions, but each symptom
may occur as frequently with other symptoms. This tetrad of symptoms is known collectively
as the Gerstmann syndrome, and its appearance has been associated with lesions of the
left angular gyrus.374,375
Other symptoms associated with primary acalculia have included alexia376,377, visuo-spatial
deficits, and conduction aphasia. On-line serial calculations may involve working memory
processes. Thus, a breakdown in serial calculation (as opposed to simple fact retrieval)
may be associated with a general deficit in working memory, word fluency, or planning.
[See section on Working Memory and Cognition below, page 146]
The Gerstmann syndrome symptom collection at first may seem like the odd quartet. Odd,
that is, until it is remembered that pre-literate calculation depended upon counting,
numerosity, and magnitude estimation. Since counting often relied upon fingers, with
fingers on different hands representing different quantities, it should not be completely
surprising that calculation, finger recognition, left-right discrimination, and writing ability
could all be impaired following an angular gyrus lesion.
The angular gyrus is located within the inferior parietal lobe of the brain. Developmentally,
of all cortical regions, the inferior parietal lobule is one of the last to mature both
functionally and anatomically. Hence, many capacities mediated by this area (e.g.
reading, calculation, the performance of reversible operations in space) are late to
develop appearing between the ages of 5-8 years. 378 It will be seen therefore that with
such a late development of that area, MDLs brain damage can have interfered with the
development and maturation of it.
MDL has at times been able to count from one to ten but this may be purely an exercise in
memory and she is unable to use numbers for any form of calculation. Even when she was
able to recite this sequence she would not have been able to use any of the individual
numbers in a simple calculation. She may possibly at best have been able to say, for
instance, what comes after eight and be able to say nine. However she would not be able
to give you an answer to the question what is one plus one or two minus one. She would
not understand what plus and minus meant and how to apply those in a calculation. She
has no idea of monetary value and at the present time if she is asked how much an item is
worth she will always say, one money. She knows what money is and she knows that we
exchange money for goods but she has no idea of the concept of monetary value or worth.

374

Mazzoni M; Pardossi L. & Cantini R, et al: Gerstmann syndrome: A case report. Cortex 26:459467, 1990.

375

Moore MR; Saver JL; Johnson KA. & Romero JA. Right parietal stroke with Gerstmann's
syndrome: Appearance on computed tomography, magnetic resonance imaging, and
single-photon emission computed tomography. Arch Neurol 48:432-435, 1991.

376

Alexia (acquired dyslexia) occurs when damage to the brain causes a patient to lose the
ability to read. It is also called word blindness, text blindness or visual aphasia.

377

Damasio, Antonio R. Varieties and Significance of the Alexias. Archieves of Neurology 34 (6):
325326; 1977.

378

Rhawn, JR. Neuropsychiatry, Neuropsychology, Clinical Neuroscience. Academic Press,

New York, 2000.

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She also has little or no understanding of the calendar or periods of time. Thus, if you tell her
something is happening next week she will have no idea of the practical use of that
information. Even the days of the week present a challenge to her. She does not know the
sequence of days in a week and a particular day will only have significance if something
important for her happens as a regular occurrence on that day.
Primary acalculia can take the form of either global or selective deficits in a large number
of number processing and calculation abilities. A large number of studies have implicated
left posterior lesions in primary acalculia, most often in the vicinity of the left angular and
supra-marginal gyri. 379 In particular, the evidence suggests that arithmetic facts and
calculation procedures are preferentially stored in that brain region. Despite the strong
association of acalculia and left posterior quadrant lesions, there are certain characteristics
of acalculia that have led to the suggestion of a right-hemispheric contribution.
The overwhelming evidence suggests that arithmetic facts and calculation procedures are
stored in the left parietal cortex. However, a contribution of frontal lobe 380 and right
parietal processes is also implicated. A more precise delineation of these contributions
awaits further investigation. (Grafman, et al, idem)

_______

Disorders of Skilled Movements, Perception and Awareness

Apraxia

is an inability to correctly perform learned skilled movements. In part, it is

defined by what it is not. 381 Patients with impaired motor performance induced by
weakness, sensory loss, tremors, dystonia, chorea, ballismus, athetosis, myoclonus, ataxia,
and seizures are not considered apraxic. Patients with severe cognitive, memory, motivational, and attentional disorders may have difficulty performing skilled motor acts because
they cannot comprehend, cooperate, remember, or attend, but these deficits are also not
considered apraxic. 382

Limb apraxia
may be the most frequently unrecognized behavioural disorder
associated with cerebral disease. Apraxia may go unrecognized as many physicians and
other health professionals do not test for limb apraxia and are not aware of the nature of
errors that are associated with it or that it may be a disabling disorder. (Heilman et al, idem)
The subtypes of limb apraxia are defined by the nature of errors made by the patient and
the means by which these errors are elicited. Lipmann383 subdivided limb apraxic disorders
into three types:

melokinetic ( or limb-kinetic),

379

Grafman, J & Rickard, T. Acalculia. In Feinberg, T E & Farah, M J. Behavioural Neurology and
Neuropsychology. McGraw-Hill, New York, 1997.

380

Tohgi H; Saitoh K & Takahashi S, et al: Agraphia and acalculia after a left prefrontal (F1, F2)
infarction. J Neurol Neurosurg Psychiatry 58:629-632, 1995.

381

Geschwind N. Disconnection syndromes in animals and man. Brain 88:237-294, 585-644, 1965.

382

Heilman, KM; Watson, RT & Rothi, LG. Disorders of Skilled Movements: Limb Apraxia . In
Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New
York, 1997.

383

Liepmann H. Apraxia. Erbgn Ges Med 1:516543,1920.

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ideomotor, and

ideational

In addition there are three additional forms of apraxia:

disassociation apraxia,

conduction apraxia, and

conceptual apraxia.

The apraxias are differentiated by the types of errors made by the patient and the means
by which these errors are elicited. (Heilman et al, idem)

Apraxia Testing

The physician must perform a thorough neurologic examination to be

certain that abnormal performance is not induced by the non apraxic motor, sensory, or
cognitive disorders mentioned above. The presence of elemental motor defects does not
prohibit apraxia testing; however, the examiner must interpret the results with the
knowledge gained from the neurologic examination. (Heilman et al, idem)
Both the right and left arm and hands should be tested independently. Patients should be
requested to pantomime to verbal command (e.g., Show me how you would use a pair of
scissors). All patients should also be asked to imitate the examiners motor acts. The
examiner may want to perform both meaningful and meaningless gestures for the patient
to imitate.
Independent of the results of the pantomime and imitation tests, the patient should be
given actual objects and tools and asked to demonstrate how to use the tool or object.
One should test transitive movements (i.e., using a tool or instrument) and intransitive
movements (i.e., communicative gestures not using tools, such as waving good-bye). When
having a patient pantomime, in addition to giving verbal commands, the examiner may
also want to show the patient a tool or a picture of the tool or object that the patient is
required to pantomime. It may be valuable to see if the patient can recognize transitive
and intransitive pantomimes performed by the examiner and discriminate between those
that are well and poorly performed. The patient should be given a task that requires several
motor acts in sequence. Last, one may want to learn if the patient knows what tools
operate on what objects (e.g., hammer and nail), what action is associated with each tool
or object, and how to fabricate tools to solve mechanical problems.
In limb kinetic apraxia, there is a loss of the ability to make finely graded, precise, individual
finger movements. Limb kinetic apraxia occurs in the limb contra-lateral to a hemispheric
lesion. This is confirmed by Heilman et al:
Whereas in right-handed individuals, ideomotor apraxia (IMA) is almost always
associated with left-hemisphere lesions, in left-handers IMA is usually associated with
right-hemisphere lesions. Ideomotor apraxia can be induced by lesions in a variety
of structures, including the corpus callosum, the inferior parietal lobe, and the
supplementary motor area. IMA has also been reported with sub-cortical lesions
that involve basal ganglia and white matter. (Idem)
It is unlikely that MDL would be able to complete these tests and therefore it must be a
possibility that she has some level of apraxia. However, it must also be considered if MDLs
apraxia is brought about through other neurological damage as she cannot perform these
tests with either limb.

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The Agnosias

This condition relates to disturbances of the recognition of objects

(agnosia) and faces (prosopagnosia). Freud introduced the term agnosia but he used it to
describe damage that affected previously learned knowledge.
The first studies of the neuropsychological deficits relating to object recognition were
carried out at the end of the 19th century, and their current classification still uses the
terminology introduced by Lissauer384 and Freud385 .
Lissauer proposed distinguishing the deficits affecting the ability to discriminate stimuli and
perceive consciously from those affecting the ability to interpret what is seen. These two
subtypes were respectively defined apperceptive and associative mental blindness.
However, the concept of mental blindness was very generic and based on theoretical
data rather than empirical observations. It consisted of a broad group of disturbances,
including the ability to distinguish colours and identify differences between new shapes and
models, as well as specific disturbances relating to the perception of objects.
Lissauer described a patient (Gottlieb L.) who made mistakes in identifying everyday
objects. He appeared confused when he tried using cutlery to eat and had difficulty in
dressing himself, but was able to copy drawings and showed no signs of any intellectual
deficit. According to Lissauer, this was an example of associative blindness. However, the
descriptions of apperceptive disturbances were rather vague, being seen more as a
prerequisite for the onset of other disturbances than as a specific deficit in itself.

Apperceptive agnosia

One might wonder whether apperceptive agnosics

should be considered agnosics at all, given that the definition of agnosia above excludes
patients whose problems are caused by elementary visual impairments. The difference
between apperceptive agnosics and patients who fall outside of the exclusionary criteria
for agnosia is that the former have relatively good acuity, brightness discrimination, colour
vision, and other so-called elementary visual capabilities. Despite these capabilities, their
perception of shape is markedly abnormal.
Recognition of real objects may be somewhat better than recognition of geometric
shapes, although this appears to be due to the availability of cues such as size and surface
properties such as colour, texture, and specularity rather than object shape. In most cases
of apperceptive agnosia, the brain damage is diffuse.
Some authors have used the term apperceptive agnosia for other, quite different types of
visual disorders, including two forms of simultanagnosia and an impairment in recognizing
objects from unusual views or under unusual lighting conditions. Simultanagnosia is a term
used to describe an impairment in perception of multi-element or multi-part visual displays.
When shown a complex picture with multiple objects or people, simulanagnostics typically
describe them in a piecemeal manner, sometimes omitting much of the material entirely
and therefore failing to interpret the overall nature of the scene being depicted. MDL quite
definitely has these characteristics.
The greatest difficulty in terms of diagnosis is to determine the limits of the alterations in
primary visual functions that are compatible with a picture of agnosia. In order to be able
to speak of a selective perceptual deficit, it is necessary to demonstrate the existence of
sufficient sensory visual capacities; consequently, visual field, visual acuity, and the

384

Lissauer, H. (1890): Ein Fall von Seelenblindheit nebst einem Beitrag zur Theorie derselben.
Archiv Psychiatrie, 21, 222-270. Translated into English and reprinted In: Lissauer on agnosia.
Cognitive neuropsychology (1988), vol. 5, ed. M. Jackson, pp. 155-192.

385

Freud, S. Zur Auffassung der Aphasien. Vienna: Deuticke; 1891.

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discrimination of colours and depth must all be normal [In MDL, these are normal].
Patients with apperceptive agnosia fail at object recognition tasks because they are
unable to organize sensory data into the structured perceptual units that make it possible to
reconstruct their shape and so recognize them. The tests at which they are deficient are
those requiring the recognition of objects seen from an untypical angle, the identification
of a particular figure mixed with others in an overlapping complex, the matching of
identical drawings of different sizes, and the copying of drawings. [These deficiencies are
all evident in MDL.]
The lesion responsible for apperceptive agnosia generally involves the right parietal lobe.
Studies have shown that patients with right posterior lesions are capable of performing
shape discrimination tests within the limits of normal levels, but are severely impaired when it
comes to tests involving unconventional perspectives and incomplete figures386 .
The first interpretation of apperceptive agnosia was made by Warrington & James387, who
defined it as a disturbance of the perceptive categorization that makes it possible to
provide a structural definition of objects (i.e. their distinctive elements and the spatial
relationships between them). This definition is based on Marr's object recognition
computational model.388,389.
It should be noted that there can be great difficulty in testing MDL for apperceptive
agnosia because the parts of her brain that are not damaged may be under-developed
and she cannot use them effectively to compensate for permanent loss. However, the
more obvious deficiencies are noted above (bold).

Associative agnosia

One can speak of associative agnosia when it is

possible for patients to analyse and integrate the perceptive structure of the stimulus, and
when there are no alterations in its internal representation. A pure deficit of this type is quite
rare.
Associative agnosia has been explained in three different ways that suggest different
answers to the question is associative agnosia a problem with perception, memory, or
both? The simplest way to explain agnosia is by a disconnection between visual
representations and other brain centres responsible for language or memory. For example,
Geschwind 390 proposed that associative agnosia is a visual-verbal disconnection. This
hypothesis accounts well for agnosics' impaired naming of visual stimuli, but it cannot
account for their inability to convey recognition non-verbally and may therefore be more
suited to explaining optic aphasia, a form of anomia limited to an impaired naming of
visual stimuli. Associative agnosia has also been explained as a disconnection between
visual representations and medial temporal memory centres.391 However, this would

386

Warrington, E.K. & Taylor, A.M. The contribution of the right parietal lobe to object
recognition. Cortex 9, 152-164; 1973.

387

Warrington, E.K. & James, M. Visual apperceptive agnosia: a clinico-anatomical study.

Cortex 24, 13-32; 1988.

388

Marr, D. Visual information processing: The structure and creation of visual representation.
Phil. Trans. Roy. Soc. (Lond.), B290, 199-218; 1980.

389

Marr, D. Vision. San Francisco: W.H. Freeman; 1982.

390

Geschwind N. Disconnexion syndromes in animals and man: Part II. Brain 88:585-645, 1965.

391

Albert ML; Soffer D; Silverberg R & Reches A. The anatomic basis of visual agnosia. Neurology
29:876- 879, 1979.

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account for a modality-specific impairment in new learning, not the inability to access old
knowledge through vision.392
The inadequacies of the disconnection accounts lead us to consider theories of associative
agnosia in which some component of perception and/or memory has been damaged.
Perhaps the most widely accepted account of associative agnosia is that stored visual
memory representations have been damaged. According to this type of account, stimuli
can be processed perceptually up to some end-state visual representation, which would
normally be matched against stored visual representations. In associative agnosia, the
stored representations are no longer available and recognition therefore fails. Note that an
assumption of this account is that two identical tokens of the object representation
normally exist, one derived from the stimulus and one stored in memory, and that these are
compared in the same way as a database might be searched in a present-day computer.
This account is not directly disconfirmed by any of the available evidence. However, there
are some reasons to question it and to suspect that subtle impairments in perception may
underlie associative agnosia. (Farah et al Idem) MDL has problems in these areas. The tests
that patients with associative agnosia fail to complete successfully are those requiring
knowledge of an object's functional and semantic characteristics. As a consequence,
there may be many semantic errors in a visual denomination task, considerable difficulties
in a test involving semantic categorization (grouping stimuli belonging to the same
category, selecting those figures from a group that have close associative links, etc.), and
difficulties relating to semantic attributes that are not present in the figure itself (e.g. when a
black and white drawing of a horse is presented and the subject is asked questions such as:
Is it an animal?
Is it dangerous?
Does it live at home? Etc.).
Because of MDLs multiple sites of brain damage she would probably not answer the
second two of these questions. It would be better in her case if the questions were:
What is in this picture?
Where does it live?
What does it eat?
MDL can recognise familiar things which late onset associative agnosia patients may not be
able to. For instance she will recognize:
a tea pot
a sugar bowl (if it has sugar in it)
She will also recognize a towel and not call it a face cloth or a handkerchief. However, she
will not know a hand towel from a tea towel (unless over a long period of time she can
associate the colours or patterns if they remained consistent).
The lesion responsible for associative agnosia is generally circumscribed to the occipito-

392

Farah, MJ & Feinberg, TE. Visual Object Agnosia. In Feinberg, T E & Farah, M J. Behavioural
Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

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temporal regions of the left hemisphere.
According to the model of Humphreys & Riddoch393, associative agnosia consists of an
inability to connect the output of a perceptive analysis made at the stage of object
recognition with a more general underlying knowledge.
One interesting aspect emerging from the study of Sartori & Job394 is the possibility that
agnosic disturbances may be limited to only some semantic categories. The patients they
described presented a deficit in the recognition of stimuli belonging to the category of
foods and living things (animals, fruit and vegetables), but not in relation to non-living
objects (clothes, furniture and means of transport). The opposite disturbance has also been
observed395, although it is much rarer. The existence of a dual dissociation suggests that the
information relating to the two semantic categories is processed in a different manner.
Humphreys & Riddoch396 sustain that the greatest difficulties encountered by patients with
associative agnosia for the categories of living things can be explained by the fact that
their greater perceptive similarity requires a more profound analysis. However, although this
interpretation is capable of explaining the behaviour of patients with a specific deficit in
the structural knowledge of objects, in the case of those in which the disturbance affects
the semantic store, it is necessary to hypothesize that the impairment lies exclusively at the
level of semantic knowledge and is manifested regardless of whether the stimulus is
presented visually or verbally.397

Prosopagnosia

The term prosopagnosia, which was coined by Bodamer 398,

refers to the inability to recognize the faces of known people, whose identification is
preserved when it can be based on acoustic information (the voice) or non-physiognomic
visual stimuli (the way of walking or dressing, or postural stance). It is also known as facial
agnosia or face blindness.
Until recently, it was thought that very few people suffered from prosopagnosia. The
condition has traditionally been studied in individuals who acquire the disorder following
neurological damage (typically from stroke or head injury), and a handful of case studies
were reported in the literature in the 20th century. However, it has recently become clear
that many more people suffer from prosopagnosia without experiencing neurological
damage. This form of the disorder is commonly referred to as developmental or
congenital prosopagnosia and these individuals simply fail to develop normal face
processing abilities despite normal intellectual and perceptual functions. Developmental
Prosopagnosics have suffered from the face recognition impairment for most of their lives,
perhaps since birth. Recent evidence suggests there may be a genetic contribution to

393

Humphreys, G.W. & Riddoch, M.J. The fractionation of visual agnosia. In: Visual object
processing: a cognitive approach, eds. G.W. Humphreys & M.J. Riddoch. London: Erlbaum;
1987.

394

Sartori, G. & Job, R. The oyster with four legs: a neuropsychological study of the interaction of
visual and semantic information. Cognitive Neuropsychol. 5,677-709; 1988.

395

Warrington, E.K. & McCarthy, R.A. Categories of knowledge: further fractionation and an
attempted integration. Brain 110,1273-1296; 1987.

396

Humphreys, G.W. & Riddoch, M.J. Object agnosias. In: Clinical neurology: international
practice and research, ed. C. Kennard. London: Bailliere Tindall; 1993.

397

Silveri, M.C. & Gainotti, G. Interaction between vision and language in category specific
impairment. Cognitive Neuropsychol. 5,677-709; 1988.

398

Bodamer, J. Die Prosopagnosie. Archiv fUr Psychiatrie und Nervenkrankheiten 179, 6-53; 1947.

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developmental prosopagnosia, and several case studies report at least one first-degree
relative who also suffers from the face recognition impairment.
MDL can recognise familiar faces but cannot always remember the persons name. She
has greater difficulty in recognising faces from photographs. In her case it is not a genetic
condition as suggested above for some sufferers. However, because of her brain damage
there has probably been a lack of development or a failure in neurological connections
that contribute to her particular disability in this area.
It is interesting to note in MDLs case that if someone she knows well, appears dressed in
unfamiliar clothing she may say to them, I dont know you (or him or her) This of itself may
not be what it seems to be because she does not have the ability to comment on the
change in apparel; and therefore she may use this phrase to stand for a comment on the
different appearance. This indicates that one has to know her really well to avoid
misunderstandings.
The ascendancy of the right over the left hemisphere in processing faces is beyond
question, having been confirmed by many normal and clinical studies. What is a matter of
debate is whether this asymmetry of function is so marked as to cause the inability to
recognize familiar faces following a lesion confined to the right side or if bilateral damage is
necessary to produce this result. 399
Bodamer (idem) was cautious in drawing anatomic inferences from his cases, since they
lacked autopsy, but he remarked that both showed evidence of bilateral lesions. Fifteen
years later, a review of the available clinical cases 400 emphasized the presence in a
substantial proportion of them of left visual field defects, a sign pointing to right brain
damage.
It was speculated that damage to this side played a crucial role in causing prosopagnosia.
Although this paper was very influential in drawing attention to the possible specialization of
the right hemisphere in face processing, its relevance to the anatomic basis of
prosopagnosia was questioned by a subsequent review focusing on case reports with
necroscopy documentation 401, which pointed out that all of the patients had bilateral
damage. New pathologic studies 402,403 corroborated this finding. Although Meadows
(idem) was cautious in drawing definite conclusions from his review of the literature
since there were also a few patients in whom surgery had shown a disease confined to the
right hemisphere and in some bilateral cases the left lesion was located in areas having no
relation to the processing of visual information the view that bilateral damage is a
necessary condition for the occurrence of Prosopagnosia 404 gained overwhelming

399

Renzi, E de. Prosopagnosia. . In Feinberg, T E & Farah, M J. Behavioural Neurology and

Neuropsychology. McGraw-Hill, New York, 1997.

400

Hecaen H & Angelergues R. Agnosia for faces (prosopagnosia). Arch NeuroI7:92-100, 1962.

401

Meadows IC. The anatomical basis of prosopagnosia. J Neurol Neurosurg Psychiatry 37:489501, 1974.

402

Cohn R; Neumann MA & Wood DI. Prosopagnosia: A clinicopathological study. Ann Neural
1:177182, 1977.

403

Nardelli E; Buonanno F & Coccia G, et al: Prosopagnosia: Report of four cases. Eur Neural
21:289297, 1982.

404

Desimone R. Face-selectivity cells in the temporal cortex of monkeys. J Cogn Neurosci 3:1-8,
1991

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consensus. Yet the exceptions to the bilaterality of damage rule remarkably increased
with the introduction of neuro-imaging procedures, which made it possible to localize the
lesion in a much greater number of patients.
It must be stressed that while this source of information cannot compete with autopsy in
terms of accuracy of localization, it has the great advantage of being available in
practically every prosopagnosic, not only in those that come to autopsy (which may
represent a biased sample) and that is available at the same time testing is carried out. A
review of the pertinent literature published up to 1992 405 brought out 27 patients with
evidence on computed tomography (CT) or magnetic resonance imaging (MRI)
complemented in five cases by positron emission tomography (PET) of damage
restricted to the right hemisphere, plus three cases with surgical documentation and one
following right hemi-spherectomy.
The pendulum is, therefore, shifting again toward the unilaterality of lesion thesis, to the
effect that damage to the right brain may be sufficient to cause prosopagnosia. However,
in face recognition there is a dimension showing a wide range of functional variation in
humans, such that only a minority of them have these skills preponderantly represented in
the right brain.
Developmental agnosia
Very few studies refer to agnosic disturbances during
the age of development, but it is not clear whether this is due to a tendency to neglect or
misclassify this type of deficit, or the fact that it is really a rare condition. In 1968, Gordon
reported the cases of two children affected by epileptic seizures who had difficulties in
recognizing objects406 .
The first seems to be compatible with the description of simultanagnosia in adults: the child
presented occipito-temporal EEG abnormalities and performed a recognition task
adequately if the figures were presented individually, but not if more than one figure was
presented at the same time. The other child presented bilateral occipital EEG
abnormalities and had difficulty in recognizing large objects. However, neither of these
cases seems to be a convincing example of object agnosia.
As far as face recognition is concerned, a large number of studies have described the
development of this ability and the disturbances that may be encountered during the age
of development.
Many of them have demonstrated that new-born infants show a preference for faces over
any other type of visual stimulus within the first few minutes of being born, which suggests
that they already have some structural information available concerning facial
characteristics. This information probably forms part of a primitive (hard-wired) system; this
will relate to another theory that suggests that there is a region located around the upper
temporal sulcus of the right hemisphere that is genetically programmed to process faces.
Any damage or dysfunction in this area at birth or before could give rise to prosopagnosia
in children. Face recognition seems to become a specialization of the right hemisphere as

405

De Renzi E; Perani D & Carlesimo GA, et al. Prosopagnosia can be associated with damage
confined to the right hemisphere: An MRI and PET study and a review of the literature.
Neuropsychologia 32:893-902, 1994.

406

Gordon, N. Visual agnosia in childhood: VI. Preliminary communication. Dev. Med. Child
Neurol. 10, 377-379; 1968.

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early as four months after birth.

407

This could mean that there was a start being made towards face recognition before MDLs
brain damage.

Finger Agnosia

In 1930, the Austrian neurologist Josef Gerstmann observed in a few

patients a concomitant impairment in discriminating their own fingers, writing by hand,
distinguishing left from right and performing calculations. He claimed that this tetrad of
symptoms constituted a syndromal entity and assigned it to a lesion of the dominant
parietal lobe and suggested that it was due to damage of a common functional
denominator. Ever since, these claims have been debated and an astute synopsis and
sceptical discussion was presented in 1966 by MacDonald Critchley in his William Gowers
lecture.408 In opening his lecture he gave an account of the patient described by Josef
Gerstmann409 , who amongst other deficits is unable to name her fingers and identify
her own or the examiners individual digits on request.
Gerstmann called this symptom finger-agnosia which Critchley considered to be an illchosen expression. In 1927, Gerstmann described two new cases and proposed that
difficulty with writing forms part of the emerging syndrome. Further observations add yet
more phenomena and, by 1930, the descriptive tetrad is complete: Gerstmanns
syndrome now consists of finger-agnosia, dysgraphia, dyscalculia and rightleft
disorientation; and it localizes to the left angular gyrus a region assumed by Gowers to
be a higher visual centre. (Compston, Idem)
Nonetheless, Gerstmann's syndrome has continued to intrigue both clinical neurologists and
researchers in neuropsychology, and more frequently than not is described in textbooks as
an example of parietal lobe damage. Benton has revisited the chequered history of this
syndrome, which can be seen as a case study of the dialectic evolution of concepts in
neuropsychology. In light of several modern era findings of pure cases he conclude that it is
legitimate to label the conjunction of symptoms first described by Gerstmann as a
syndrome, but that it is very unlikely that damage to the same population of cortical
neurons should account for all of the four symptoms. Instead, he proposed that a pure form
of Gerstmann's syndrome might arise from disconnection, via a lesion, to separate but colocalized fibre tracts in the subcortical parietal white matter, a hypothesis for which he has
recently provided evidence using combined imaging of functional and structural
organization in the healthy brain. This has previously been described as part of the
Gerstmann syndrome 410, which is a combination of finger agnosia with right-left confusion, acalculia, and agraphia. However, it has been demonstrated that these are
unrelated symptoms, which may or may not happen to occur together. 411

407

Riva, D; Saletti, V; & Nichelli, F. The organization of memory in temporo-mesial structures in

developmental age. In, Riva, D; & Benton, A. Localization of Brain Lesions and
Developmental Functions. John Libby, London; 2000.

408

Compston, A. The enigma of Gerstmanns syndrome (The William Gowers lecture delivered
on 2 December 1965). By Macdonald Critchley. [Brain 1966: 89; 183198]; Brain 133 (2): 314316; 2010.

409

Writing from Vienna in 1924 (Wiener Klinische Wochenschrift 1924: 37; 10101012).

410

Gerstmann J. Zur Symptomatologie der Hirnliisio nen im Obergangsgebiet der unteren

Parietal- und mittleren Occipitalwindung. Nervenarzt 3:691696,1930.

411

Benton AL. The fiction of the Gerstmann syndrome. J Neurol Neurosurg Psychiatry 24:176181, 1961.

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Finger agnosia has been considered as a minor form of auto-topagnosia (Gerstmann,
idem) but whereas auto-topagnosia as characterized by errors in pointing to proximal body
parts has been observed exclusively in patients with left brain damage, finger agnosia
occurs with approximately equal frequency in patients with left and right brain damage.
(Poeck, Sauguet, Gainotti; idem) & 412 . It has already been mentioned that there are
patients with auto-topagnosia in whom identification of fingers is preserved. If they are
compared with those right-brain-damaged patients who have difficulties with the
localization of fingers but not with pointing to proximal body parts (Sauguet idem), there
emerges a double dissociation between auto-topagnosia and finger agnosia.
Common neuropsychological wisdom would suggest that a task which is sensitive to both
left and right-hemispheric damage does not tap a single psychological function.
Presumably, disturbances of finger localization have different reasons in left- and right-braindamaged patients.
The value of verbal tasks of finger identification has been called into question because they
may be more sensitive to language disorders than to defective orientation on the body.
413,414 However, a considerable number of brain-damaged patients fail on nonverbal tasks
of finger localization, like pointing on a drawing of a hand to fingers touched on the
patient's own hand (Poeck et al; Sauguet et al, idem) & 415.
However, we do have to be careful when assessing MDL especially using the lesion
method. It can be tempting to assume that a deficiency is due to a lesion in a particular
area, even more so when that area is already involved in other deficiencies. It has to be
remembered that due to the array of MDLs developmental problems she may not perform
well in tasks of recognition because she has not been educated in them.
MDL knows that she has a thumb and she may even be aware that her fifth finger is called
her little finger but she does not know the names of the other fingers. That is not a lack of
perception per se but a lack in naming. Likewise she knows what ears are for; she knows
that she has ears and if she was asked to point to someones ear in a picture she may well
be successful. The particular aspect of MDLs problem then, in her type of agnosia, is that if
she was asked to touch her own ear (which of course she cannot see) then she would not
be able to do it. If her ear itched then she would find it but could not do so on command.
This situation applies to all parts of her body that she cannot see. This then must be
considered, for her, not so much a lack in body perception but a failure in her
proprioceptor system.

Visual Object Agnosia

The condition of visual object agnosia refers to the

impairment of object recognition in the presence of relatively intact elementary visual
perception, memory, and general intellectual function. Although MDL might appear to
suffer with this problem, in her case it may not be due to standard patho-physiology.
Her inability (at times) not to recognise objects that she has seen before and could name at

412

Kinsbourne M & Warrington EK. A study of finger agnosia. Brain 85:47-66, 1962.

413

Poeck K & Orgass B. An experimental investigation of finger agnosia. Neurology 19:801-807,

1969.

414

Sauguet J; Benton AL & Hecaen H. Disturbances of the body schema in relation to language
impairment and hemispheric locus of lesion. J Neurol Neurosurg Psychiatry 34:496-501, 1971.

415

Gainotti G; Cianchetti C & Tiacci C. The influence of the hemispheric side of lesion on
nonverbal tasks of finger localization. Cortex 8:364-381, 1972.

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some earlier point in time may have more to do with her present memory ability and a
general confusional state than with the patho-physiology associated with this disability.

Disorders of Perception

There is a considerable amount of information and research

on this subject and it falls into two sections disorders that follow left brain damage (LBD)
and those that follow right brain damage (RBD). For the sake of relevance the following will
relate to RBD unless there is a necessary corollary that includes LBD.
Right brain-damaged patients perform more poorly than left brain-damaged patients on a
series of elementary space perception tasks, from point localization to depth perception
and detection of line orientation both in a bi-dimensional and in a three-dimensional
space.416
The superiority of the right hemisphere for this kind of task, brought out by cerebral damage,
is paralleled by the left visual field advantage, shown by normal subjects in conditions of
lateralized tachistoscopic projection. 417 The same hemispheric asymmetry is also found in
both normals 418 and in brain-damaged patients419,420 and is likely responsible for the
prominent contribution of the right hemisphere to tactile nonsense-shape discrimination.
Patients with RBD have been found to perform more poorly than patients with LBD on a task
where they had to run the forefinger of the ipsilateral hand along the raised outlines of a
meaningless block and then to recognize it on a multiple-choice visual display421 . The
same selective impairment of RBD patients was reported when they were asked to
manipulate a nonsense shape and then to match it to sample. 422
LeDoux and his colleagues investigated a patient with a visuo-spatial disturbance
characteristic of posterior right hemisphere disease who was examined under different
conditions of stimulus presentation. The visuo-spatial defect, which was shown by the
failure to perceive abnormalities concerning the left side of objects and the misperception
of spatial relations, was present under conditions of unrestricted visual exposure. However,
when the stimulus material was briefly exposed in the right visual field, performance
improved substantially. These data suggest that the visuo-spatial defect seen after right
hemisphere disease is attributable to factors other than the incapacity of the left
hemisphere to process visuo-spatial information. Their observations, together with other

416

De Renzi, E. Visuo-spatial and Constructional Disorders. In Feinberg, T E & Farah, M J.

Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

417

De Renzi E. Disorders of Space Exploration and Cognition. Chichester, England, Wiley, 1982.

418

Benton AL; Varney NR & Hamsher de SK. Visuo-spatial judgment: A clinical test. Arch Neurol
35:364367, 1978.

419

De Renzi E; Faglioni P & Scotti G. Judgment of spatial orientation in patients with focal brain
damage. J Neurol Neurosurg Psychiatry 34:489-495, 1971.

420

Fontenot DJ & Benton AL. Tactile perception of direction in relation to hemispheric locus of
lesion. Neuropsychologia 9:83-88, 1971.

421

De Renzi E & Scotti G. The influence of spatial disorders in impairing tactual discrimination of
shapes. Cortex 5:53-62, 1969.

422

Bottini G; Cappa S; Sterzi R & Vignolo LA. Intramodal somaesthetic recognition disorders
following right and left hemisphere damage. Brain 118:395-399, 1995.

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evidence, lead them to question those theories of cerebral lateralization based on the
notion that visuo-spatial processing is special to the right hemisphere423.
By far the most common way to demonstrate an impairment of spatial skills in braindamaged patients is to ask them to copy drawings or three-dimensional patterns, a task
that demands accurate analysis and reproduction of the spatial arrangement and the
reciprocal relation of the elements (lines, or blocks) composing the model. Copying drawings is a task that enjoys particular popularity in clinical practice because it is easy to
administer at the bedside and is the simplest way to bring out constructional apraxia. This
symptom, known to neurologists for more than sixty years 424, consists in the inability to
assemble the elements of a two-dimensional or three-dimensional whole, respecting their
orientations and spatial relationships.
MDL likes to do jig-saw puzzles but she can only manage to deal with those that have largesized pieces. She does not seem to have the ability to recognise the shape of the piece in
terms of part of it reciprocating with another. She used the picture on each individual
piece and matches it by colour first; she always needs to be prompted to look for similarities
but of course as these are only partial images it takes time for the whole picture and the
parts of it to be represented in her memory. When this has been achieved she takes delight
in being able to work it out by herself.
Constructional skills are required by many mechanical tasks and children's games, and they
also enter into a number of non-verbal mental tests, such as the block-design and pictureassembly sub tests of the Wechsler Adult Intelligence Scale (WAIS). However, the more
complex the task, the less specific its impairment because of the great number of skills it
involves; it is, therefore, more appropriate to study constructional apraxia with simpler tests
(e.g., copying geometric drawings of increasing complexity, three-dimensional block
constructions, and the spatial arrangement of sticks).
Kleist (idem) viewed constructional apraxia as a left parietal deficit, due to the disruption of
a centre (tentatively localized in the left angular gyrus) that would represent the interface
between the analysis of visuo-spatial information and the planning of hand movements.
On this assumption, the deficit would be attributable to neither a perceptual nor an
executive impairment but to the stage where movement programs, which are organized
by the left hemisphere, must be monitored by spatial analysis. However, this hypothesis was
abandoned when subsequent studies showed that constructional apraxia is by no means
limited to left parietal damage and is indeed as frequent or even more frequent following
right brain damage.
Since this side of the brain is not involved in the organization of actions, while it plays a
prominent role in space perception, it seemed logical to conceive of constructional
apraxia associated with right brain damage as dependent on defective visuo-spatial
analysis. What about the nature of constructional apraxia following left brain damage?
The discussion revolved around the question of whether it differs from right constructional
apraxia in terms of frequency, severity, quality of errors, and impairment of other cognitive
abilities with which it is associated. In the sixties, the view prevailed that the deficit
underlying constructional apraxia is basically apraxic when the lesion affects the left

423

LeDoux JE: Smylie CS; Ruff R; & Gazzaniga MS. Left hemisphere visual processes in a case of
right hemisphere symptomatology. Implications for theories of cerebral lateralization. Arch
Neurol. 1980 Mar; 37(3):157-9

424

Kleist K. Gehirnpathologie. Leipzig, Barth, 1934.

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hemisphere (which is dominant for praxis) and agnosic when it affects the right hemisphere
(which is dominant for space perception), and it was proposed425 to reserve the term
constructional apraxia for the deficit shown by LBD patients and that of visuo-spatial
agnosia for the deficit shown by RBD patients. However, this dichotomy has not passed the
test of time.
Looking at the question of the frequency and severity of constructional apraxia in
unselected samples of patients with unilateral hemispheric damage; contrasting findings
have been reported. A scrutiny426 of the relevant papers has pointed out that, while the
incidence of constructional apraxia in RBD patients was approximately the same across the
studies (about one third of patients were impaired), in LBD samples, it was much more
variable, ranging from 14 to 37 per cent. What made the difference was apparently the
type of test employed to assess constructional apraxia: the percentage of LBD patients with
constructional apraxia was low when performance was tested with tasks such as block
designs, which are part of intelligence scales and involve more than constructional abilities,
while it was at the same level as that found in RBD patients when tested with simpler tasks.
It is reasonable to suspect that the choice of complex tests entailed the exclusion from the
investigation of aphasics with severe comprehension deficits, resulting in a sampling bias
that is all the more risky as there is evidence that constructional apraxia is significantly
associated with receptive language impairment, even when it is measured with elementary
copying tasks427,428. Also, differences in the severity of the disorder were remarkably
reduced when the hemispheric samples were unselected, and they were seldom consistent
enough to reach significance.
If quantitative scores do not reliably discriminate RBD from LBD patients, are there clues in
the quality of their performance that suggest whether their disability has a perceptual or
motor origin? The only sign that has been consistently verified in RBD patients is failure to
reproduce left-sided details, a manifestation of their neglect of the left side of space. (De
Renzi, 1997 idem)
Flel and colleagues have determined that the right hemisphere is predominantly involved
in tasks associated with spatial attention. However, left hemispheric dominance for spatial
attention can be found in healthy individuals, and both spatial attention and language
can be lateralized to the same hemisphere. Their research suggests that it is not the
hemispheric side, but the intra-hemispheric pattern of activation that is the distinct feature
for the neural processes underlying language and attention. 429
Another approach to the discrimination of the mechanisms underlying constructional
apraxia in the two hemispheric groups has been the search for a differential association
between constructional disability and the performance on tests taxing manipulative skills
and space perception, respectively. It has been hypothesized that left apraxics would

425

McFie J & Zangwill OLO. Visual-constructive disabilities associated with lesions of the left
cerebral hemisphere. Brain 83:243-260, 1960.

426

De Renzi E. Disorders of Space Exploration and Cognition. Chichester, England, Wiley, 1982

427

Arena R & Gainotti G. Constructional apraxia and visuoperceptive disabilities in relation to

laterality of cerebral lesion. Cortex 14:463-473, 1978.

428

Benton AL. Visuoconstructive disability in patients with cerebral disease: Its relationship to side
of lesion and aphasic disorder. Doc OphthalmoI34:6776, 1973.

429

Flel A; Jansen A; Deppe M; Kanowski M; Konrad C; Sommer J; & Knecht S. Atypical

hemispheric dominance for attention: functional MRI topography. J Cereb Blood Flow Metab.
2005 Sep; 25(9):1197-208.

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score poorly on the former but not on the latter, while right apraxics would show the
opposite pattern. (De Renzi, 1997 idem)
The evidence that constructional apraxia reflects the disruption of different abilities,
depending on the damaged side, is at most suggestive but has not been unequivocally
demonstrated. Although an executive impairment remains a possible component of the
defective performance of LBD patients, visuo-spatial disorders are likely to be influential in
both hemispheric groups. (De Renzi, 1997 idem)
The anatomical correlates of constructional apraxia are in keeping with the assumption
that spatial disorders contribute to the difficulty of both hemispheric groups but that
executive disorders may also play a role in LBD patients.
Parietal damage is a frequent anatomic correlate of constructional apraxia after damage
to either hemisphere, although the association is closer in RBD patients than in LBD
patients430. It must, however, be added that the reproduction of a structured model is a
sequential task that requires a certain degree of planning and is, therefore, liable to be
sensitive to the functioning of frontal structures. 431 Indeed, there is evidence that frontal
damage may result in constructional apraxia432 and that the performance improves if
planning cues are provided.433 Supportive of the idea that different mechanisms underlie
parietal and frontal constructional apraxia is the finding that the disorder is associated with
poor performance on a line bisection task in RBD patients having damage to the parietooccipital cortex but not in those with frontal, sub-cortical damage. 434
Since the introduction of imaging techniques in clinical practice, it has been increasingly
recognized that sub-cortical structures contribute to cognitive functions, and disorders of
language, praxis, lateralized attention, and so on have been reported following damage to
basal nuclei. The same holds for constructional apraxia, whose incidence and severity do
not differ in sub-cortical as compared to cortical lesions435. Whether the deficit is due to the
interruption of pathways connecting cortical areas, resulting in their hypo-metabolism or to
the specific participation of basal nuclei in the performance is a matter of debate for this as
well as for other cognitive disorders.

Disorders of Spatial Memory

MDL does have problems of spatial memory
and it is highly probable that these are due to RBD. However, due to her injury being premental development, it is impossible to know how she compensated for this deficit once
mental development began. This ability is of course one that develops later in childhood,
once there is an ongoing demand for it.
Thus if she had a draughts board in front of her that had four black draughts on it, each on a

430

Ajuriaguerra J; Hcaen H & Angelergues R. Les apraxies: Varits cliniques et latralisation

lsionelle. Rev Neurol 102:566-594, 1960.

431

Luria AR & Tsvetkova LS. The programming of constructive activity in local brain injuries.
Neuropsychologia 2:95-108, 1964.

432

Benton AL. Differential behavioural effects in frontal lobe disease. Neuropsychologia 6:53-60,
1968

433

Pillon B. Troubles visuoconstructifs et mthodes de compensation: Resultats de 85 patients

atteints de lsions crbrales. Neuropsychologia 19:375-383, 1981.

434

Marshall RS; Lazar RM & Binder JR, et al: Intrahemispheric localization of drawing dysfunction.
Neuropsychologia 32:493-501, 1994.

435

Kirk A & Kertesz A. Subcortical contribution to drawing. Brain Lang 21:57-70; 1993.

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white square and she was asked to move them to four black squares, she probably could
not do it. She can follow instructions for one item at a time, e.g. please give me the red
cube; but she wouldnt remember that if she was asked to give the same cube again five
minutes later if the colour wasnt mentioned.
MDL does also have visual field defects in that she cannot point to objects that she has just
seen if she were to closes her eyes. Indeed this would be a difficult assessment to make for
she is unable to close her eyes on request.
Both RBD and LBD patients with visual field defects have a reduced spatial memory span.
436 The impairment is not attributable to the visual field deficit per se or to scanning and
misreaching disorders. It is, therefore, likely that the presence of visual field defects merely
points to the posterior location of lesions. In some patients the spatial short-term memory
deficit is so striking as to be also apparent in everyday life. Unlike short-term memory, longterm spatial memory has been found to be associated with right-sided lesions. (De Renzi,
1997 idem)

Topographical Disorientation

The most striking manifestation of spatial

memory deficit is topographic disorientation namely, the inability to find one's way in a
familiar environment and to learn new paths, in the absence of global amnesia, severe
mental deterioration, or disorders of visual perception and exploration.
The basic deficit underlying the patient's difficulty is the inability to retrieve an abstract map
of the route, which specifies the spatial relationships defining the position of a place with
respect to other places and the subject and to transform them in guidelines for walking.
It seems that MDL may have developed a macro-sense of direction within a prescribed
field. This only relates to location but she has little spatial memory for objects in a localised
field. Even so, there is always a topographical disorientation.
Landmark recognition and spatial map construction are the main mental operations that
assist navigation through familiar surroundings, and their discrete disruption underlies two
forms of route-finding disability, topographic agnosia and topographic amnesia. 437 The
nature of topographic agnosia has not been extensively investigated. The failure to identify
a specific building might result from perceptual impairment that prevents the appreciation
of the small, distinctive features identifying an exemplar of a category whose elements are
similar or from the inability to match the perceived building with its representation stored in
memory. The problem is whether the agnosia is class-specific or extends to other categories
(e.g., faces) that demand the recognition of the stimulus in its uniqueness.
Failure to recognize familiar environments is by no means a constant feature of patients
with topographic disorientation; even when it is present, it may not be the main reason for
route-finding disability. The amnestic nature of this form of topographic disorientation is
confirmed by the patient's failure to give a verbal description of the route, to trace it on a
road map, and to draw a map of a familiar place. Patients endeavour to find salient
objects, but these are of little help because they are devoid of orientation value and do
not tell them, for instance, whether they must proceed straight ahead, or turn left. Of
course, agnosic and amnesic disorders can coexist in the same patient, as both are

436

De Renzi E; Faglioni P & Previdi P. Spatial memory and hemispheric locus of lesion. Cortex
13:424433, 1977.

437

Paterson A & Zangwill OL. A case of topographical disorientation associated with a unilateral
cerebral lesion. Brain 68:188-121, 1945.

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dependent on right hemispheric damage.
The study of the anatomic correlates of topographic disorientation has pointed out the
crucial role played by the posterior regions of the brain, especially of the right hemisphere.
In some cases damage is bilateral but in others it is confined to the right side, where the
areas more frequently involved are the parietal lobe and the medial occipito-temporal
cortex. (De Renzi, 1997 idem)
In MDLs case there are difficulties mainly of a cognitive nature due to her lack of
understanding and of communication. So we dont know how much she can actually
compensate for her particular brain damage or how much of her difficulty is due to a lack
of experience in having to locate herself in a familiar environment. She is never out alone,
or at least has not been so for over twenty-five years. However, it is interesting again to
compare her later situation with that when she was a child. At the age of eight or nine she
could walk by herself from home to a post box and post a letter and then return home
whilst being unaccompanied for the whole journey. The post box was out of sight from the
entrance to her home. In her present situation of the last twenty years she has over-riding
anxiety and this will further diminish her cognitive ability and also introduce sympathetic
system involvement.
She does recognise familiar environments but not necessarily how to find them. She always
recognises the approach to her own home and will go to the door without hesitation. If she
is in the garden, then she can find her way back to the door of the house and would do so
even if there were other house doors adjacent. Should she find herself several streets away
from her home she may not be able to find her own way back home until she had made
the journey on foot twenty or thirty times over a short period. This is important because she
also does suffer from memory decay and if she was away from her home for say a year, she
would need time to reorient herself to what was once familiar. These failings are essentially
a consequence of RBD. (See also Prosopagnosia above p64)
In MDLs case the knowledge of the location of her brain lesions is entirely academic for
there cannot be any possibility of their reversal. The essential need to understand them
then, relates completely to the explanation of her deficits so that they can be a source of
positivity in dealing with her care and its planning.
The overall problems with the assessment by neurologists of MDLs neurological deficits are
made difficult by the fact that most recognised tests are based on the variations between
post-trauma abilities and pre-trauma abilities. MDL had no pre-traumatic abilities that are
of use to us in these contexts and her brain had to develop skills from the non-damaged
parts.
This is an entirely individual process and there cannot be any predictions made as to how
that would proceed. That is why, in her case, we can only work backwards and plot her
lack of neurological capabilities on the brain map and so try to find some developmental
characteristics that fit in with what is known about the consequences of damage in
particular areas.
Another consideration arising from MDLs brain damage and the time of its occurrence is
that she is not aware that she has a neurological deficiency indeed she is obviously
unable to have the knowledge of anything so complicated as that sort of understanding.
She has not experienced any pre-injury life of consequence and that remains in her
consciousness and what we havent experienced we cannot know what it would be like if
we had experienced it. There is then no emergent concern for MDL to try to re-engage or
re-capture what might have been there before. Firstly because she was far too young to
have experiential events to which she can relate and, secondly, she did not have a
development of consciousness to a level where such memories could be formed.
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This is why it is so important not to categorise her as Learning Disabled as that is too
simplistic a condition and unless all of her behaviour and neurological characteristics are
related to brain areas then she can neither be properly assessed nor can her care be
planned adequately.
Garnett et al has looked at how there could be an increase in the understanding of
relationships between general traumatic injury in children and long-term use of resources in
the health care and social services (HSS) sectors by these children and their families. They
concluded that paediatric trauma appears to have long-term effects on expenditures on
and use of HSS by the affected children and their families. Their findings emphasize the
need for long-term assessment and improved delivery of services to the families of the
injured children. 438

The Proprioceptor System

In some neuro-biological dysfunctions there can be

distortions in the sensory system of the body. Without proper neurobiological support, the
ability to touch, see, and hear can be distorted. When vestibular and proprioceptor
systems are inadequate, such perceptions as the ability to know where one is in space, to
have a sense of time, and even to have a sense of humour can be distorted in such a way
that the individual has difficulty perceiving the world correctly. Visual, auditory, and tactile
responses must be able to perceive, interpret and process information so that we can learn
about the world around us. Without good sensory integration, learning and behaviour is
more difficult and the individual often feels uncomfortable about him-/herself, and cannot
easily cope with ordinary demands and stress. 439
The proprioceptor system consists of sensory information caused by contraction and
stretching of muscles and by bending, straightening, pulling and compression of the joints
between the bones. Because there are so many muscles and joints in the body, the
proprioceptor system is almost as large as the tactile system. Most proprioceptor input is
processed in areas of the brain that do not produce conscious awareness. Without good
automatic responses, such things as eye-hand coordination are very difficult.
Connected to these is the vestibular system that is the sensory system which responds to the
position of the head in relation to gravity and accelerated or decelerated movement.
There are two types of vestibular receptors in the inner ear in a structure called the
labyrinth. One type of receptor responds to the force of gravity. The other type of receptor
is in the semicircular canals in the ear. These canals are responsible for our sense of
movement. The vestibular system is a unifying one. All other types of sensation are
processed in reference to this basic vestibular information. The activity in the vestibular
system provides a framework for the other aspects of our experience. Vestibular input
seems to prime the entire nervous system to function effectively. When the vestibular
does not function in a consistent and accurate way, the interpretation of other sensations
will be inconsistent and inaccurate, and the nervous system will have trouble getting
started.
The visual system has become our major means of relating to space, but the vestibular,
proprioceptor and tactile systems must contribute to visual development and function.
Together these systems allow us to move about in space, catch a ball, and process the

438

Garnett, A & Browne, G. The Relationship between Traumatic Injury in Children and Long-Term
Use of Health and Social Services by Children and Their Families. J Trauma Nurs. 2016 Jul-Aug;
23(4):215-26. doi: 10.1097/JTN.0000000000000219.

439

Ayers, A. J. Sensory Integration and the Child, Western Psychological Services, 1979, 191pp.
p.51

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visual body language of others. In order to process more abstract information such as
reading, writing, spelling or calculation, such visual abilities as visual-motor, visual
perceptual, visual spatial, visual memory, visual figure-ground and visual closure capacities
must be in place. These capacities only work well when the tactile, vestibular and
proprioceptor systems are intact. It is clear that for MDL these systems have faults and are
not well coordinated.
I mention this here not only because it is associated but also because it is another area in
which MDL has problems. She never closes her eyes except when asleep; and that may be
one problem that may cause a deficiency in sleep initiation (but see below). She also does
not like to have her head in line with her body when she is lying down. She only seems
comfortable when lying if her head is inclined forwards by about thirty degrees from the
horizontal. She will resist all attempts to get her to lie in a completely prone position.

Ideomotor apraxia

Ideomotor apraxia is a symptom of left brain damage, which

is usually considered as a disorder of motor control. 440,441,442,443 (See Memories of Skilled
Movements p10.) In particular, defective imitation of gestures has been considered as
testifying a deficit of motor execution. In the words of de Renzi, Since the examiner
provides the model and the patient has only to copy it, errors can only be due to a deficit
of motor execution. (De Renzi, idem) This argument seems to be particularly convincing if
novel and meaningless gestures are to be imitated. Whereas imitation of familiar and
meaningful gestures could be mediated by pre-existing knowledge of the gestures spatial
configuration, imitation of meaningless gestures appears to test a direct route from visual
perception to motor execution. 444,445,446
There is, however, an alternative interpretation of the task demands of imitation of
meaningless gestures. It proposes that general topographic knowledge about the human
body mediates the transition from visual perception to motor execution. 447,448,449,450

440

Liepmann H. Drei Aufsiitze aus dem Apraxiegebiet. Berlin: Karger, 1908.

441

Poeck K. The two types of motor apraxia. Arch Ital Bioi 120:361-369, 1982.

442

de Renzi E. Apraxia, in Boller F, Grafman J (eds): Handbook of Neuropsychology. New York:

Elsevier, 1990, vol 2,.pp 245-263.

443

Heilman KM & Rothi UG. Apraxia, in Heilman KM, Valenstein E (eds): Clinical
Neuropsychology. New York: Oxford University Press, 1993, pp 141-164.

444

Barbieri C & de Renzi E. The executive and ideational components of apraxia. Cortex 24:535544, 1988.

445

Rothi LJ; Ochipa C & Heilman KM. A cognitive neuropsychological model of limb praxis. Cog
Neuropsychol 8:443-458, 1991.

446

Roy EA & Hall C. Limb apraxia: A process approach, in Proteau L, Elliott D (eds): Vision and
Motor Control Amsterdam: Elsevier, 1992, pp 261-282.

447

Morlaas J. Contribution l'tude de l'apraxie. Paris: Amde Legrand, 1928.

448

Goldenberg G. Imitating gestures and manipulating a manikin - The representation of the

human body in ideomotor apraxia. Neuropsychologia 33:63-72, 1995.

449

Goldenberg G; Hermsdrfer J & Spatt J. Ideomotor apraxia and cerebral dominance for
motor control. Cog Brain Res. 1996; 3:95-100.

450

Goldenberg G. Defective imitation of gestures in patients with left and right hemisphere
lesions. J Neurol Neurosurg Psychiatry. 1996; 61: 176-180.

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The idea that defective imitation of gestures is due to a lack of topographic knowledge
about the human body likens it to autotopagnosia. The parallel between defective
imitation of meaningless gestures and autotopagnosia was strengthened by a study by
Goldenberg who examined imitation of three kinds of gestures:

for imitation of hand postures, the patients were required to copy different positions
of the hand relative to the head while the configuration of the fingers remained
invariant;

for imitation of finger postures, patients were asked to replicate different

configurations of the fingers, and the position of the whole hand relative to the
body was not considered for scoring;

for imitation of combined gestures, both a defined position of the hand relative to
the body and defined configuration of the fingers were required. (Goldenberg,
idem)

Regardless of whether imitations of hand positions and finger configurations were tested
each on their own or together, they proved to show differential susceptibility to left and
right brain damage. Whereas imitation of finger configurations was about equally impaired
in left- and right-brain-damaged patients, defective imitation of hand positions occurred
exclusively in left-brain-damaged patients, and whereas controls as well as right- braindamaged patients committed fewer errors with hand positions than with finger configurations, the reverse was the case in left-brain-damaged patients. This dissociation between
gestures requiring orientation relative to the proximal body and gestures requiring
orientation within the hand closely resembles the above-mentioned dissociation between
autotopagnosia and finger agnosia.
A lack of general knowledge about the human body should lead to errors regardless of
whether gestures are to be replicated on another body or on oneself. Indeed, patients
who display apraxia on imitation of hand positions commit more errors than either left-braindamaged patients without apraxia or right-brain-damaged patients when trying to
replicate the same positions on a manikin.

Pantomime comprehension and ideomotor apraxia451

Mariella Pazzaglia from the IRCCS Fondazione Santa Lucia and University of Rome La
Sapienza, describes a rapidly growing body of clinical research on the complex interplay
of both production and comprehension mechanisms in actions derived from gesture
comprehension studies described in patients with apraxia.
Gesture comprehension deficit correlates with damage to the opercular and triangularis
portions of the inferior frontal gyrus, two regions that are involved in complex aspects of
action-related processing. In contrast, no such relationship seems to be found with lesions
centred on the inferior parietal cortex. These research findings suggest that lesions to left
frontal regions that are involved in planning and performing actions are causatively
associated with deficits in the recognition of the correct execution of meaningful
gestures.452

451

Rothi LJ, Heilman KM, Watson RT. Pantomime comprehension and ideomotor apraxia. J
Neurol Neurosurg Psychiatry 1985; 48:20710.

Pazzaglia M, Smania N, Corato E, Aglioti SM. Neural underpinnings of gesture

discrimination in patients with limb apraxia. J Neurosci 2008;28:303041.
452

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The inextricable link between action perception and action execution was reported for the
first time in a neuropsychological study of apraxia patients (Rothi et al, 1985). In that article,
Rothi et al not only provided the first direct evidence of the existence of a bidirectional
relationship between action perception and motor activity, but also provided causative
information on the neural structures involved in the visual mapping of actions in patients
with brain damage. Using a non-verbal paradigm, the authors identified a clear
association between a deficit in performing gestures and the ability to recognise the
pantomime of gestures appropriately in left hemisphere-lesioned patients with apraxia but
not in those with aphasia.
These observations suggest that the representational aspects of gestures prevent action
imitation and influence the execution of a given movement, typically affected in apraxia.
Patients with apraxia presented lesions centred, mainly on the parietal cortex, but
extending into the frontal regions. The authors revealed that, although both frontal and
parietal structures are involved in the execution of actions, the left posterior regions seem to
be primarily linked to the specific ability to comprehend the meaning of pantomime. This
anatomical and functional investigation of apraxia patients highlighted, for the first time, a
series of unexpected characteristics of these sensorimotor areas.
In fact, a decade later, neurophysiological research performed in monkeys showed that
these two areas, which probably host mirror neurons, are the core regions of the system of
action observation and execution. 453, 454, 455, 456 In particular, it has been claimed that direct
matching between action perception and execution is enabled by neural activity that
overlaps largely in the inferior frontal gyrus and the inferior parietal lobe.457 One
interpretation of such data is that motor system modulation during action perception
facilitates and assists the reading of the actions of others and promotes readiness to predict
movements and perform actions.458
It is also known that patients with parietal damage and impaired ability to imitate or
discriminate an observed action lose the capacity to monitor early phases of planning of

Fogassi L, Ferrari PF, Gesierich B, Rozzi S, Chersi F, Rizzolatti G. Parietal lobe: from
action organization to intention understanding. Science 2005;308:6627.
453

Gallese, V; Fadiga, L; Fogassi L; & Rizzolatti G. Action recognition in the premotor

cortex. Brain 1996;119:593609.
454

di Pellegrino G, Fadiga L, Fogassi L, Gallese V, Rizzolatti G. Understanding motor

events: a neurophysiological study. Exp Brain Res 1992;91:17680.
455

Grafton ST, Arbib MA, Fadiga L, Rizzolatti G. Localization of grasp representations in

humans by positron emission tomography. 2. Observation compared with imagination. Exp
Brain Res 1996;112:10311.
456

457

Pazzaglia, M; Smania, N; Elisabetta Corato, E; & Maria Aglioti, S. Neural Underpinnings of

Gesture Discrimination in Patients with Limb Apraxia. JNeurosci. 19 March 2008, 28(12): 30303041; doi: 10.1523 5748-07.2008.

Kalenine S, Buxbaum LJ, Coslett HB. Critical brain regions for action recognition:
lesion symptom mapping in left hemisphere stroke. Brain 2010;133:326980.

458

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their own movements.459 Apraxia patients with injury in parietal areas not only have major
problems in comprehending actions but also frequently exhibit failure of the anticipatory
motor process that drives forthcoming movements via predictive mechanisms.460
In MDLs case then and considering that she has an extreme lack of knowledge about the
human body and also that she cannot, on command, locate parts of her own body by
name, it would seem that she is affected more by general apraxia than by ideomotor
apraxia.

_____________________

The Emotional Brain

Significant progress has been made in identifying brain regions involved in certain domains
of emotional behaviour, particularly fear. Most of this advance in knowledge has evolved
from animal models of emotion, although extensions of this work into human populations
have begun to be established461.
Early research showed that emotional expression appeared to be mediated by diencephalic
structures, including the thalamus and hypothalamus, located below the cortex but above
the midbrain. 462,463 In addition, the diffuse sympathetic arousal in the periphery seemed to
be too undifferentiated to determine distinct emotional states464. Later it was determined465
that the emotional circuit consisted of the hypothalamus, anterior thalamus and the
cingulate cortex.
The ante-limbic system concept, has been primarily linked to cognitive functions, such as

Fontana AP, Kilner JM, Rodrigues EC, Joffily M, Nighoghossian N, Vargas CD, Sirigu A.
Role of the parietal cortex in predicting incoming actions. Neuroimage. 2012 Jan
2;59(1):556-64. Epub 2011 Jul 23.
459

460

Pazzaglia, M; Pizzamiglio, L; Pes, E; Maria Aglioti, S. The Sound of Actions in Apraxia. Current
Biol.Vol 18, Issue 22, 25 November 2008, Pages 17661772.

461

LaBar, KS & LeDoux, JE. Emotion and the Brain: An Overview. In Feinberg, T E & Farah, M J.
Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

462

Kotter R & Meyer N. The limbic system: A review of its empirical foundation. Behav Brain Res
52:105-127,1992.

463

LeDoux JE. Emotion, in Plum F (ed): Handbook of Physiology: I. The Nervous System. Higher
Functions of the Brain. Bethesda, MD: American Physiological Society 1987, vol 5, pp 419-460.

464

LeDoux JE. Emotion and the limbic system concept. Concepts Neurosci 2:169-199, 1991

465

Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry 79:217-224, 1937.

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declarative memory 466, spatial cognition, 467,468 and contextual / configural / relational
processes.469,470,471 Subsequent work has consistently implicated the amygdala in
emotional processing. 472 Thus, the inclusion of the amygdala may explain the longstanding survival of the limbic system concept as a model for emotional processing in the
brain.

Emotions and our Mental Life

We've all felt love and hate and fear and
anger and joy; but what is it that ties mental states like these together into the bundle that
we commonly call emotions? What makes this bundle so different from other mental
packages, ones that we are less inclined to use the term emotion for? How do our emotions influence every other aspect of our mental life, shaping our perceptions, memories,
thoughts, and dreams? Why do our emotions often seem impossible to understand? Do
we have control over our emotions or do they control us? Are emotions cast in neural stone
by our genes or taught to the brain by the environment? Can we have unconscious
emotional reactions and unconscious emotional memories? Can the emotional slate ever
be wiped clean, or are emotional memories permanent? 473
You may have opinions, and even strong ones, about the answers to some of these
questions, but whether your opinions constitute scientifically correct answers can't be
determined by intuitions alone. Occasionally, scientists turn everyday beliefs into facts, or
explain the workings of intuitively obvious things with their experiments. However, facts
about the workings of the universe, including the one inside your head, are not necessarily
intuitively obvious. Sometimes, intuitions are just wrong the world seems flat but it is not
and science's role is to convert these common-sense notions into myths, changing truisms
into old wives' tales. Frequently, though, we simply have no prior intuitions about
something that scientists discover there is no reason why we should have deep-seated
opinions about the existence of black holes in space, or the importance of sodium,
potassium, and calcium in the inner workings of a brain cell. Things that are obvious are not
necessarily true, and many things that are true are not at all obvious. (LeDoux, Idem)
LeDoux views emotions as biological functions of the nervous system. He believes that
figuring out how emotions are represented in the brain can help us understand them. This
approach contrasts sharply with the more typical one in which emotions are studied as
psychological states, independent of the underlying brain mechanisms. Psychological
research has been extremely valuable, but an approach where emotions are studied as
brain functions is far more powerful. (Idem)

466

Squire LR. Mechanisms of memory. Science 232:1612-1619, 1987

467

O'Keefe J & Nadel L. The Hippocampus as a Cognitive Map. Oxford, England: Clarendon,
1978.

468

Nadel L. Hippocampus and space revisited. Hippocampus 1:221-229, 1991.

469

Hirsh R. The hippocampus and contextual retrieval of information from memory: A theory.
Behav Bioi 12:421-444, 1974.

470

Sutherland RJ & Rudy JW. Configural association theory: The role of the hippocampal
formation in learning, memory, and amnesia. Psychobiology 17:129-144, 1989.

471

Cohen NJ & Eichenbaum H. Memory, Amnesia, and the Hippocampal System. Cambridge,
MA: MIT Press, 1993.

472

LeDoux JE. Emotion and the amygdala, in Aggleton JP (ed): The Amygdala: Neurobiological
Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 339-352.

473

LeDoux, J. The Emotional Brain: The mysterious underpinnings of emotional life. Weidenfeld &
Nicholson, London; 1998

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_______

THE HYPOTHALAMUS
The hypothalamus may be thought of as the anatomical axis about which the other major
limbic areas (septum, amygdala, hippocampus, and neocortex) are organized.
Physiologically, its demonstrated importance to both endocrine and autonomic functions
indicates its probable involvement in emotions, sex and aggression. Cannon postulated
the idea some 50 years ago, and there is now considerable supporting evidence.
Some of the most interesting experiments in this area have been conducted by Flynn and
associates at Yale University. Flynn found that electrical stimulation of the lateral hypothalamus in cats evoked a deliberate, stealthy and well-organized form of predatory
aggression which he called quiet stalking attack. In contrast, medial hypothalamic
stimulation evoked an explosive, hissing, spitting and clawing type of predation called
affective attack. In each case the objective of the attack was the same killing the rat.
However, this was virtually the only similarity between the two types of aggression.
Results from experiments in which the two hypothalamic components have been lesioned
are not in complete accordance with the stimulation results. For example, destruction of
the lateral hypothalamus appears to reduce aggressiveness (along with the vigour of
almost every other behaviour). On the other hand, a cat with a lateral hypothalamic lesion
on only one side of the brain will show great interest in, and possibly attack, a rat in one half
of its visual field, while completely ignoring a rat in the other half of its visual field. The results
argue against the loss of predatory aggression as being a generalized disturbance. So, with
respect to the involvement of the lateral hypothalamus in predatory aggression, the lateral
hypothalamic stimulation and lesion results are complementary.
The case with respect to medial hypothalamic involvement in aggression is not as clear.
Since stimulation of the medial hypothalamus produces affective attack, it would be
reasonable to expect that lesions of the medial hypothalamus would inhibit the same
behaviour. However, medial hypothalamic lesions almost universally produce a marked
increase in most forms of aggression. This type of paradoxical result in the study of emotionality often characterizes experimental manipulations of limbic function.

Regulation of Body Temperature In human beings the body temperature is maintained

at an average of 368C (984F). This is the optimum temperature for the many complex
chemical processes to occur. If the temperature is raised the metabolic rate is increased
and if it is lowered the rate of metabolism is reduced. To ensure this constant temperature
a fine balance is maintained between heat produced in the body and heat lost to the
environment.

The centre controlling temperature is situated in the cerebrum and involves a group of
nerve cells in the hypothalamus called the heat regulating centre. There is also a group of
nerve cells in the medulla oblongata known as the vasomotor centre which controls the
calibre of the blood vessels, especially the small arteries and the arterioles, and they control
the amount of blood which circulates in the capillaries in the dermis.
The heat regulating centre and vasomotor centre are thought to be extremely sensitive to
the temperature of the blood and any significant change stimulates them to activity. From

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these centres sympathetic nerves convey impulses to the sweat glands, arterioles and the
arrector muscles of the hairs in the skin.

Destruction of the anterior hypothalamus destroys the ability to cope with heat
stress, but it does not affect the ability to cope with cold stress. Conversely, destruction of

the posterior hypothalamus destroys the ability to cope with cold stress without affecting
the response to heat stress. Complementary data come from studies in which hypothalamic function has been altered by electrical stimulation through implanted electrodes.
Electrical stimulation of anterior hypothalamus results in decreased body temperature and
a suppression of shivering in the cold. Electrical stimulation of the posterior hypothalamus
results in increased body temperature and shivering, even in a warm environment. These
results indicate that the anterior hypothalamus facilitates heat loss, and the posterior
hypothalamus facilitates heat production. 474
Of great interest in thermo-regulatory research is Myers' identification of a potential
physiological basis for the set-point for body temperature. Myers presents evidence that
the temperature set-point is maintained by a balance between sodium (Na +) and calcium
(Ca2+) ions in a restricted area of the posterior hypothalamus. Application of Na + ions
increases body temperature, whereas application of Ca2+ ions to the same site decreases
body temperature. The changes did not occur in response to other ions, such as potassium
(K +) or magnesium (Mg2+), nor if the Na + or Ca2 + ions were applied to other parts of the
hypothalamus.
Myers claims that the set-point is determined by the ion balance and not by other means.
He notes that the subject will actively defend the ion-induced changes over a long period,
whereas other hypothalamic manipulations simply impair regulation.
There is therefore a possibility that MDLs problem when she is saying that she is feeling hot
when her skin is cool and her face not flushed could be due to damage in the
hypothalamus.
This then further narrows the area of damage in MDLs hypothalamus to the lateral aspect as
MDL has never shown any form of aggression during the whole of her life.

_______

THE AMYGDALA
The amygdala and emotions

What is it about the activation of the

amygdala that converts an experience into an emotional experience? To understand this
we need to consider some of the various consequences of activating the amygdala. This
sequence of neurological events provide the basic ingredients that, when added to the
working memory with short-term sensory representations and the long-term memories
activated by these sensory representations, there is created an emotional experience.

Ingredient 1 Direct Amygdala Influences on the Cortex:

474

The amygdala has

Atrens, D & Curthoys, I. The Neurosciences and Behaviour: An Introduction. Academic Press
1982.

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projections to many cortical areas. 475 In fact the projections of the amygdala to the cortex
are considerably greater than the projections from the cortex to the amygdala. In addition
to projecting back to cortical sensory areas from which it receives inputs, the amygdala
also projects to some sensory processing areas from which it does not receive inputs. For
example, in order for a visual stimulus to reach the amygdala by way of the cortex, the
stimulus has to go through the primary cortex, to a secondary region, and then to a third
cortical area in the temporal lobe (which does the short-term buffering of visual object
information). This third area then projects to the amygdala. The amygdala not only
projects back to this area but also to the other two earlier visual processing regions.
As a result, once the amygdala is activated, it is able to influence the cortical areas that
are processing the stimuli that are activating it. This might be very important in directing
attention to emotionally relevant stimuli by keeping the short-term object buffer focused on
the stimuli to which the amygdala is assigning significance. The amygdala also has an
impressive set of connections with long-term memory networks involving the hippocampal
system and areas of the cortex that interact with the hippocampus in long-lasting
information storage.
These pathways may contribute to the activation of long-term memories relevant to the
emotional implications of immediately present stimuli. Although the amygdala has
relatively meagre connections with the lateral prefrontal cortex, it sends rather strong
connections to the anterior cingulate cortex, one of the other partners in the frontal lobe
working memory executive circuitry. It also sends connections to the orbital cortex, another
component of working memory that may be especially involved in working memories that
are about rewards and punishments.
Mild traumatic brain injury (MTBI) is often associated with selective impairment of both
working memory and the executive functions. Research indicates that one of the
commonest deficits present in MTBI patients falls in the domain of working memory. Kumar
et al suggest that MTBI may lead to working memory deficits as the contribution of
executive processes to support the working memory is diminished following MTBI.476
Abstract Deficits in working memory are a common consequence of pediatric traumatic
brain injury (TBI) and are believed to contribute to difficulties in a range of cognitive and
academic domains. Working memory is the brain's ability to collect, retain and use
information that's needed in order to perform tasks and respond to immediate demands.
Treble et al used brain imaging studies that measured verbal and visuospatial working
memory via a group of children that sustained a TBI and a control group that did not.
Reduced integrity of the corpus callosum after TBI may disrupt the connectivity between
bilateral frontoparietal neural networks underlying. 477 [See Working Memory & Cognition p.
145]

475

Amaral, D G; Price, J L; Pitkanen, A. & Carmichael, S T. Anatomical organization of the

primate amygdaloid complex. In The amygdala: Neurobiological aspects of emotion,
memory, and mental dysfunction, J. P. Aggleton, ed. (New York: Wiley-Liss), pp. 1-66; 1992.

Kumar S, Rao SL, Chandramouli BA, Pillai S. Reduced contribution of executive

functions in impaired working memory performance in mild traumatic brain injury patients.
Clin Neurol Neurosurg. 2013 Jan 29.
476

477

Treble A; Hasan KM; Iftikhar A; Stuebing KK; Kramer LA; Cox CS Jr.; Swank PR & Ewing-Cobbs L.
Working memory and corpus callosum microstructural integrity after paediatric traumatic
brain injury: a diffusion tensor tractography study. J Neurotrauma. 2013 Oct 1;30(19):1609-19.
doi: 10.1089/neu.2013.2934. Epub 2013 Aug 24.

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The comparisons showed that children who had experienced this problem demonstrated
poorer visuospatial skills and working memory that are often associated with disruptions
found in brain connectivity between neural networks that underlie working memory.
Through the study, the authors proposed that the identification of neruoanatomical
biomakers may be indicative of changes found in the brain's microstructure that could
allow for early identification of children who may be at an increased risk for impaired
working memory and for earlier intervention.
Reduced microstructural integrity of the corpus callosum, particularly in subregions
connecting parietal and temporal cortices, may act as a neuropathological mechanism
contributing to long-term working memory deficits. The future clinical use of
neuroanatomical biomarkers may allow for the early identification of children at highest risk
for working memory deficits and earlier provision of interventions for these children.
This research confirms a longstanding belief that the corpus callosum is consistently
involved with traumatic brain injury, and the study's specific analyses of callosal integrity,
together with its evaluation of working memory in a pediatric brain-injured population,
make this a particularly important contribution to the field of pediatric TBI.
By way of these connections with specialized short-term buffers, long-term memory
networks, and the networks of the frontal lobe, the amygdala can influence the information
content of working memory. There is obviously a good deal of redundancy built into this
system, making it possible for the conscious awareness of amygdala activity to come about
in several ways.
To summarize: the connections from the amygdala to the cortex allow the defence
networks of the amygdala to influence attention, perception, and memory in situations
where we are facing danger. At the same time though, these kinds of connections would
seem to be inadequate in completely explaining why a perception, memory, or thought
about an emotional event should feel different from one about a non-emotional event.
They provide working memory with information about whether something good or bad is
present, but are insufficient for producing the feelings that come from the awareness that
something good or bad is present. For this we need other connections as well.

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Pathways to the Amygdala

Information about external stimuli reaches the amygdala by way of direct pathways from the thalamus as well as by way of pathways from the thalamus to
the cortex to the amygdala.
The direct thalamo-amygdala path is a shorter and thus a faster transmission
route than the pathway from the thalamus through the cortex to the amygdala.
However, because the direct pathway bypasses the cortex, it is unable to
benefit from cortical processing.
As a result, it can only provide the amygdala with a crude representation of the
stimulus. It is thus a quick and dirty processing pathway. The direct pathway
allows us to begin to respond to potentially dangerous stimuli before we fully
know what the stimulus is. This can be very useful in dangerous situations.
However, its utility requires that the cortical pathway be able to override the
direct pathway. It is possible that the direct pathway is responsible for the
control of emotional responses that we don't understand. This may occur in all
of us some of the time, but may be a predominant mode of functioning in
individuals with certain emotional disorders.

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Ingredient 2 Amygdala-Triggered Arousal:

In addition to the direct
influences of the amygdala on the cortex, there are a number of indirect channels through
which the effects of amygdala activation can impact on cortical processing. An extremely
important set of such connections involves the arousal systems of the brain.
It has long been believed that the difference between being awake and alert, on the one
hand, and drowsy or asleep on the other is related to the arousal level of the cortex.478
When you are alert and paying attention to something important, your cortex is aroused.
When you are drowsy and not focusing on anything, the cortex is in the unaroused state.
During sleep, the cortex is in the unaroused state, except during dream sleep when it is
highly aroused. In dream sleep, in fact, the cortex is in a state of arousal that is very similar
to the alert waking state, except that it has no access to external stimuli and only processes
internal events479.
When arousal occurs, cells in the cortex and in the thalamic regions that supply the cortex
with its major inputs, become more sensitive.480,481 They go from a state in which they tend
to fire action potentials at a very slow rate and more or less in synchrony to a state in which
they are generally out of sync but with some cells being driven especially strongly by
incoming stimuli.
While much of the cortex is potentially hypersensitive to inputs during arousal, the systems
that are processing information are able to make the most use of this effect. For example, if
arousal is triggered by the sight of a snake, the neurons that are actively involved in
processing the snake, retrieving long-term memories about snakes, and creating working
memory representations of the snake are going to be especially affected by arousal. Other
neurons are inactive at this point and don't reap the benefits. In this way, a very specific
information processing result is achieved by a very nonspecific mechanism. This is a
wonderful system.
A number of different systems appear to contribute to arousal. Four of these are located in
regions of the brain stem. Each has a specific chemical identity, which means the cells in
each contain different neurotransmitters that are released by their axon terminals when the
cells are activated.
One group makes acetylcholine (ACh), another noradrenalin, another dopamine, and
another serotonin. A fifth group, also containing ACh, is located in the forebrain, near the
amygdala. The axons of each of these cell groups terminate in widespread areas of the
forebrain. In the presence of novel or otherwise significant stimuli the axon terminals release
their neurotransmitters and arouse cortical cells, making them especially receptive to

478

Moruzzi, G. & Magoun, HW. Brain stem reticular formation and activation of the EEG.
Electroencephalography and Clinical Neurophysiology 1, 455-73; 1949.

479

Hobson, J A, & Steriade, M. Neuronal basis of behavioral state control. In Handbook of

Physiology. Section 1: The Nervous System. Vol. 4: Intrinsic Regulatory Systems of the Brain. V. B.
Mountcastle, ed. (Bethesda, MD: American Physiological Society), pp. 701-823; 1986.

480

This applies to arousal occurring during waking states. Arousal also occurs during sleep,
especially dream or REM sleep. In this case the cortex becomes insensitive in external inputs
and is focused instead on internal stimuli. [Hobson and Steriade (I 986); McCormick and Bal
(I994)].

481

McCormick, DA. & Bal, T. Sensory gating mechanisms of the thalamus. Current Opinion in
Neurobiology 4, 550-56; 1994.

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incoming signals.
Arousal is important in all mental functions. It contributes significantly to attention,
perception, memory, emotion, and problem solving. Without arousal, we fail to notice what
is going on we don't attend to the details. But too much arousal is not good either. If you
are over-aroused you become tense and anxious and unproductive. You need to have just
the right level of activation to perform optimally. 482
Emotional reactions are typically accompanied by intense cortical arousal. Certain
emotion theories around the mid-20th century proposed that emotions represent one end of
an arousal continuum that spans from being completely unconscious (in a coma), to
asleep; to awake but drowsy; to alert; to emotionally aroused. This high level of arousal is,
in part, the explanation for why it is hard to concentrate on other things and work efficiently
when you are in an emotional state. Arousal helps lock you into the emotional state you
are in. This can be very useful (you don't want to get distracted when you are in danger),
but can also be an annoyance (once the fear system is turned on, it's hard to turn it off
this is the nature of anxiety).
Although each of the arousal systems probably contributes to arousal in the presence of
stimuli that are dangerous or that warn of danger, it appears that interactions between the
amygdala and the nearby ACh-containing system in the forebrain are particularly
important.483,484 This ACh-containing system is called the nucleus basalis. Damage to the
amygdala or to the nucleus basalis prevents stimuli that warn of danger, like conditioned
fear stimuli, from eliciting arousal. Moreover, stimulation of the amygdala or the nucleus
basalis elicits cortical arousal artificially. The administration of drugs that block the actions
of ACh in the cortex prevents these effects on arousal of conditioned stimuli, amygdala
stimulation, or nucleus basalis stimulation from occurring. Together, these and other findings
suggest that when the amygdala detects danger it activates the nucleus basalis, which
then releases ACh throughout the cortex. The amygdala also interacts with the other
arousal systems located in the brain stem, and the overall effect of amygdala activation on
arousal certainly involves these as well.
Although there are a number of different ways that the nucleus basalis cells can be turned
on, the way they are turned on by a dangerous stimulus is through the activity of the
amygdala. (Kapp et al, idem, 1992) Other kinds of emotional networks most likely have
their own ways of interacting with the arousal systems and altering cortical processing.
Arousal occurs to any novel stimulus that we encounter and not just to emotional stimuli.
The difference is that a novel but insignificant stimulus will elicit a temporary state of arousal
that dissipates almost immediately but arousal is prolonged in the presence of emotional
stimuli. If you are face-to-face with a predator it is crucial that you do not lose interest in
what is going on or be distracted by some other event. While this seems so obvious as to
be silly, it is only so because the brain does it so effortlessly.
Why is arousal perpetuated to emotional but not to other stimuli? Again, the answer
probably has to do with the involvement of the amygdala. The arousal elicited by a novel

482

This is generally known in psychology as the Yerkes-Dodson law.

483

Kapp, BS; Whalen, PJ; Supple, WE, & Pascoe, JP. Amygdaloid contributions to conditioned
arousal and sensory information processing. In The amygdala: Neurobiological aspects of
emotion, memory, and mental dysfunction, J. P. Aggleton, ed. (New York: Wiley-Liss); 1992.

484

Weinberger, NM. Retuning the brain by fear conditioning. In The cognitive neurosciences, M S
Gazzaniga, ed. (Cambridge: MIT Press), pp. 1071-90; 1995.

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stimulus does not require the amygdala. Instead, it is mediated by direct inputs from
sensory systems to arousal networks. It appears in fact that the cortex arouses itself since
sensory stimuli first go to the cortex and are then sent back to the brain stem and these inputs trigger the arousal system, which then arouses the cortex485.
These kinds of arousal effects quickly habituate. If the stimulus is meaningful, say
dangerous, then the amygdala is brought into the act and it also activates arousal systems.
This adds impetus to keep arousal going. The continued presence of the stimulus and its
continued interpretation by the amygdala as dangerous continues to drive arousal systems,
and these systems, in turn, keep cortical networks that are processing the stimulus in a state
of hypersensitivity. The amygdala, it should be noted, is also the recipient of arousal system
axons, so that amygdala activation of arousal systems also helps keep the amygdala
aroused. These are self-perpetuating, vicious cycles of emotional reactivity. Arousal locks
you into whatever emotional state you are in when arousal occurs, unless something else
occurs that is significant enough and arousing enough to shift the focus of arousal. It can be
seen then that damage to this system may cause MDLs arousal system to continue to be
active when otherwise it would have been refocused either through cognitive interaction or
by appropriate involvement of another person.
The information content provided by arousal systems is weak. The cortex is unable to
discern that danger (as opposed to some other emotional condition) exists from the pattern
of neural messages it receives from arousal systems. Arousal systems simply say that something important is going on. The combination of non-specific cortical arousal and specific
information provided by direct projections from the amygdala to the cortex allows the
establishment of a working memory that says that something important is going on and that
it involves the fear system of the brain. These representations converge in working memory
with the representations from specialized short-term memory buffers and with
representations from long-term memory triggered by current stimuli and by amygdala
processing. The continued driving of the amygdala by the dangerous stimulus keeps the
arousal systems active, which keeps the amygdala and cortical networks actively engaged
in the situation as well. Cognitive inference and decision making processes controlled by
the working memory executive become actively focused on the emotionally arousing
situation, trying to figure out what is going on and what should be done about it. All other
inputs that are vying for the attention of working memory are blocked out.
We now have many of the basic ingredients for a complete emotional experience; but one
more is needed.

Ingredient 3 Bodily Feedback:

The activation of the amygdala results in the
automatic activation of networks that control the expression of a variety of responses:
species-specific behaviours (freezing, fleeing, fighting, facial expressions), autonomic
nervous system (ANS) responses (changes in blood pressure and heart rate, piloerection,
sweating), and hormonal responses (release of stress hormones, like adrenaline and adrenal
steroids, as well as a host of peptides, into the bloodstream). The ANS and hormonal
responses can be considered together as visceral responses responses of the internal
organs and glands (the viscera). When these behavioural and visceral responses are
expressed, they create signals in the body that return to the brain.
This system has not got to be learned or developed during childhood, it is hard-wired an all
humans have it. Despite that and as Rees explains, the (ANS) has been strikingly neglected
in Western medicine. Despite its profound importance for regulation, adjustment and

485

Lindsley, D B. Emotions. In Handbook of Experimental Psychology, S. S. Stevens, ed. (New

York: Wiley), pp. 473-516; 1951.

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coordination of body systems, it lacks priority in training and practice and receives scant
attention in numerous major textbooks. The ANS is integral to manifestations of illness,
underlying familiar physical and psychological symptoms. When ANS activity is itself
dysfunctional, usual indicators of acute illness may prove deceptive. Recognising the
relevance of the ANS can involve seeing the familiar through fresh eyes, challenging
assumptions in clinical assessment and in approaches to practice. 486
Its importance extends from physical and psychological well-being to parenting and
safeguarding, public services and the functioning of society. Exploration of its role in
conditions ranging from neurological, gastrointestinal and connective tissue disorders,
diabetes and chronic fatigue syndrome, to autism, behavioural and mental health
difficulties may open therapeutic avenues. The ANS offers a mechanism for so-called
functional illnesses and illustrates the importance of recognising that stress takes many
forms, physical, psychological and environmental, desirable and otherwise. (Idem)
Evidence of intrauterine and post-natal programming of ANS reactivity suggests that
neonatal care and safeguarding practice may offer preventive opportunity, as may
greater understanding of epigenetic change of ANS activity through, for example,
accidental or psychological trauma or infection. Dr Rees paper was written in order to
accelerate recognition of the importance of the ANS throughout paediatrics, and of the
potential physical and psychological cost of neglecting it.
The opportunities are enormous for bodily feedback during emotional reactions to
influence information processing by the brain and the way we consciously feel.
Nevertheless, much debate has occurred over whether feedback has any effect on
emotional experience and if so how much. William James is the father of the feedback
theory. He argued that we do not cry because we are sad or run from danger because we
are afraid, but instead we are sad because we cry and are afraid because we run. James
was attacked by Cannon, who argued that feedback, especially from the viscera, would
be too slow and undifferentiated to determine what emotion you are feeling at the
moment. Let's ignore the fact that James included somatic as well as visceral feedback in
his theory for now and just consider the validity of Cannon's claims about the viscera.
In Cannon's day, the visceral systems were indeed thought to respond uniformly in all
situations. However, we now know that the ANS, which controls the viscera, has the ability
to respond selectively, so that visceral organs can be activated in different ways in different
situations. Studies show, for example, that different emotions (anger, fear, disgust, sadness,
happiness, surprise) can be distinguished to some extent on the basis of different
autonomic nervous system responses (like skin temperature and heart rate) 487,488.
The main hormone that was thought to be important for emotional experience in Cannon's
time was adrenaline, which is under the control of the ANS and thus was thought to
respond uniformly in different situations. However, we now know that there are steroid and
peptide hormones that are released by body organs during emotional arousal and that

486

Rees, CA. Lost among the trees? The autonomic nervous system and paediatrics. Arch Dis
Child 2012-301863.

487

Ekman, P; Levenson, R W; & Friesen, W V. Autonomic nervous system activity distinguishes

among emotions. Science 221, 1208-10; 1983.

488

Levenson, RW. Autonomic nervous system differences among emotions. Psychological

Science 3, 23-27; 1992.

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travel in the blood to the brain. It is conceivable that activation of different emotional
systems in the brain results in different patterns of hormone release from body organs, which
in turn would produce different patterns of chemical feedback to the brain that could have
unique effects in different emotions.
Regardless of their specificity, though, visceral responses have relatively slow actions, too
slow in fact to be the factor that determines what emotion you experience in a given
moment. At a minimum, it takes a second or two for signals to travel from the brain to the
viscera and then for the viscera to respond and for the signals created by these responses
to return to the brain. For some systems the delay is even longer. It's not so much the travel
time from the brain to the organs by way of nerve pathways that is slow, it's the response
time of the organs themselves. Visceral organs are made up of what is called smooth
muscle, which responds much more slowly than the striated muscles that move our skeleton
during behavioural acts. Also, for hormonal responses, the travel time in the blood to the
brain can be slow, and for some hormones (like adrenal steroids) the effects on the brain
can require the synthesis of new proteins and can take hours to be achieved.
On the other hand, emotional states are dynamic. For example, fear can turn into anger or
disgust or relief as an emotional episode unfolds; and it is possible that visceral feedback
contributes to these emotional changes over time. While arousal is non-specific and tends
to lock you into the state you are in when the arousal occurs, unique patterns of visceral,
especially chemical, feedback have the potential for altering which brain systems are
active and thus may contribute to transitions from one emotion to another within a given
emotional event.
So Cannon was right about the inability of visceral responses to determine emotional
feelings, but more because of their slow time course than their lack of specificity. At the
same time, though, Cannon's critique was somewhat inappropriate given that James had
argued for the importance of somatic as well as visceral feedback. And the somatic
system clearly has the requisite speed and specificity to contribute to emotional
experiences (it takes much less than a second for your striated muscles to respond to a
stimulus and for the sensations from these responses to reach your cortex). This point was
noted many years ago by Sylvan Tomkins and was the basis of his facial feedback theory of
emotion489, which has been taken up and pursued in recent years by Carroll Izard. 490,491
While most contemporary ideas about somatic feedback and emotional experience have
been about feedback from facial expressions, a theory by Antonio Damasio, the somatic
marker hypothesis, calls upon the entire pattern of somatic and visceral feedback from the
body492. Damasio proposes that such information underlies gut feelings and plays a
crucial role in our emotional experiences and decision making processes.
When all the interactions between the various systems are taken together, the possibilities
for the generation of emotion-specific patterns of feedback are staggering. This is
especially true when considered from the point of view of what would be necessary to
scientifically document the existence of these patterns, or, even more difficult, to prove
that feedback is not important.

489

Tomkins, S S. Affect, imagery, consciousness (New York: Springer; 1962).

490

Izard, C E. Human emotions (New York: Plenum; 1977).

491

Izard, C E. Basic emotions, relations among emotions, and emotion-cognition relations.

Psychological Review 99, 561-65; 1992.

492

Damasio, A. Descarte's error: Emotion, reason, and the human brain (New York:
Grosset/Putnam; 1994).

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One approach to this problem has been to study emotional feelings in persons who have
spinal cord injuries, in whom the flow of information from the brain to the body and from the
body back to the brain is interrupted to a great degree. An early study claimed that
patients with the most severe damage had a dulling of the intensity of emotional feelings
and a reduction in the range of emotions experienced, lending support to the idea that
feedback plays an important role493. Later studies suggest that the first study was flawed
and that when the experiment is done properly no deficits in emotional feelings result494.
However, spinal cord injury does not completely interrupt information flow between the
brain and body. For example, spinal cord injury can spare the vagus nerve, which transmits
much information from the visceral organs to the brain, and it also fails to interfere with the
flow of hormones and peptides from the brain to the body and from the body to the brain.
In addition, the nerves controlling facial movements and sending sensations from facial
movements back to the brain are intact, since these go directly between the brain and
face without going through the spinal cord. Failure to find a dulling of emotional
experiences, or a restriction of the range of emotional experiences, in these patients does
not really prove anything.
There is one remaining argument against a contribution of feedback to emotion that needs
to be considered. Although somatic responses, like facial or somatic muscle movements,
have the requisite speed and specificity to contribute to emotional feelings, it has been
argued that these cannot do the trick either. The same response (like running) can occur
during different emotions (running to obtain food or to escape from danger) and
diametrically opposed responses can occur during the same emotion (we can run or freeze
in fear). While these comments are obviously true, it is important to remember that bodily
feedback occurs in a biological context. Bodily feedback, when detected by the brain, is
recorded by the systems that produced the responses in the first place. Although we may
run both to get food and to escape from danger, the feedback from the somatic and
visceral responses that return to the brain will interact with different systems in these two
instances. The feedback from running from danger will find the food-seeking system idle but
the defence system active. The same pattern of feedback can have unique contributions
when it interacts with specific brain systems.
William James said that he found it impossible to imagine an emotional experience
occurring in the absence of the bodily responses that accompany it he didn't believe in
disembodied emotions495. LeDoux agrees with this view for several reasons. (Idem, 1998)
Most of us feel our emotions in our body, which is why we have such expressions as an
aching heart and a gut-wrenching experience. While personal experience is not a good
way to prove anything (we've seen the perils of introspection as scientific data), there's
nothing wrong with using it as a take-off point for a more penetrating analysis. Also, the evidence against feedback playing a role is weak the spinal cord studies are inconclusive
at best. In addition, there is plenty of feedback available during emotional responses, and
quite a bit of it is fast enough and specific enough to play a role in subjective experiences.
Finally, studies by Paul Ekman and by Robert Zajonc have shown that feedback is indeed
used.496,497,498 For example, Ekman had subjects move certain facial muscles. Unbeknownst

493

Hohmann, G W. Some effects of spinal cord lesions on experienced emotional feelings.

Psychophysiology 3; 1966.

494

Bermond, B; Nieuwenhuyse, B; Fasotti, L; & Schuerman, J. Spinal cord lesions, peripheral

feedback, and intensities of emotional feelings. Cognition and Emotion 5,201-20; 1995.

495

James, W. Principles of psychology (New York: Holt; 1890).

496

Ekman, P. Facial expressions of emotion: New findings, new questions. Psychological Science
3, 34-38; 1992.

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to the subjects, they were being made to exhibit the facial expressions characteristic of
different emotions. They then had to answer some questions about their mood. It turns out
that the way the subjects felt was significantly influenced by whether they had been
wearing positive or negative emotion expressions. Putting on a happy face may not be
such a bad idea when you are feeling blue.
There is one other way, though, that should be mentioned. It involves what Damasio calls
as if loops. In certain situations, it may be possible to imagine what bodily feedback
would feel like-if it occurred. This as if feedback then becomes cognitively represented in
working memory and can influence feelings and decisions.
So, this is how the brain arranges emotional feeling. It includes all the things needed to turn
an emotional reaction into a conscious emotional experience. There is a specialized
emotion system that receives sensory inputs and produces behavioural, autonomic, and
hormonal responses. Also, cortical sensory buffers that hold on to information about the
currently present stimuli. In addition we have got a working memory executive that keeps
track of the short-term buffers, retrieves information from long-term memory, and interprets
the contents of the short-term buffers in terms of activated long-term memories. We also
have cortical arousal; and, finally, we have bodily feedback-somatic and visceral
information that returns to the brain during an act of emotional responding.
When all of these systems function together a conscious emotional experience is inevitable.
When some components are present and others lacking, emotional experiences may still
occur, depending on what's there and what's not.

Ingredient 4 Amygdala, Stress and Cardiovascular events:

Research by Tawakol et al links regional brain activity in the amygdala to subsequent
cardiovascular disease. In this first study to make this link, the amygdala activity
independently and robustly predicted cardiovascular disease events. Amygdala activity is
involved partly via a path that includes increased bone-marrow activity and arterial
inflammation. These findings provide novel insights into the mechanism through which
emotional stressors can lead to cardiovascular disease in human beings. 499
Emotional stress has long been linked with an increased risk of cardiovascular disease
(CVD), which affects the heart and blood vessels - but the way this happens has not been
properly understood. This study points to heightened activity in the amygdala an area of
the brain that processes emotions such as fear and anger - as helping to explain the link.
The researchers suggest that the amygdala signals to the bone marrow to produce extra
white blood cells, which in turn act on the arteries causing them to become inflamed. This
can then cause heart attacks, angina and strokes.As a result, when stressed, this part of the
brain appears to be a good predictor of cardiovascular events. (Idem)

The above section on the amygdala and emotions should allow considerable thought to be
given to MDLs care situation. When the processes that are described are fully understood

497

Ekman, P. Facial expression and emotion. American Psychologist 48; 1993.

498

Adelman, PK. & Zajonc, RB. Facial efference and the experience of emotion. Annual Review
of Psychology 40, 249-80; 1989.

499

Tawakol et al. Relation between resting amygdalar activity and cardiovascular events: a
longitudinal and cohort study. Lancet Published online 11 January 2017. DOI:
http://dx.doi.org/10.1016/S0-6736(16)31714-7

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and set against her inability to rationalise through a failed system of cognition, it can be
seen not only just how frightening it can be for someone to be in an environment where
they do not feel safe but also increasingly so because they know that either the person who
is caring for them understands their fears and relieves them or does neither. Being in a
position of not feeling free to escape is not only a physical but also a mental suffering.

The Neurology of Emotions

Emotional signals, either visual or auditory, can be

considered as aspects of both an emotional response and social communication.
Recognition of emotion draws on a distributed set of structures that include the occipitotemporal neocortex, amygdala, orbito-frontal cortex and right fronto-parietal cortices.
Recognition of fear may draw especially on the amygdala and the detection of disgust
may rely on the insula and basal ganglia. Two important mechanisms for recognition of
emotions are the construction of a simulation of the observed emotion in the perceiver,
and the modulation of sensory cortices via top-down influences. 500 See also Table 5
below. 501
The amygdala participates in the recognition of emotional signals via at least two classes of
input mechanisms: a subcortical route via the superior colliculus and the pulvinar thalamus,
and a cortical route via the visual neocortex. Human lesion studies have consistently found
impaired recognition of emotional facial expressions following bilateral amygdala damage,
often disproportionate for fear, but sometimes encompassing multiple negative emotions,
including fear, anger, disgust, and sadness. It has been argued that the amygdala is
principally involved in processing stimuli related to threat and danger, that it triggers
cognitive resources to help resolve ambiguity in the environment, or that the emotions
whose recognition depends most on the amygdala are related to behavioural
withdrawal.502
This impairment may be intensified when a brain injured person needs to recognise
emotional facial expressions of individuals of different ethnic backgrounds. There seems to
be an increasing amount of evidence which indicates that humans have significant
difficulties in understanding emotional expressions in those who are from a different ethnic
culture. There is, in these cases, a reduction in the recognition accuracy and, if available, a
stronger amygdala activation. Derntl et al have undertaken research into this with nonbrain injury subjects. This revealed bilateral amygdala activation to emotional expressions
in Asian and European subjects. However, in the Asian sample, a stronger response of the
amygdala emerged and was paralleled by reduced recognition accuracy, particularly for
angry male faces. They also observed a significant inverse correlation between duration of
presence and amygdala activation. 503
The study revealed that bilateral amygdala activation was required in order to understand
emotional expressions in Asian and European females and males. In the Asian sample, a
stronger response of the amygdala bilaterally was observed and this was paralleled by
reduced performance, especially for anger and disgust depicted by male expressions.

500

Adolphs, R. Neural systems for recognizing emotion. Current Opinion in Neurobiology 2002;
Apr; 12(2): 169-77.

501

Adolphs R. Recognizing emotion from facial expressions: psychological and neurological

mechanisms. Behav Cognit Neurosci Rev 2002, 1:21-61.

502

Adolphs, R. Neural systems for recognizing emotion. Current Opinion in Neurobiology 2002;
Apr; 12(2): 169-77.

503

Derntl, B; Habel, U; Robinson, S; Windischberger, C; Kryspin-Exner, I; Gur, RC & Moser, E.

Culture but not gender modulates amygdala activation during explicit emotion recognition.
BMC Neuroscience 2012, 13:54 doi:10.1186/1471-2202-13-54. Published: 29 May 2012

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Taken together, while gender exerts only a subtle effect, culture and duration of presence
as well as gender of poser are shown to be relevant factors for emotion processing,
influencing not only behavioural but also neural responses in female and male immigrants.
This suggests that in brain injured patients the ethnic background of their nurses and carers
may have some importance. (Derntl, idem)
Unilateral damage to the amygdala generally results in more subtle impairments. An
impaired ability to learn new emotional facial expressions correlated with the extent of
unilateral amygdala damage504, and two studies505,506 found that subjects with damage to
the right amygdala were impaired, as a group, in their recognition of negative emotions
from facial expressions.

TABLE FIVE

The Indelibility of Emotional Memory

The finding that when the medial prefrontal

cortex is damaged, routine fear conditioning becomes resistant to extinction has another
important implication. It also suggests that extinction prevents the expression of
conditioned fear responses but does not erase the implicit memories that underlie these
responses. 507 Extinction, in other words, involves the cortical control over the amygdala's

504

Boucsein K; Weniger G; Mursch K; Steinhoff BJ & Irle E. Amygdala lesion in temporal lobe
epilepsy subjects impairs associative learning of emotional facial expressions.
Neuropsychologia 2001, 39:231-236.

505

Anderson AK; Spencer DD; Fulbright RK & Phelps EA. Contribution of the anteromedial
temporal lobes to the evaluation of facial emotion. Neuropsychology 2000, 14:526-536.

506

Adolphs R; Tranel D & Damasio H. Emotion recognition from faces and prosody following
temporal lobectomy. Neuropsychology 2001, 15:396-404

507

LeDoux, J E; Romanski, L. M; & Xagoraris, A E. Indelibility of subcortical emotional memories.

Journal of Cognitive Neuroscience 1, 238-43; 1989.

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output rather than a wiping clean of the amygdala's memory slate. Fear Conditioning; see
p 132.
The idea that extinction does not involve the erasure of emotional memories but instead
prevents their expression is consistent with a number of findings about conditioned
responses. 508,509,510 Pavlov, for example, found that extinguished responses would simply
recover spontaneously with the passage of time. It is also known that if a rat is conditioned
by pairing a tone and shock in one box, and the fear response elicited by the tone is
completely extinguished in another box, the conditioned response elicited by the tone will
be renewed if the rat is returned to the original training box. An extinguished response can
also be reinstated by giving the rat an exposure to the unconditioned stimulus or,
importantly, to other forms of stressful stimulation. Stress, in other words, can bring back
extinguished, or perhaps weakly established, but unextinguished, conditioned responses.
511 Each of these examples demonstrates that emotional memories are not erased by
extinction but are simply held in check. Extinguished memories, like Lazarus, can be called
back to life.
Unconscious fear memories established through the amygdala appear to be indelibly
burned into the brain. They are probably with us for life. This is often very useful, especially in
a stable, unchanging world, since we don't want to have to learn about the same kinds of
dangers over and over again. But the downside is that sometimes the things that are
imprinted in the amygdala's circuits are maladaptive. In these instances, we pay dearly for
the incredible efficiencies of the fear system.
It is important therefore to consider how MDLs amygdala has been changed, or whether it
is in the neural connections between the amygdala and other structures where any
damage lies. Whatever the outcome of that, it is important to recognise the impact of
prolonged anxiety and fear can have if these historical events are impossible to extinguish.
Psychiatrist Roger Pitman has astutely noted that findings from studies of fear conditioning in
rats have important implications for how anxiety is treated512. The classic treatment, based
on Mowrer's and Miller's theory, was to force the patient to be exposed to the anxietycausing stimuli without allowing any avoidance or escape behaviour and thereby try to
extinguish the anxiety that the stimuli elicit. But in light of the indelibility of the amygdala's
hold on traumatic memories, he suggests a bleaker, though perhaps more realistic,
assessment. We may not be able to get rid of the implicit memories that underlie anxiety
disorders. If this is the case, the best we can hope for is to exercise control over them. In
MDLs case by controlling her environment. Fear Conditioning; see p 132
It is becoming clear then that emotions may be tied to certain parts of the brain but that
does not mean that one emotion sits in a particular spot and jumps to the alert phase when
something happens that frightens you. As an analogy, lets look at something you probably

508

Bouton, ME. & Peck, CA. Context effects on conditioning, extinction, and reinstatement in an
appetitive conditioning preparation. Animal Learning and Behavior 17, 188-98; 1989.

509

Bouton, ME., & Swartzentruber, D. Sources of relapse after extinction in Pavlovian and
instrumental learning. Clinical Psychology Review 11, 123-40; 1991.

510

Bouton, M E. Conditioning, remembering, and forgetting. Journal of Experimental Psychology:

Animal Behavior Processes 20, 219-31; 1994.

511

Jacobs, WJ. & Nadel, L. Stress-induced recovery of fears and phobias. Psychological Review
92, 512-31; 1985.

512

Shalev, AY; Rogel-Fuchs, Y; & Pitman, RK. Conditioned fear and psychological trauma.
Biological Psychiatry 31,863-65; 1992.

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do almost every day try to start your car. You switch on the ignition and turn the key or
press the button nothing happens. Now it is no good assuming that it is the switch that is
wrong (of course it could be, but unlikely). There are several things that might be
contributing to your engine failing to start and they may need differing skills to put that right.
So, with fear, you might be frightened because of a memory; or a noise that triggers your
emotion; or a threatening stranger approaches you; or you wake up from a bad dream.
There will be a common physiological reaction in varying degrees of intensity resulting from
any of these but the beginnings of the trigger may start in different parts of the brain before
being centralised into a voluntary or involuntary action. Noise sensitivity is also an important
and under-researched symptom that can result from traumatic brain injury.513 MDL has a
constant dislike of mechanical noise, e.g. vacuum cleaners, drills and loud music.
Sometimes referred to as hyperacusis, when it is a marked intolerance to normal
environmental sound, noise sensitivity is a common symptom in patients with tinnitus,
Williams syndrome, autism, and other neurologic diseases. It has been suggested that an
imbalance of excitation and inhibition in the central auditory system may play an important
role in hyperacusis. Recent studies found that noise exposure, one of the most common
causes of hearing loss and tinnitus, can increase the auditory cortex (AC) response,
presumably by increasing the gain of the AC. Noise exposure induces a decrease of sound
evoked potential in the inferior colliculus. However, significant increases of AC response
including sound evoked potentials and the spike firing rates of AC neurons were noted by
Sun et al.514
This research suggests that noise exposure induces hyper-excitability of the AC presumably
by increasing the post-synaptic response of AC neurons and that noise exposure can cause
exaggerated sound reactions which may be related with the enhanced responsiveness of
the AC neurons.
Some of these behaviours will be consistent with your common-sense intuitions about fears
that you have faced in the past; whereas others will seem unlikely if not strange and
unaccountable. Every new incident that causes you to have the emotion of fear will be
stored in readiness for the next time it happens. As will your reaction to them. Being startled
could be the initiating trigger of your fear but if you have realized afterwards that you
reacted too strongly, your brain will store that reaction and the next time you could be
startled by the same event you will respond less actively. Eventually if you recognize that
the trigger was something completely harmless and put you in no danger, then your
reaction would move on to extinction. That means that your brain would tell you instantly
not to bother about it, and so you wouldnt
Now, here is the interesting bit, if parts of the brain that deal with fear are damaged then the
extinction response may not work; or it may take longer to learn and so allow for the signal
to give a weaker response. It has been found that the way in which extinction works can
involve different parts of the brain depending upon when the extinction process began.
Behavioural evidence indicates that extinction is a form of inhibitory learning. Extinguished
fear responses reappear with the passage of time (spontaneous recovery), a shift of
context (renewal), and unsignaled presentations of the unconditioned stimulus
(reinstatement). However, there is also evidence to suggest that extinction is an

513

Landon J; Shepherd D; Stuart S; Theadom A & Freundlich S. Research Reports Hearing

every footstep: noise sensitivity in individuals following traumatic brain injury. Neuropsychol
Rehabil. 2012 Jun;22(3):391-407.

514

Sun W; Deng A; Jayaram A & Gibson B. Noise exposure enhances auditory cortex responses
related to hyperacusis behavior. Brain Res. 2012 Feb 9.

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unlearning process corresponding to depotentiation of potentiated synapses within the
amygdala. Because depotentiation is induced more readily at short intervals following
long-term potentiation induction and is not inducible at all at a sufficient delay, it may be
that extinction initiated shortly following fear acquisition preferentially engages
depotentiation unlearning, whereas extinction initiated at longer delays recruits a different
mechanism.
Myers et al, investigated this possibility through a series of behavioural experiments which
examined the recoverability of conditioned fear following extinction. Consistent with an
inhibitory learning mechanism of extinction, rats extinguished 2472 hours following
acquisition, exhibited moderate to strong reinstatement, renewal, and spontaneous
recovery. In contrast, and consistent with an erasure mechanism, rats extinguished 10 min
to 1 hour after acquisition exhibited little or no reinstatement, renewal, or spontaneous
recovery. These data support a model in which different neural mechanisms are recruited
depending on the temporal delay of fear extinction. 515
Justin, et al also found that, short acquisition-extinction intervals (immediate extinction) can
lead to either more or less spontaneous recovery than long acquisition-extinction intervals
(delayed extinction). 516 Langton et al found that repetitive aversive experiences prior
extinction learning can prevent a facilitating of extinction. 517
Despite the common perception that anxiety and fear are linked, they are distinctly
different emotions. Fear is a physical response to danger, says Daniel R. Weinberger of
the National Institute of Mental Healths Clinical Brain Disorders Branch. Anxiety is a
psychological response to perceived danger. Fear is generated by a specific stimulus.
Seeing a snake in the grass, for example, can trigger a fear response. Anxiety, which is not
necessarily tied to a specific stimulus, is a feeling of being at risk, but from no imminent
danger. Though of course for those who have a loss of skills in time-relation, that could be
nullified and the threat could seem to be immediate until relieved either by reassurance or
by a change in environment.
A good deal is now known about the neural circuitry involved in how conditioned fear can
augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as
shock pathways that project via the thalamus and perirhinal or insular cortex to the
basolateral amygdala. In addition, fear and anxiety emanate from different regions of the
amygdala. 518
Michael Davis tells us that the fear response comes from the central nucleus of the
amygdala, the region responsible for commands for bodily responses associated with fear.
Anxiety originates in an area responsible for emotions that mediates slower-onset, longerlasting behavioural responses that may persist after a perceived threat terminates. (Idem)
Davis has studied the fear process called extinction, in which fear is reduced after
repeated exposure to a fearful event without adverse consequences. He found that a

515

Myers, K M; Ressler, K J & Davis, M. Different mechanisms of fear extinction dependent on

length of time since fear acquisition. Learning & Memory; 2006. 13: 216-223.

516

Johnson, JS; Escobar, M & Kimble, WL. Long-term maintenance of immediate or delayed
extinction is determined by the extinction-test interval. Learning & Memory; 2010. 17: 639-644

517

Langton, JM & Richardson, R. The effect of D-cycloserine on immediate vs. delayed

extinction of learned fear. Learning & Memory; 2010. 17: 547-551

518

Davis, M. Neural Systems Involved in Fear and Anxiety Measured With Fear-Potentiated
Startle. American Psychologist, November 2006. p741-756.

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receptor for a particular protein called N-methyl-D-aspartate (NMDA) in the amygdala is
critical for the extinction of a conditioned fear. Davis also discovered that a compound
called D-cycloserine (DCS) injected into rats amygdalas enhanced the function of the
NMDA receptor and accelerated fear extinction. The idea is not to replace exposure
therapy, but to speed it up.
LeDoux puts forward several hypotheses about the brain and emotion.
1.
The proper level of analysis of a psychological function is the level at which that
function is represented in the brain. Psychology textbooks often carve up the mind into
functional pieces, such as perception, memory, and emotion. These are useful for
organizing information into general areas of research but do not refer to real functions. The
various classes of emotions are mediated by separate neural systems that have evolved for
different reasons. The system we use to defend against danger is different from the one we
use in other systems. The feelings that result from activating these different systems do not
have a common origin.
2.
The brain systems that generate emotional behaviours are highly conserved through
many levels of evolutionary history. All animals, including people, have to satisfy certain
conditions to survive in the world and fulfil their biological imperative to pass their genes on
to their offspring. At a minimum, they need to obtain food and shelter, protect themselves
from bodily harm, and procreate. This is as true of insects and worms as it is of fish, frogs,
rats, and people. Each of these diverse groups of animals has neural systems that
accomplish these behavioural goals. Within the animal groups that have a backbone and
a brain (fish, amphibians, reptiles, birds, and mammals, including humans), it seems that the
neural organization of particular emotional behavioural systems like the systems
underlying fearful, sexual, or feeding behaviours is similar across species. This does not
imply that all brains are the same. It means instead that our understanding of what it is to
be human involves an appreciation of the ways in which we are like other animals as well
as the ways in which we are different.
3.
The system that detects danger is the fundamental mechanism of fear, and the
behavioural, physiological, and conscious manifestations are the surface responses it
orchestrates. This is not meant to imply that feelings are unimportant. It means that if we
want to understand feelings we have to dig deeper.
4.
If emotional feelings and emotional responses are effects caused by the activity of
a common underlying system, we can then use the objectively measurable emotional
responses to investigate the underlying mechanism and, at the same time, illuminate the
system that is primarily responsible for the generation of the conscious feelings.
Understanding emotions in the human brain is clearly an important quest, as most mental
disorders are emotional disorders.
5.
Conscious feelings, like the feeling of being afraid or angry or happy or in love or
disgusted, are in one sense no different from other states of consciousness, such as the
awareness that the roundish, reddish object before you is an apple; that a sentence you
have just heard was spoken in a particular foreign language or that you've just solved the
mystery of where you left your car keys. What differs between the state of being afraid and
the state of perceiving red is not the system that represents the conscious content (fear or
redness) but the systems that provide the inputs to the system of awareness. There is but
one mechanism of consciousness and it can be occupied by mundane facts or highly
charged emotions. Emotions easily push mundane events out of awareness, but nonemotional events (like thoughts) do not so easily displace emotions from the mental
spotlight wishing that anxiety or depression would go away is usually not enough.
6.

Emotions are things that happen to us rather than things we will to occur. Although
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people set up situations to modulate their emotions all the time going to the cinema or
amusement parks; having a tasty meal; consuming alcohol and other recreational drugs
in these situations, external events are simply arranged so that the stimuli that
automatically trigger emotions will be present. We have little direct control over our
emotional reactions. Anyone who has tried to fake an emotion, or who has been the
recipient of a faked one, knows all too well the futility of the attempt.
While conscious control over emotions is weak, emotions can flood consciousness. This is so
because the wiring of the brain at this point in our evolutionary history is such that
connections from the emotional systems to the cognitive systems are stronger than
connections from the cognitive systems to the emotional systems. Once emotions occur
they become powerful motivators of future behaviours; they chart the course of momentto-moment action as well as set the sails toward long-term achievements. Also, our
emotions can get us into trouble. When fear becomes anxiety; desire gives way to greed
or annoyance turns to anger; anger to hatred; friendship to envy; love to obsession or
pleasure to addiction; our emotions start working against us. Mental health is maintained
by emotional hygiene, and mental problems, to a large extent, reflect a breakdown of
emotional order. Emotions can have both useful and pathological consequences.
(LeDoux, 1998, idem)
Recent advances in understanding brain function have been greatly benefited by the
decomposition of global behavioural constructs into component parts or sub-domains. This
approach has led to the discovery of parallel processing streams in vision519 and to the
development of multiple memory systems in the brain.520,521,522

Social Behaviour and the Amygdala

David Amaral, 523 has presented animal data

on the neuroanatomy of the amygdala and its connections with the orbitofrontal and
temporal cortices. This was done with a view toward developing a larger picture of how
the amygdala affects social behaviour through which one could investigate how
disruptions of amygdaloid connections might affect social impairments of functioning such
as autism.
He suggested that early works by Brothers524 and Rosvald and colleagues525,526 were
important in understanding these connections. Rhesus dominance hierarchies were
disrupted when a subject had progressive amygdaloid lesions and was then reintroduced

519

Ungerleider LG & Mishkin M. Two cortical visual systems, in Ingle DJ, Goodale MA, Mansfield
RJW (eds): Analysis of Visual Behavior. Cambridge, MA: MIT Press, 1982.

520

Tulving E & Schacter DL. Priming and human memory systems. Science 247:301-306, 1990.

521

Weiskrantz L. Problems of learning and memory: One or multiple memory systems? Phil Trans R
Soc Lond B 329:99-108, 1990.

522

Squire LR; Knowlton B & Musen G. The structure and organization of memory. Annu Rev
Psychol 44:453-495, 1993.

523

Amaral D. Amygdala, social behavior and autism. Program and abstracts of the American
Academy of Child and Adolescent Psychiatry 49th Annual Meeting; October 22-27, 2002; San
Francisco, California. Institute IIIB.

524

Brothers L. The social brain: a project for integrating primate behavior and neurophysiology in
a new domain. Concepts Neurosci. 1990;1:27-51.

525

Rosvald HE, Mirsky AF, Sarason I. Amygdalectomy and social behavior. J Comp Physiol
Psychol. 1954;11:10-93.

526

Rosvald HE, Mirsky AF, Sarason I, Bransome ED, Beck LM. A continuous performance test of
brain damage. J Consult Psychol. 1956;90:343-350.

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to a troupe. This permitted the inference that the amygdala was related to the emitting of
socially appropriate behaviours, and that its lesions disrupted that functioning. Connections
of the amygdala with the neocortex, basal forebrain, hippocampus, thalamus, and
hypothalamus supported this.
Transmission of high-level sensory information to these centres is thought to influence or
modify incoming sensory information at an early stage. Initially, the hypothesis was that
positive or negative valence was assigned to the incoming sensory stimulus by outputs from
the amygdala, and that other brain centres were aligned to produce approach or
avoidance reactions. With this view, the amygdala was regarded as essential for social
interactions. However, evaluation of the primates in a variety of social situations (viz.
unconstrained dyad situations) resulted in discovering that the animals with bilateral lesions
appeared more social and affiliative rather than less, and appeared less reluctant to
confront novel stimuli. The lesioned animals also responded differently from other lesioned
animals, in contrast with controls. Here too, increased social and affiliative behaviours
occurred, rather than less.
With this observation of releasing social inhibitions, the social function of the amygdala was
redefined as a brake to inhibit behaviour and permit the animal time for evaluation of
specific environmental stimuli (both inanimate objects and other organisms) with regard to
assessing dangerousness. If dangerousness is perceived, then other brain areas are
orchestrated to produce appropriate behavioural responses integrating sensory, motor,
visceral, and autonomic responses.

Anxiety and Stress

Anxiety, according to Mowrer, motivates us to deal with

traumatic events in advance of their occurrence; and because anxiety reduction brings
about relief or security, it is a powerful reinforcer of instrumental behaviours (arbitrary
responses that are learned because they satisfy some need or accomplish some goal).
Responses that reduce anxiety are thus learned and maintained. 527
Mowrer felt that anxiety is initially learned much like Watson had suggested stimuli that
are present during painful or traumatic events acquire the capacity to elicit anxiety. John
Watson, the father of behaviourism, claimed to have conditioned an animal phobia in an
eleven-month-old boy, Little Albert, by making a loud clanging sound while the boy was
happily playing with a rat. Thereafter, the boy avoided playing with the rat and cried when
he was near it. To explain this finding, Watson proposed that certain stimuli (loud noises,
painful stimuli, sudden loss of physical support) are innately capable of eliciting fear
reactions. When these unconditioned stimuli occur, other stimuli that happen to be present
acquire the capacity to elicit conditioned fear. According to Watson, neuroses arise as a
result of these traumatic learning situations and then persist and influence behaviour
throughout life. 528
As anxiety is uncomfortable; when the stimuli that elicit it are present the anxious person will
be motivated to change the circumstances, to remove herself from where the anxietycausing stimuli are, and to avoid such situations in the future. The reduction in anxiety that
these responses produce then reinforces the behaviours and perpetuate their
performance. This is often useful, but sometimes it leads to neurotic symptoms.

527

Mowrer, O. H. A stimulus-response analysis of anxiety and its role as a reinforcing agent.

Psychological Review, 1939; 46:553-565.

528

Watson, J. B. & Rayner, R. Conditioned emotional reactions. Journal of Experimental

Psychology 3, 1-14; 1920.

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Consider a real-life example. A man is mugged in a lift. From that day on, he becomes
afraid of riding in lifts. He avoids them as much as possible. He consults a therapist, who
tries to reassure him that it is highly unlikely that he will be mugged again in a lift, especially
if he rides at busy times. But the reassurance is not helpful. The man must get to his office
on the thirteenth floor. This makes him anxious. In spite of the inconvenience that it causes
him, each day he takes the stairs. The reduction in anxiety that results from taking the stairs,
according to Mowrer's theory, maintains the neurotic behaviour of taking the stairs.
For someone with brain damage like MDLs they often cannot, be motivated to change the
circumstances, to remove herself from where the anxiety-causing stimuli are, and to avoid
such situations in the future. Firstly, they are usually not able to physically remove
themselves from any situation as they are always under someones control who may not
feel the anxiety as does the brain-damaged person or may even be causing it. Secondly,
they may not have the neurological capacity to reduce the anxiety of their own volition
and this has to be done for them if possible. So, not only do the carers have to think for the
person but they also have to act. Frequently, there will be conflict here with the PC brigade.
More and more since this idea was set loose amongst society, especially disabled society,
there has been a reluctance to do anything that might be seen as a direct imposition of
able will against disabled will. Common-sense must prevail and circumstances alter cases.
Stress as a cause of illness is a well-established aetiology.529 It has now been established
that there is a retrospective biomarker for extended stress and Karlen et al have found that
cortisol in hair might well serve as such a marker of increased cortisol production that
reflects exposure to major life stressors and possibly psychological illnesses with important
implications for clinical practice.530 The experiencing of serious life events seems to be more
important in raising cortisol levels in hair than does perceived stress. This has considerable
importance for MDL in that it is relatively simple to measure cortisol from cut hair. The
researchers used hair from the posterior vertex (apex) area. The cortisol was measured
using a competitive radioimmunoassay in methanol. The extracts of hair had been frozen in
liquid nitrogen and mechanically pulverised. NOTE: During a period of about 18 months and
may be as a result of medication(s), MDLs hair changed from being absolutely straight to
being curly. Photographic evidence of this is available. Her hair eventually returned to its
original state. (Hair loss and curly hair is a rare side effect of sodium valproate.) 531
There is ample evidence that psychological stress (PS) adversely affects many diseases.
(Soliman et al, Idem, 2012) Recent evidence has shown that intense stressors can increase
inflammation within the brain, a known mediator of many diseases. 532 Barnum et al found
that adolescent mice subjected to chronic PS had increased basal expression of
inflammation within the midbrain. Chronic unpredicted stress and chronic PS mice also had
an impaired inflammatory response to a subsequent lipopolysaccharide challenge and PS

529

Soliman A, Udemgba C, Fan I, Xu X, Miler L, Rusjan P, Houle S, Wilson AA, Pruessner J, Ou XM,
Meyer JH. Convergent Effects of Acute Stress and Glucocorticoid Exposure upon MAO-A in
Humans. J Neurosci. 2012 Nov 28;32(48):17120-17127.

530

Karlen, J; Ludvidsson, J; Frostell, A; Theodorsson, E; & Faresjo, T. Cortisol in hair measured in

young adults - a biomarker of major life stressors? BMC Clinical Pathology; 2011, 11: 12
Published: 25 October 2011.

531

Ebrahimi, H; Shamsadini, S. & Eshkavari. SS. Frequency of sodium valproate-induced hair

loss and Curly Hair. 1735-2657/05/42-143-145; Iranian Journal of Pharmacology &
Therapeutics. 2005; IJPT 4:143-145, 2005.

532

Barnum, CJ; Pace, TWW; Hu, F; Neigh, GN & Tansey, MG. Psychological stress in adolescent
and adult mice increases neuroinflammation and attenuates the response to LPS
(lipopolysaccharide) challenge. Journal of Neuroinflammation 2012, 9:9 (16 January 2012)

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mice displayed increased anxiety and depressive-like behaviours following chronic stress.
(Idem)
This research indicated that adult mice, subjected to acute predatory stress, had increased
gene expression of inflammatory factors. It concluded that the results demonstrate that
predatory stress, an ethologically relevant stressor, can elicit changes in neuro-inflammation
and behaviour. (Idem)

Traumatic Stress

The difference between a fear conditioning theory of phobia and

PTSD is one of where the conditioning process gets its strength. In the case of prepared
phobic learning, the conditioned stimulus makes the learning especially strong. The
unconditioned stimulus is typically unpleasant and may even be painful, but is not
necessarily extraordinary.

However, in the case of PTSD, the conditioned stimulus events are less notable than the
unconditioned stimulus. PTSD, in fact, is defined in DMS-III-R as involving a trauma that is far
outside the realm of experiences in ordinary life. Fear Conditioning; see p 132

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There is now evidence for the existence of a complex form of post-traumatic disorder in
survivors of prolonged, repeated trauma. This syndrome is currently under consideration for
inclusion in DSM-IV under the name of DESNOS (Disorders of Extreme Stress Not Otherwise
Specified). The current diagnostic formulation of PTSD derives primarily from observations of
survivors of relatively circumscribed traumatic events. This formulation fails to capture the
protean sequelae of prolonged, repeated trauma. In contrast to a single traumatic event,
prolonged, repeated trauma can occur only where the victim is in a state of captivity,
under the control of the others.533 This is now recognised under legislation for deprivation of
liberty. The psychological impact of subordination to deprivation of liberty has many
common features, whether it occurs within the public sphere of politics or within the private
sphere of sexual and domestic relations.
MDL has been in a state of deprivation of liberty in 2004, 2007 (twice) and from later in 2007
continuously to the present. She has also had periods of extreme stress at various other
times, earlier in her life.
Once we assume that the trauma in PTSD is an extraordinary event, a fairly standard view of
the way the amygdala mediates conditioned fear provides a plausible account of this
disorder. Until recently, we didnt know exactly what combination of factors came
together to make up the horrendous events at the neuronal level, but it was easily
imagined that such a neural condition existed; one that bombards the amygdala with
electrical and chemical signals that are particularly potent as reinforcers of Pavlovian
conditioning. These powerful reinforcing stimuli are then linked synaptically with the sounds,
sights, and smells of the events, which also reach the amygdala. Later, the occurrence of
these same conditioned stimuli, or stimuli related to them, elicit profound fear responses by
reactivating these powerfully potentiated amygdala circuits.
Simmons et al 534 used a multiple control group design for testing the hypothesis that trauma
disrupts emotional circuits relevant to face processing, and that the subsequent
development of PTSD is related to less engagement of frontal top-down circuitry535,536.

533

Herman, JL. Complex PTSD: A Syndrome in Survivors of Prolonged and Repeated Trauma. Jnl.
Trau.Stress; Vol 5, No 3, 1992

534

Simmons, AN; Matthews, SC; Strigo, IA; Baker, DG; Donovan, HK; Motezadi, A; Stein, MB; &
Martin P Paulus, MP. Altered amygdala activation during face processing in Iraqi and
Afghanistani war veterans Biology of Mood & Anxiety Disorders 2011, 1:6 Publication date 12
October 2011 ISSN 2045-5380

535

Shin LM; Rauch SL; & Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal
function in PTSD. Ann N Y Acad Sci 2006, 1071:67-79.

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Soldiers exposed to combat in Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF)
are at high risk for post-traumatic stress disorder (PTSD)537. Breslau 538 & Boscarino 539
recognised that PTSD is an aversive reaction to a life-threatening, emotionally salient event
that is associated with increased mortality and morbidity. The majority of those who
experience such an event have a substantial stress response540 that is characterized by
activation in physiological and neuroendocrine systems. 541,542,543,544 Such stress responses
are associated with hyper-activation in the insula and amygdala brain structures that are
involved in processing emotional information.545,546
Amygdala activation has been strongly linked to negative affective states in fear
processing547,548,549 and PTSD. 550,551,552 (& Shin LM, et al, Idem 2006.) A number of studies

536

Liberzon I; & Sripada CS. The functional neuroanatomy of PTSD: a critical review. Prog Brain
Res 2008, 167:151-169.

537

Hoge CW; Auchterlonie JL; & Milliken CS. Mental health problems, use of mental health
services, and attrition from military service after returning from deployment to Iraq or
Afghanistan. JAMA 2006, 295:1023-1032.

538

Breslau N. The epidemiology of posttraumatic stress disorder: what is the extent of the
problem? J Clin Psychiatry 2001, 62(Suppl 17):16-22.

539

Boscarino JA. Posttraumatic stress disorder and mortality among U.S. Army veterans 30 years
after military service. Ann Epidemiol 2006, 16:248-256.

540

North CS; Nixon SJ; Shariat S; Mallonee S; McMillen JC; Spitznagel EL; & Smith EM. Psychiatric
disorders among survivors of the Oklahoma City bombing. JAMA 1999, 282:755-762.

541

Geracioti TD Jr; Carpenter LL; Owens MJ; Baker D;, Ekhator NN; Horn PS; Strawn JR; Sanacora
G; Kinkead B; Price LH; & Nemeroff CB. Elevated cerebrospinal fluid substance p
concentrations in posttraumatic stress disorder and major depression. Am J Psychiatry 2006,
163:637-643.

542

Bremner JD; Vythilingam M; Anderson G; Vermetten E; McGlashan T; Heninger G; Rasmusson

A; Southwick SM; & Charney DS. Assessment of the hypothalamic-pituitary-adrenal axis over
a 24-hour diurnal period and in response to neuroendocrine challenges in women with and
without childhood sexual abuse and posttraumatic stress disorder. Biol Psychiatry 2003, 54:710718.

543

Liberzon I; Abelson JL; Flagel SB; Raz J; & Young EA; Neuroendocrine and psychophysiologic
responses in PTSD: a symptom provocation study. Neuropsychopharmacology 1999, 21:40-50.

544

Bremner JD; Licinio J; Darnell A; Krystal JH; Owens MJ; Southwick SM; Nemeroff CB; & Charney
DS. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress
disorder. Am J Psychiatry 1997, 154:624-629.

545

Simmons AN; Paulus MP; Thorpe SR; Matthews SC; Norman SB; & Stein MB. Functional
activation and neural networks in women with posttraumatic stress disorder related to
intimate partner violence. Biol Psychiatry 2008, 64:681-690.

546

Etkin A; & Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional

processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 2007,
164:1476-1488.

547

Shin LM; & Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 2010, 35:169-91.

548

Barad M; Gean PW; & Lutz B. The role of the amygdala in the extinction of conditioned fear.
Biol Psychiatry 2006, 60:322-328.

549

Rudy JW; Huff NC; & Matus-Amat P. Understanding contextual fear conditioning. Neurosci
Biobehav Rev 2004, 28:675-685.

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have successfully used face tasks to probe affective circuits such as the amygdala to
better understand affective symptomatology in PTSD. 553,554,555,556,557,558 These findings
suggest strongly that PTSD is related to amygdala hyper-activation, it has also been
suggested that the experience of emotional trauma in and of itself may relate to significant
differences in the functioning of emotional processing circuits. (Simmons, et al, Idem; 2011)
Exposure to combat where there is a risk of death (in other words, Criterion A for the
diagnosis of PTSD559; can have significant psychiatric or cognitive repercussions560 even
when it does not result in PTSD. However, one important difference between those
exposed to trauma who develop PTSD versus those who do not may be in the increased
avoidance of aversive experiences and emotions561. This maladaptive response to aversive
emotions following trauma may enhance and maintain symptoms of PTSD562 by diminishing
the likelihood of fear extinction563 . [See Fear Extinction, Pgs. 120 &, 121)

550

Rauch SL; Shin LM; & Phelps EA. Neurocircuitry models of posttraumatic stress disorder and
extinction: human neuroimaging research--past, present, and future. Biol Psychiatry 2006,
60:376-382.

551

Hull AM. Neuroimaging findings in post-traumatic stress disorder. Systematic review. Br J

Psychiatry 2002, 181:102-110.

552

Simmons AN; & Matthews SC. Neural circuitry of PTSD with or without mild traumatic brain
injury: a meta-analysis. Neuropharmacology 2011.

553

Bryant RA; Kemp AH; Felmingham KL; Liddell B; Olivieri G; Peduto A; Gordon E; Williams LM.
Enhanced amygdala and medial prefrontal activation during nonconscious processing of
fear in posttraumatic stress disorder: An fMRI study. Hum Brain Mapp 2008, 29:517-523

554

Fonzo GA; Simmons AN; Thorp SR; Norman SB; Paulus MP; & Stein MB. Exaggerated and
disconnected insular-amygdalar blood oxygenation level-dependent response to threatrelated emotional faces in women with intimate-partner violence posttraumatic stress
disorder. Biol Psychiatry 2010, 68:433-441.

555

Bryant RA, et al. (idem)Hum Brain Mapp 2008, 29:517-523.

556

Shin LM; Wright CI; Cannistraro PA; Wedig MM; McMullin K; Martis B; Macklin ML; Lasko NB;
Cavanagh SR; Krangel TS; Orr SP; Pitman RK; Whalen PJ; & Rauch SL. A functional magnetic
resonance imaging study of amygdala and medial prefrontal cortex responses to overtly
presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 2005, 62:273-281.

557

Armony JL; Corbo V; Clement MH; & Brunet A. Amygdala response in patients with acute
PTSD to masked and unmasked emotional facial expressions. Am J Psychiatry 2005, 162:19611963.

558

Protopopescu X; Pan H; Tuescher O; Cloitre M; Goldstein M; Engelien W; Epstein J; Yang Y;

Gorman J; LeDoux J; Silbersweig D; & Stern E. Differential time courses and specificity of
amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol
Psychiatry 2005, 57:464-473.

559

American Psychiatric Association: Diagnostic and statistical manual of mental disorders: DSMIV-TR. 4th edn. Washington, DC: American Psychiatric Association; 2000.

560

Vasterling JJ; Proctor SP; Amoroso P; Kane R; Heeren T; & White RF. Neuropsychological
outcomes of army personnel following deployment to the Iraq war. JAMA 2006, 296:519-529.

561

Foa EB; & Kozak MJ. Emotional processing of fear: exposure to corrective information. Psychol
Bull 1986, 99:20-35.

562

Krause ED; Kaltman S; Goodman LA; & Dutton MA. Avoidant coping and PTSD symptoms
related to domestic violence exposure: a longitudinal study. JTrauma Stress 2008, 21:83-90.

563

Foa EB. Psychological processes related to recovery from a trauma and an effective
treatment for PTSD. Ann N Y Acad Sci 1997, 821:410-424.

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Recent neural models of PTSD and trauma exposure suggest that the functional networks
associated with the amygdala may be of similar importance to understanding emotional
processing as the amygdala itself564. These theories posit that PTSD is, in part, a
manifestation of ineffective top-down modulation of the amygdala and limbic circuitry by
the prefrontal cortex.565,566 This model has been proposed as a mechanism for the
depersonalization seen in PTSD567. For example, it has been shown that reduced functional
connections between the amygdala and prefrontal cortex relate to increased levels of
depersonalization following emotional trauma, suggesting that impaired functioning of this
prefrontal modulatory network may be related to clinical symptoms in traumatized
individuals. 568
Studies have shown that, using a simple face-matching task, there is a clinically meaningful
differences in amygdala activation in groups with mood and anxiety disorders569,570,571 and
shown significant changes in response to psychopharmacological intervention.572,573 A
simple face-matching task has also been successful in delineating differences in
functionally connected networks in psychiatric populations574. While face tasks do not use
trauma-related stimuli and do not directly provoke re-experiencing symptoms in PTSD, they
do require appraisal of social emotions, thus they appear to provide a method to measure
affective circuitry in a theoretically and clinically meaningful way.
LeDoux explains that conditioned stimuli activate the amygdala unconsciously, but at the
same time reach the temporal lobe memory system and can lead to the recall of the initial
trauma or to the recall of recent episodes in which the initial trauma is relieved. These
conscious memories, together with the awareness of now being in a state of strong
emotional arousal (due to the unconscious activation of fear responses through the
amygdala), then gives rise to conscious anxiety and worry. These cognitions about the

564

Liberzon I; & Sripada CS. The functional neuroanatomy of PTSD: a critical review. Prog Brain
Res 2008, 167:151-169.

565

Shin LM. et al (Idem); Ann N Y Acad Sci 2006, 1071:67-79.

566

Liberzon I, et al. (idem) Prog Brain Res 2008, 167:151-169.

567

Sierra M; & Berrios GE. Depersonalization: neurobiological perspectives. BiolPsychiatry 1998,

44:898-908.

568

Lanius RA; Williamson PC; Boksman K; Densmore M; Gupta M; Neufeld RW; Gati JS; & Menon
RS. Brain activation during script-driven imagery induced dissociative responses in PTSD: a
functional magnetic resonance imaging investigation. Biol Psychiatry 2002, 52:305-311.

569

Matthews SC; Strigo IA; Simmons AN; O'Connell RM; Reinhardt LE; & Moseley SA. A multimodal
imaging study in U.S. veterans of Operations Iraqi and Enduring Freedom with and without
major depression after blast-related concussion. Neuroimage 2011, 54(Suppl 1):S69-S75.

570

Matthews SC; Strigo IA; Simmons AN; Yang TT; & Paulus MP. Decreased functional coupling of
the amygdala and supragenual cingulate is related to increased depression in unmedicated
individuals with current major depressive disorder. J Affect Disord 2008, 111:13-20.

571

Stein MB; Simmons AN; Feinstein JS; & Paulus MP. Increased amygdala and insula activation
during emotion processing in anxiety-prone subjects. Am J Psychiatry 2007, 164:318-327.

572

Arce E; Simmons AN; Lovero KL; Stein MB; & Paulus MP. Escitalopram effects on insula and
amygdala BOLD activation during emotional processing. Psychopharmacology (Berl) 2008,
196:661-672.

573

Paulus MP; Feinstein JS; Castillo G; Simmons AN; & Stein MB. Dose-dependent decrease of
activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch
Gen Psychiatry 2005, 62:282-288.

574

Matthews SC, et al (idem). J Affect Disord 2008, 111:13-20.

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emotional arousal, in turn, flow from the neocortex and hippocampus to further arouse the
amygdala. The bodily expression of the amygdala's responses keeps the cortex aware that
emotional arousal is ongoing, and further facilitates the anxious thoughts and memories.
The brain enters into a vicious cycle of emotional and cognitive excitement and, like a
runaway train, just keeps picking up speed.
It seems that in PTSD, as for phobic learning, the direct projections to the amygdala from
subcortical sensory processing regions are involved. If this were so, it would explain why the
attacks are so impulsive and uncontrollable and tend to generalize so readily. As noted
below (pgs. 130 &136), the subcortical pathways are quick and dirty transmission routes.
They turn the amygdala on and start emotional reactions before the cortex has a chance
to figure out what it is that is being reacted to. Since these pathways are not very capable
of distinguishing between stimuli, generalization readily occurs.
Perhaps trauma, for some reasons (genetic or experiential) in some persons, biases the
brain in such a way that the thalamic pathways to the amygdala predominate over the
cortical ones, allowing these low-level processing networks to take the lead in the learning
and storage of information. Later exposure to stimuli that even remotely resemble those
occurring during the trauma would then pass, like greased lightning, over the potentiated
pathways to the amygdala, unleashing the fear reaction. Quite possibly, it is harder for one
to gain conscious wilful control over these subcortical pathways. At the same time,
because conscious memories are formed during anxiety attacks, the bodily sensations
associated with those attacks, when recognized consciously, become potent elicitors or at
least facilitators of anxiety. 575

Some points to remember

You can't have a conscious emotional feeling of being afraid without aspects of the
emotional experience being represented in working memory. Working memory is the
gateway to subjective experiences, emotional and non-emotional ones, and is indispensable in the creation of a conscious emotional feeling.
You can't have a complete feeling of fear without the activation of the amygdala. In the
presence of a fear-arousing stimulus, and the absence of amygdala activation (for
example, if your amygdala were damaged), you might use your cognitive powers to
conclude that in situations like this you usually feel fearful, but the fearful feelings would be
lacking because of the importance of amygdala inputs to working memory, of amygdala-triggered arousal, and of amygdala-mediated bodily responses that produce feedback.
Cognitive mechanisms, like as-if loops, might compensate to some extent, but they can't
fully. (Of course if the cognitive processes are not working properly then there are other
considerations that might bring about a different result.)
There is now research information on several patients with amygdala damage.576,577,578
However, these people had a congenital disorder. Whenever the brain is damaged in

575

LeDoux, J. The Emotional Brain: The mysterious underpinnings of emotional life. Weidenfeld &
Nicholson, London; 1998.

576

Adolphs, R; Tranel, D; Damasio, H; & Damasio, A R. Fear and the human amygdala. Journal of
Neuroscience 15,5879-91; 1995.

577

Bechara, A; Tranel, D; Damasio, H; Adolphs, R; Rockland, C; & Damasio, A R. Double

dissociation of conditioning and declarative knowledge relative to the amygdala and
hippocampus in humans. Science 269, 1115-18; 1995..

578

Young, AW; Aggleton, J P; Hellawell, DJ; Johnson, M; Broks, P; & Hanley, JR. Face processing
impairments after amygdalotomy. Brain 118, 15-24; 1995.

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early life, there are numerous compensatory mechanisms. For example, if the visual cortex
is damaged, the auditory cortex can take on some visual functions. We have to be very
cautious in using negative findings in patients with developmental disorders to infer what
normally goes on in the brain.
You can't have a sustained feeling of fear without the activation of arousal systems. These
play an essential role in keeping conscious attention directed toward the emotional
situation, and without their involvement emotional states would be fleeting. You might be
temporarily aroused but your emotion would dissipate as soon as it occurred. Although all
novel stimuli activate arousal systems; particularly important to the persistence of emotional
responses and emotional feelings is the activation of arousal systems by the amygdala.
Amygdala-triggered arousal not only arouses the cortex but also arouses the amygdala,
causing the latter to continue to activate the arousal systems, creating the vicious cycles of
emotional arousal.
You can't have a sustained emotional experience without feedback from the body or
without at least long-term memories that allow the creation of as-if feedback. But even
as-if feedback has to be taught by real-life feedback. The body is crucial to an emotional
experience, either because it provides sensations that make an emotion feel a certain way
right now or because it once provided the sensations that created memories of what
specific emotions felt like in the past.
You probably can have an emotional feeling without the direct projections to the cortex
from the amygdala. These help working memory know which specialized emotion system is
active, but this can be figured out indirectly. Nevertheless, the emotion will be different in
the absence of this input than it would be in its presence.
You can have an emotional feeling without being conscious of the eliciting stimulus
without the actual eliciting stimulus being represented in a short-term cortical buffer and
held in working memory. Stimuli that are not noticed, or that are noticed but their
implications are not, can unconsciously trigger emotional behaviours and visceral responses. In such situations, the stimulus content of working memory will be amplified by the
arousal and feedback that result, causing you to attribute the arousal and bodily feelings to
the stimuli that are present in working memory. However, because the stimuli in working
memory did not trigger the amygdala, the situation will be misdiagnosed. If there is nothing
in particular occupying working memory, you will be in a situation where your feelings are
not understood. If emotions are triggered by stimuli that are processed unconsciously, you
will not be able to later reflect back on those experiences and explain why they occurred
with any degree of accuracy.
Contrary to the primary supposition of cognitive appraisal theories, the core of an emotion
is not an introspectively accessible conscious representation. Feelings do involve conscious
content, and we don't necessarily have conscious access to the processes that produce
the content. Even when we do have introspective access, the conscious content is not
likely to be what triggered the emotional responses in the first place. The emotional
responses and the conscious content are both products of specialized emotion systems
that operate unconsciously.
Conscious emotional feelings and conscious thoughts are in some sense very similar. They
both involve the symbolic representation in working memory of sub-symbolic processes
carried out by systems that work unconsciously. The difference between them is not due to
the system that does the consciousness part but instead is due to two other factors. One is
that emotional feelings and mere thoughts are generated by different sub-symbolic
systems. The other is that emotional feelings involve many more brain systems than do
thoughts.
When we are in the throes of emotion, it is because something important, perhaps life
threatening, is occurring, and much of the brain's resources are brought to bear on the
problem. Emotions create a flurry of activity all devoted to one goal. Thoughts, unless they
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trigger emotional systems, don't do this. We can daydream while doing other things, like
reading or eating, and go back and forth between the daydream and the other activities.
If we are faced with danger or other challenging emotional situations, we don't have time
to spare nor do we have available mental resources. The whole self gets absorbed in the
emotion. As Klaus Scherer has argued, emotions cause a mobilization and synchronization
of the brain's activities.579,580,581

FEAR CONDITIONING
Background and Definitions
The pathways by which sensory information
reaches the amygdala for emotional evaluation in fear conditioning have been detailed,
particularly in the auditory domain. The direct pathway may function to prime the
amygdala to respond quickly to danger, leaving more intricate analysis of the incoming
signal for the cortical pathway. This neurobiological warning signal can grant organisms an
evolutionary advantage by rapidly communicating the existence of potentially threatening
environmental stimuli. Either of these transmission routes is sufficient to mediate conditioned
fear to single auditory cues but the cortical pathway may be necessary for appropriate
responses to tones that must be discriminated from one another. These parallel input
pathways converge in the lateral nucleus of the amygdala, which serves as a sensory
interface to the region. Neurons in the lateral nucleus that respond to acoustic input are
also sensitive to somato-sensory stimulation. 582
Whilst it is clear that the amygdala plays a central role in the computation of emotional
stimulus value, there is recent evidence that other brain regions make contributions to
aspects of emotional processing within a fear-conditioning framework. The integrity of the
hippocampus, for example, is not essential for conditioning to simple phasic cues but is
critical for conditioning to contextual stimuli 583,584,585 . These findings are consistent with
cognitive theories regarding the role of the hippocampus in complex stimulus processing.
586,587,588,589 This contextual information may be important in allowing organisms to learn

579

Scherer, KR. Neuroscience projections to current debates in emotion psychology. Cognition

and Emotion 7, 1-41; 1993.

580

Leventhal, H. & Scherer, K. The relationship of emotion to cognition: A functional approach to

a semantic controversy. Cognition and Emotion 1, 3-28; 1987.

581

Scherer, KR. On the nature and function of emotion: A component process approach. In
Approaches to emotion, K. R. Scherer and P. Ekman, eds. (Hillsdale, N]: Erlbaum), pp. 293-317;
1984.

582

LaBar, KS & LeDoux, JE. Emotion and the Brain: An Overview. In Feinberg, T E & Farah, M J.
Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

583

Kim JJ & Fanselow MS. Modality-specific retrograde amnesia of fear. Science 256:675677,1992.

584

Phillips RG & LeDoux JE. Differential contribution of amygdala and hippocampus to cued
and contextual fear conditioning. Behav Neurosci 106:274285,1992.

585

Phillips RG & LeDoux JE. Lesions of the dorsal hippocampal formation interfere with
background but not foreground contextual fear conditioning. Learn Mem 1:34-44, 1994.

586

Nadel L. Hippocampus and space revisited. Hippocampus 1:221-229, 1991.

587

Hirsh R. The hippocampus and contextual retrieval of information from memory: A theory.
Behav Bioi 12:421-444, 1974

588

Sutherland RJ & Rudy JW. Configural association theory: The role of the hippocampal
formation in learning, memory, and amnesia. Psychobiology 17:129-144, 1989.

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and remember the environmental sub texts in which threatening stimuli occur. The
hippocampus may be exerting its influence via anatomic interactions with the amygdala.
These connections provide a neural passageway by which higher-order cognitive and
mnemonic processes can trigger and shape emotional experience, and vice versa.
In addition, lesions of the ventro-medial pre-frontal cortex selectively interfere with the
extinction of emotional learning in fear conditioning studies. 590, 591 . This result extends the
long-observed perseveration phenomena following prefrontal cortex damage 592,593 into the
emotional domain. The extinction process appears to involve active brain processing594,
which may be regulated by prefrontal-amygdala projections595. The neural traces laid
down in amygdala neurons during emotional learning are relatively indelible, and their
suppression requires neocortical input. 596,597 If extended into human populations, these
results may have clinical relevance for neurologic patients with persistent affective
disorders.

Ready to Fear

A behavioural psychologist, Neal Miller investigated how fear might

serve as a drive, like hunger or sex; an internal signal that motivates one to act in a way
that reduces the drive. Just as a hungry animal looks for food, a fearful one tries to get
away from the stimuli that arouse fear. He trained rats to avoid being shocked by jumping
over a hurdle that separated two compartments whenever a buzzer sounded. 598
The first phase involved fear conditioning the buzzer came on and the rats were
shocked. Then, through random actions, they learned that if they jumped over the hurdle
during the buzzer, they could avoid getting shocked. Once the rat figured this out, it would
jump every time it heard the buzzer, even if the shock was turned off. The shock was no

589

Cohen NJ & Eichenbaum H. Memory, Amnesia, and the Hippocampal System. Cambridge,
MA: MIT Press, 1993

590

Morgan MA; Romanski LM & LeDoux JE. Extinction of emotional learning: Contribution of
medial prefrontal cortex. Neurosci Left 163:109-113, 1993.

591

Morgan MA & LeDoux JE. Differential contribution of dorsal and ventral medial prefrontal
cortex to the acquisition and extinction of conditioned fear in rats. Behav Neurosci 109:681688, 1995.

592

Fuster JM. The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal
Lobe, 2d ed. New York: Raven Press, 1989

593

Janowsky JS; Shimamura AP; Kritchevsky M & Squire LR. Cognitive impairment following
frontal lobe damage and its relevance to human amnesia. Behav Neurosci 103:548-560, 1989.

594

Falls WA; Miserendino MJD & Davis M. Extinction of fear-potentiated startle: Blockade by
infusion of an NMDA antagonist into the amygdala. J Neurosci 12:854-863, 1992.

595

Amaral DG; Price JL; Pitkanen A & Carmichael ST. Anatomical organization of the primate
amygdaloid complex, in Aggleton IP (ed): The Amygdala: Neurobiological Aspects of
Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 1-66.

596

Rolls ET. A theory of emotion and consciousness, and its application to understanding the
neural basis of emotion, in Gazzaniga M (ed): The Cognitive Neurosciences. Cambridge, MA:
MIT Press, 1995, pp 1091-1106.

597

LeDoux IE; Romanski LM & Xagoraris AE. Indelibility of subcortical emotional memories. J
Cogn Neurosci 1:238-243, 1989.

598

Miller, N E Studies of fear as an acquirable drive: I. Fear as motivation and fear reduction as
reinforcement in the learning of new responses. Journal of Experimental Psychology 38, 89-10;
1948.

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longer present and was thus no longer the motivator. The avoidance response seemed, as
Mowrer had suggested, to be maintained by the anticipation of shock, by the fear elicited
by the warning signal. However, to prove that fear was the motivator, Miller changed the
rules for the rat.
Previously, when the rat jumped over the hurdle, the buzzer went off, and turning the buzzer
off seemed to be sufficient reinforcement to keep the rat jumping. But now the buzzer
stayed on when the rat jumped and would only go off if the rat pressed a lever; once this
was learned Miller changed the game again, forcing the rat to learn still another response
to turn the buzzer off.
While the initial response was learned because it allowed the rat to avoid the shock, the
subsequent ones were never associated with the shock. They were reinforced by the fact
that they turned off the sound. According to Miller, the findings showed that fear is a drive,
an internal energizer of behaviour, and that behaviours that reduce fear are reinforced
and thereby become habitual ways of acting (note, however, that fear is an internal
bodily signal, like hunger, and does not necessarily refer to subjective, consciously
experienced fear in this theory).
In the early 1970s, Martin Seligman, an experimental psychologist, whilst studying
conditioned fear in animals, pointed out some striking differences between human anxiety
and laboratory conditioned fear599. Especially important to Seligman was the fact that
avoidance conditioning extinguishes quickly if the animal is prevented from making the
avoidance response and alternative solutions for escape or avoidance are not provided.
Recall that Miller's rats kept jumping over the hurdle when the buzzer sounded even when
the shock was turned off. (See Above)
They never had the chance to find out that the shock was off because they kept jumping.
But Seligman's point is that if the hurdle is replaced with a wall, thus preventing the avoidance response, the rat soon learns that the buzzer is no longer followed by a shock and
begins to ignore the buzzer. If the wall is now removed and the hurdle returned, jumping no
longer occurs in response to the buzzer. Forcing the rat to see that the buzzer doesn't lead
to danger extinguishes the fear and this leads to the extinction of the neurotic avoidance
response. In contrast, telling an acrophobic that no one has ever accidentally fallen off the
Empire State Building and that he will be just fine if he goes to the top, or forcing him to go
up there to prove the point, does not help, and can even make the fear of heights worse
rather than better. Human phobias seem more resistant to extinction, and more irrational,
than conditioned fears in animals.
The key to this difference, in Seligman's view, is the fact that while laboratory experiments
use arbitrary, meaningless stimuli (flashing lights or buzzers), phobias tend to involve specific
classes of highly meaningful objects or situations (insects, snakes, heights). He argued that
perhaps we are prepared by evolution to learn about certain things more easily than
others, and that these biologically driven instances of learning are especially potent and
long lasting. Phobias, in this light, reflect our evolutionary preparation to learn about danger and to retain the learned information especially strongly.
In a relatively stable environment, it is generally a good bet that the dangers a species
faces will change slowly. As a result, having a ready-made means of rapidly learning about
things that were dangerous to one's ancestors, and theirs, is in general useful. But since our
environment is very different from the one in which early humans lived, our genetic
preparation to learn about ancestral dangers can get us into trouble, as when it causes us

599

Seligman, M E P (1971). Phobias and Preparedness. Behavior Therapy 2, 307-20; 1971.

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to develop fears of things that are not particularly dangerous in our world. (LeDoux, 1998,
idem)

Shall we be Frightened or not?

You encounter a rabbit whilst walking along a path in the woods. Light reflected from the
rabbit is picked up by your eyes. The signals are then transmitted through the visual system
to your visual thalamus, and then to your visual cortex, where a sensory representation of
the rabbit is created and held in a short-term visual object buffer. Connections from the
visual cortex to the cortical long-term memory networks activate relevant memories (facts
about rabbits stored in memory as well as memories about past experiences you may have
had with rabbits). By way of connections between the long-term memory networks and
the working memory system, activated long-term memories are integrated with the sensory
representation of the stimulus in working memory, allowing you to be consciously aware
that the object you are looking at is a rabbit.
A few strides later down the path and you come across a snake coiled up next to a log.
Your eyes also pick up on this stimulus. Conscious representations are created in the same
way as for the rabbit by the integration in working memory of short-term visual
representations with information from long-term memory. However, in the case of the
snake, in addition to being aware of the kind of animal you are looking at, long-term
memory also informs you that this kind of animal can be dangerous and that you might be
in danger.
According to cognitive appraisal theories, the processes described so far would constitute
your assessment of the situation and should be enough to account for the fear that you
are feeling as a result of encountering the snake. The difference between the working
memory representation of the rabbit and the snake is that the latter includes information
about the snake being dangerous. These cognitive representations and appraisals in
working memory are not enough to turn the experience into a full-blown emotional
experience. Something else is needed to turn cognitive appraisals into emotions, to turn
experiences into emotional experiences. That something, of course, is the activation of the
system built by evolution to deal with dangers; and that crucially involves the amygdala.
Many people, but not all, who encounter a snake in a situation such as the one described
will have a full-blown emotional reaction that includes bodily responses and emotional
feelings. 600 This will only occur if the visual representation of the snake triggers the amygdala. A whole host of connections will then be activated. Activation of these is what
makes the encounter with the snake an emotional experience, and the absence of
activation is what prevents the encounter with the rabbit from being one. 601
Neurons in the area of the thalamus that project to the primary auditory cortex are narrowly
tuned they are very particular to what they will respond. However, cells in the thalamic
areas that project to the amygdala are less particular they respond to a much wider
range of stimuli and are said to be broadly tuned. Music will sound the same to the

600

Erdelyi, M H. The recovery of unconscious (inaccessible) memories: Laboratory studies of

hypermnesia. In The psychology of learning and motivation: Advances in research and
theory, G. Bower, ed. (New York: Academic Press), pp. 95-127; 1984.

601

If, in your past, you have experienced rabbits in association with some trauma or stress, then
the rabbit too could serve as a trigger stimulus that would turn on the amygdala and its
outputs.

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amygdala by way of the thalamic projections but quite different by way of the cortical
projections. So when two similar stimuli are used in a conditioning study, the thalamus will
send the amygdala essentially the same information, regardless of which stimulus it is
processing, but when the cortex processes the different stimuli it will send the amygdala
different signals. If the cortex is damaged, the animal has only the direct thalamic pathway
and thus the amygdala treats the two stimuli the same both elicit conditioned fear.
Although the thalamic system cannot make fine distinctions, it has an important advantage
over the cortical input pathway to the amygdala. That advantage is time. In a rat it takes
about twelve milliseconds (twelve one-thousandths of a second) for an acoustic stimulus to
reach the amygdala through the thalamic pathway, and almost twice as long through the
cortical pathway. The thalamic pathway is thus faster. It cannot tell the amygdala exactly
what is there, but can provide a fast signal that warns that something dangerous may be
there. It is a quick and dirty processing system.

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Thalamocortical pathways carrying vestibular information.

Imagine walking in the woods. A crackling sound occurs. It goes straight to the amygdala
through the thalamic pathway. The sound also goes from the thalamus to the cortex,
which recognizes the sound to be a dry twig that snapped under the weight of your boot,
or that of a rattlesnake shaking its tail. But by the time the cortex has figured this out, the
amygdala is already starting to defend against the snake. The information received from
the thalamus is unfiltered and biased toward evoking responses. The cortex's job is to
prevent the inappropriate response rather than to produce the appropriate one.
Alternatively, suppose there is a slender curved shape on the path. The curvature and
slenderness reach the amygdala from the thalamus, whereas only the cortex distinguishes a
coiled up snake from a curved stick. If it is a snake, the amygdala is ahead of the game.
From the point of view of survival, it is better to respond to potentially dangerous events as if
they were in fact the real thing than to fail to respond. The cost of treating a stick as a
snake is less, in the long run, than the cost of treating a snake as a stick. (LeDoux, 1998,
Idem)
So we can begin to see the outline of a fear reaction system. It involves parallel
transmission to the amygdala from the sensory thalamus and sensory cortex. The
subcortical pathways provide a crude image of the external world, whereas more detailed
and accurate representations come from the cortex. While the pathway from the
thalamus only involves one link; several links are required to activate the amygdala by way
of the cortex. Since each link adds time, the thalamic pathway is faster. Interestingly, the
thalamo-amygdala and cortico-amygdala pathways converge in the lateral nucleus of the
amygdala. In all likelihood, normally both pathways transmit signals to the lateral nucleus,
which appears to play a pivotal role in coordinating the sensory processes that constitute
the conditioned fear stimulus. Once the information has reached the lateral nucleus it can
be distributed through the internal amygdala pathways to the central nucleus, which then
unleashes the full repertoire of defensive reactions. 602

Fear Conditioning in Humans

Human subjects do exhibit reliable conditioned

fear responses603,604,605 although these responses may be influenced somewhat by certain
personality characteristics606,607 and cognitive processes608. Despite its success in animal
research, fear conditioning has not been widely used in the neuropsychological assessment
of human brain function, where little is known about the neural basis of emotion.

602

Johnson-Laird, PN. The computer and the mind: An introduction to cognitive science
(Cambridge: Harvard University Press; 1988).

603

Hodes RL; Cook EW & Lang PJ. Individual differences in autonomic response: Conditioned
association or conditioned fear? Psychophysiology 22: 545-560, 1985.

604

Grillon C; Ameli R & Woods SW, et al. Fear-potentiated startle in humans: Effects of
anticipatory anxiety on the acoustic blink reflex. Psychophysiology 28:588-595, 1991.

605

Fredrickson M; Annas P & Georgiades A, et al. Internal consistency and temporal stability of
classically conditioned skin conductance responses. Bioi Psychol 35:153-163, 1993.

606

Eysenck HJ. The conditioning model of neurosis. Behav Brain Sci 2:155-199, 1979.

607

Guimaraes FS; Hellewell J & Hensman R, et al. Characterization of a psychophysiological

model of classical fear conditioning in healthy volunteers: Influence of gender, instruction,
personality and placebo. Psychopharmacology 104:231-236, 1990.

608

Davey G (ed): Cognitive Processes and Pavlovian Conditioning in Humans. Chichester,

England: Wiley, 1987.

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It has been shown that, as in other species, the integrity of the medial temporal lobe is
important for conditioned emotional learning in humans, although assessment of the
relative contributions of particular structures within this region must await future investigation
in patients with more restricted damage and functional imaging studies in healthy adults.
(LaBar, 1997 idem) Fear conditioning paradigms have also been proposed as a model
system for studying emotional processing in clinical populations with affective and
traumatic memory disorders.609,610
The amygdala has been implicated in aspects of fear regulation in both human611,612,613
and non-human studies. 614 The amygdala also appears to be involved in stimulus reward
learning615,616 and may contribute to dysfunction characterized by other disorders of affect
(Aggleton, 1992, idem). Gray 617 has incorporated the septo-hippocampal system into a
behavioural inhibition model of anxiety and stress, with an emphasis on its role in cognitive
monitoring and coping strategies. This conception reflects how cognitive influences enter
into emotional networks and complements the investigation of the role of the hippocampus
in more complex aspects of conditioned fear. (LaBar, 1997, idem)
The integrity of the orbitofrontal cortex is critical for the appropriate adjustment of
behavioural responses to changing reinforcement contingencies, which may account for
some of the emotional deficits following frontal lobe damage 618. The orbitofrontal cortex
may also function as a link between internal somatic states and social perceptions in the
guidance of behaviour619, and prefrontal-cingulate-amygdala connectivity with effector

609

Ohman A. Fear-relevance, autonomic conditioning, and phobias: A laboratory model. in

Sjoden PO, Bates S, Dockens WS (eds): Trends in Behavior Therapy. New York: Academic Press,
1979, pp 107-133.

610

Charney DS; Deutch A Y, & Krystal JH, et al. Psychobiologic mechanisms of posttraumatic
stress disorder. Arch Gen Psychiatry 50:294-305, 1993.

611

Adolphs R; Tranel D; Damasio H & Damasio AR. Impaired recognition of emotion in facial
expressions following bilateral damage to the human amygdala. Nature 372:669-672, 1994.

612

Aggleton JP. The functional effects of amygdala lesions in humans: A comparison with
findings from monkeys, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of
Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 485-504.

613

Halgren E. Emotional neurophysiology of the amygdala within the context of human

cognition, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory,
and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 191-228.

614

Slotnick BM. Fear behavior and passive avoidance deficits in mice with amygdala lesions.
Physiol Behav 11:717-720, 1973.

615

Gaffan D. Amygdala and the memory of reward, in Aggleton JP (ed): The Amygdala:
Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss,
1992, pp 471-484.

616

Everitt BJ & Robbins TW. Amygdala-ventral striatal interactions and reward-related processes,
in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and
Mental Dysfunction. New York: Wiley- Liss, 1992, pp 401-430.

617

Gray JA. The Psychology of Fear and Stress. 2d ed. Cambridge, England: Cambridge
University Press, 1987

618

Rolls ET. A theory of emotion and consciousness, and its application to understanding the
neural basis of emotion,in Gazzaniga M (ed): The Cognitive Neurosciences. Cambridge, MA:
MIT Press, 1995, pp 1091-1106.

619

Damasio A; Tranel D & Damasio H. Somatic markers and the guidance of behavior: Theory
and preliminary testing, in Levin H, Eisenberg H, Benton A (eds): Frontal Lobe Function and
Dysfunction. New York: Oxford University Press, 1991, pp 217-229.

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structures seems to be particularly important for mediating socio-emotional interactions.
Thus, particular structures of the limbic forebrain appear to play distinct roles in affective
processing, some of which can be understood as relating to more general functions of
these regions outside of the emotional domain. Of the structures comprising the limbic
system hypothesis, the amygdala has been most consistently linked with emotional stimulus
evaluation, a function originally attributed to the hypothalamus by previous theorists.
There seems undeniable evidence that the amygdala research carries an important
message that is connected with MDLs emotional and anxiety problems. What is not known
is if the problem is within the amygdala or whether it is to do with the interconnections
between it and other parts of the brain. MDLs fear responses need of course to be well
understood because if they are not, then there could be confusion about the origins of them
and how to mitigate the outcomes. This means that each component should be analysed
so that it can be ascertained if a lasting fear is due to a failure of extinction or whether it is
due to a reasonable objection to environmental influences. Consideration also needs to be
given to the fact that MDL does not easily understand or learn coping strategies.
______

EMOTIONAL DISORDERS IN RELATION TO

UNILATERAL BRAIN DAMAGE
The hypothesis of hemispheric specialization for psychological phenomena other than
language and cognitive functions, such as emotions and affect, is a recent one in the
history of neuropsychology. Up to that time, clinical studies of emotional disorders did not
attribute any differences between left and right brain lesions.
The problem of a possible hemispheric asymmetry in the regulation of emotions was raised
by some clinical observations made around fifty years ago. They were independently
made during pharmacologic inactivation of the right and left hemispheres and during
observation of the emotional behaviour of unilaterally brain-damaged patients.620,621 The
interest of these early clinical studies does not reside only in the fact that they called the
attention of neuropsychologists to a problem that had been previously substantially
neglected. It also stems from the fact that the theoretical models proposed by those who
made these clinical observations later served to orient most of the experimental studies
devised to clarify the links between emotions and hemispheric specialization. 622 Gainotti
found that there was a response of either appropriate or inappropriate forms of emotional
reaction, depending upon the sided location of the injury.
Emotion perception forms an integral part of social communication, and is critical to attain
developmentally appropriate goals. This skill, which emerges relatively early in development

620

Gainotti G. Reaction catastrophiques et manifestations d'indiffrence au cours des

atteintes crbrales. Neuropsychologia 7:195-204, 1969.

621

Gainotti G. Emotional behavior and hemispheric side of the lesion. Cortex 8:41-55, 1972.

622

Gainotti G. Emotional Disorders in Relation to Unilateral Brain Damage. In Feinberg, T E &

Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

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is driven by increasing connectivity among regions of a distributed socio-cognitive neural
network, and may be vulnerable to disruption from early childhood TBI. 623
Ryan et al (idem) found that survivors of severe childhood TBI had significantly poorer
emotion perception than controls and young adults with mild to moderate injuries.
Furthermore, poorer emotion perception was associated with reduced volume of the
posterior corpus callosum and the presence of frontal pathology. They considered that their
research findings lent support to the vulnerability of the immature 'social brain' network to
early disruption, and underscored the need for context-sensitive rehabilitation that
optimized early family environments to enhance recovery of emotion perception skills after
childhood TBI.
Green et al found that patients with recently acquired TBI are impaired in their ability to
perceive emotions in faces. Diffuse axonal injury (DAI) alone may cause facial emotion
perception deficits. 624 They examined whether facial emotion perception was
compromised in adults with recent traumatic brain injury (TBI). Few studies have examined
emotion perception in TBI; those that have, examined chronic patients only. Recent and
chronic TBI populations differ according to degree of functional reorganization of the brain,
use of compensatory strategies, and severity of cognitive impairmentsany of which might
differentially affect presentation of emotion perception deficits. A secondary aim of the
study was to utilize the TBI populationin whom DAI is a cardinal neurological featureto
examine the suggestion of Adolphs et al. See below[Journal of Neuroscience 20(7) (2000)
2683] that damage to white matter tracts should give rise to emotion perception deficits.
Thirty TBI participants were involved in the study and 30 age-matched controls were tested.
A 2 x 3 mixed design was employed. The dependent variable was accuracy on neutral and
emotional face perception tests. It was found that (1) The TBI group performed significantly
less accurately than the matched controls on the facial emotion perception tasks, whereas
the groups performed equivalently on a non-emotional face perception control task. (2) A
sub-group of TBI participants without evidence of focal injury to areas of the brain most
commonly implicated in facial emotion perception was as impaired on the emotion
perception tasks as a second sub-group who had sustained focal lesions to these areas. This
suggests an alternative neurological mechanism for deficits in the first sub-group, such as
DAI.
Autism spectrum disorder (ASD) also involves a fundamental impairment in processing
social-communicative information from faces. Several recent studies have challenged
earlier findings that individuals with autism spectrum disorder (ASD) have no activation of
the fusiform gyrus (fusiform face area, FFA) when viewing faces. Hadjikhani et al have
examined activation to faces in the broader network of face-processing modules that
comprise what is known as the social brain. 625 Using 3T functional resonance imaging, they
measured BOLD signal changes in 10 ASD subjects and 7 healthy controls passively viewing
non-emotional faces. They replicated their original findings of significant activation of face
identity-processing areas (FFA and inferior occipital gyrus, IOG) in ASD. Also they identified

623

Ryan NP; Anderson V; Godfrey C; Beauchamp MH; Coleman L; Eren S; Rosema S; Taylor K &
Catroppa C. Predictors of very long-term sociocognitive function after pediatric traumatic
brain injury. J Neurotrauma. 2013 Oct 22.

624

Green RE, Turner GR, Thompson WF. Deficits in facial emotion perception in adults with recent
traumatic brain injury. Neuropsychologia. 2004;42(2):133-41.

625

Hadjikhani, N; Joseph, RM; Snyder, J & Tager-Flusberg. H. Abnormal activation of the social
brain during face perception in autism. Human Brain Mapping 28(5):441 (2007) PMID
17133386

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hypo-activation in a more widely distributed network of brain areas involved in face
processing [including the right amygdala, inferior frontal cortex (IFC), superior temporal
sulcus (STS), and face-related somatosensory and premotor cortex].
In ASD, it was found that there were functional correlations between a subgroup of areas
in the social brain that belong to the mirror neuron system (IFC, STS) and other faceprocessing areas. The severity of the social symptoms measured by the Autism Diagnostic
Observation Schedule was correlated with the right IFC cortical thickness and with
functional activation in that area. When viewing faces, adults with ASD show atypical
patterns of activation in regions forming the broader face-processing network and social
brain, outside the core FFA and IOG regions. These patterns suggest that areas belonging
to the mirror neuron system are involved in the face-processing disturbances in ASD.
It is not just simple face recognition that can be affected following brain injury, there can
also be a failure in recognition of the emotional presentation of anothers face due to
abnormal activation of the social brain during face perception and this is also found in
autistic spectrum disorder which is also a neuropathological condition and that can be
related to Theory of Mind. (See p 31)

Comprehension and Expression of Emotions in Right- and Left-brain-Damaged

Patients
Since the exact nature of the emotional modifications observed after
right and left brain injury remain controversial, a large series of investigations were
undertaken to clarify this issue by means of experiments with both normal subjects and
patients with unilateral hemispheric damage. Although these investigations have explored
various aspects of the emotional behaviour, the attention of neuropsychologists has been
focused mainly on the most cognitive components of emotions, namely the
comprehension of emotional stimuli and the (facial or vocal) expression of emotions. This
was partly due to the assumption that the type of information processing typical of the right
hemisphere (and characterized by a syncretic and holistic rather than by a sequential and
analytical style) may be particularly suited to the treatment of emotional information626.
The methodology of investigations conducted on patients with focal brain injury has
consisted in matching the capacity of right- and left brain-damaged patients to
comprehend and/or express emotions at the facial level or through the tone of voice.
According to Adolphs et al, although lesion and functional imaging studies have broadly
implicated the right hemisphere in the recognition of emotion, neither the underlying
processes nor the precise anatomical correlates are well understood. They analyzed focal
brain lesions as a function of task performance in 108 subjects by co-registration in a
common brain space, and statistical analyses of their joint volumetric density revealed
specific regions in which damage was significantly associated with impairment.
This showed that recognizing emotions from visually presented facial expressions requires
right somatosensory-related cortices. The findings are consistent with the idea that we
recognize another individual's emotional state by internally generating somatosensory
representations that simulate how the other individual would feel when displaying a certain
facial expression. Follow-up experiments revealed that conceptual knowledge and
knowledge of the name of the emotion draw on neuro-anatomically separable systems.
Right somatosensory-related cortices thus constitute an additional critical component that

626

Tucker DM. Neural substrates of thought and affective disorders, in Gainotti G, Caltagirone C
(eds): Emotions and the Dual Brain. Heidelberg: SpringerVerlag, 1989, pp 225-234.

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functions together with structures such as the amygdala and right visual cortices in
retrieving socially relevant information from faces. 627
On the other hand, investigations conducted on normal subjects have allowed a better
control of the hypothesis, assuming a different specialization of the right and left
hemispheres for negative and positive emotions, respectively. Even if some studies have
supported the hypothesis of an interaction between hemisphere and positive or negative
emotional valence, most have failed to confirm it. On the contrary, the great majority of
these investigations have substantially confirmed the hypothesis of a general superiority of
the right hemisphere for functions of emotional comprehension and expression. (Gainotti,
1997, idem)
This fact has led some authors to hypothesize that right hemispheric dominance for
emotions may mainly concern the communicative aspects of emotional behaviour rather
than other, more basic components of emotions. This line of thought has been developed
in particular by Ross 628, who has suggested that disorders of nonverbal communication
might be the primary defect of right-brain-damaged patients and that emotional
disturbances usually observed in these patients may simply be a consequence of their
basic inability to comprehend and express emotions. (Gainotti, 1997, idem)
According to this viewpoint, the indifference reaction of right-brain damaged patients
should not be considered as an inappropriate form of emotional behaviour but simply the
consequence of a basic inability to correctly evaluate emotional signals and to express an
otherwise intact emotional experience.
However, Gainotti (1997, idem) believes that the data suggesting right hemispheric
dominance for functions of emotional communication may have been overemphasized in
previous studies and that the emotional indifference of right-brain-damaged patients cannot simply be considered the consequence of a defect of emotional communication.
However, because of the diffuse brain damage that MDL has suffered and the way that she
behaves in these contexts must give some credence to the other view, especially as
research has not yet reached MDLs type of brain damage.
Kucharska-Pietura et al recognize the importance of the right hemisphere in emotion
perception but also note that its precise role is disputed. They compared the
performance of 30 right hemisphere damaged (RHD) patients, 30 left hemisphere
damaged (LHD) patients, and 50 healthy controls on both facial and vocal affect
perception tasks of specific emotions. 629
The results showed that right hemisphere patients were markedly impaired relative to
left hemisphere and healthy controls on test performance. This included labelling and
recognition of facial expressions and recognition of emotions conveyed by prosody.
It was observed at the level of individual basic emotions, positive versus negative, and
emotional expressions in general. The impairment remained highly significant despite

627
Adolphs R; DamasioH; Tranel D; Cooper G & Damasio AR. A Role for Somatosensory
Cortices in the Visual Recognition of Emotion as Revealed by Three-Dimensional Lesion
Mapping. The Journal of Neuroscience, 1 April 2000, 20(7): 2683-2690
628

Ross, ED. The Aprosodias. . In Feinberg, T E & Farah, M J. Behavioural Neurology and
Neuropsychology. McGraw-Hill, New York, 1997.

629

Kucharska-Pietura, K; Phillips, ML; Gernand, W; & David, AS. Perception of emotions from
faces and voices following unilateral brain damage. Neuropsychologia; Volume 41, Issue 8,
2003, 1082-1090.

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co-varying for the group's poorer accuracy on a neutral facial perception test and
identification of neutral vocal expressions. They considered that these data confirm
the primacy of the right hemisphere in processing all emotional expressions across
modalities, both positive and negative.
The results of investigations conducted in right- and left-brain-damaged patients seem to
show that right hemispheric damage disrupts not only the communicative aspects of
emotions but also the generation of the autonomic components of the emotional response
and therefore the inner experience of emotions. Data consistent with the hypothesis of a
leading role of the right hemisphere in the generation of the autonomic components of
emotions and of the concomitant emotional experience have also recently been obtained
during lateralized presentation of emotionally laden films to normal subjects. These authors
found that both the increase of diastolic and systolic blood pressure and the subjective
rating of the intensity of the emotional experience were higher during presentation of the
film to the right rather than to the left hemisphere. (Gainotti, 1997, idem)
Allerdings et al have studied the relationship between neuropsychological functioning and
emotion recognition and they examined in eleven individuals with moderate to severe TBI
and a control group of 13 individuals matched for age, sex, and education. Emotion
recognition stimuli were from Ekman and Friesen's pictures of facial affect. The group with
TBI showed neuropsychological deficits consistent with those commonly found following
moderate to severe TBI. The group with TBI also identified significantly fewer emotion
recognition stimuli than the control group. The number of correctly identified emotion
recognition stimuli was significantly correlated with measures of verbal cognitive processing
in the group with TBI. These findings suggest that the role of left hemisphere brain
mechanisms in the recognition of facial (nonverbal) emotion may be more important than
previously recognized. 630
Callahan et al in studying deficits that were found in patients with facial emotion
recognition revealed that they displayed a liberal bias when rating facial expressions,
leading them to associate intense ratings of incorrect emotional labels to sad, disgusted,
surprised and fearful facial expressions. These findings are generally in line with prior studies
which also report important facial affect recognition deficits in TBI patients, particularly for
negative emotions.631

_______

SLEEP

Sleep is not simply a passive lapse from wakefulness. Rather, both sleep and wakefulness
are actively maintained by discrete areas of the brain stem and other brain areas as well.

630

Allerdings, MD; & Alfano, DP. Neuropsychological correlates of impaired emotion recognition
following traumatic brain injury. Brain Cogn. 2006 Mar; 60 (2): 193-4.

Callahan BL; Ueda K; Sakata D; Plamondon A & Murai T. Liberal bias mediates
emotion recognition deficits in frontal traumatic brain injury. Brain Cogn. 2011 Dec;
77(3):412-8.

631

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A number of experimenters have shown that electrical and chemical stimulation of certain
parts of the thalamus and hypothalamus could also induce sleep or wakefulness. These
experiments illustrate the point that brain functions are rarely centred. Instead, they are
typically represented by systems which may extend over large areas of the brain.
Tamaki et al have studied the interhemispheric asymmetry in sleep depth as it occurs for
the rst night in a new place. This is called the first-night effect (FNE). This interhemispheric
asymmetry occurs in the default-mode network (DMN). The less-asleep hemisphere shows
increased vigilance in response to deviant stimuli. One brain hemisphere may work as a
night watch during sleep in a novel environment. They found that when humans sleep in a
novel environment, the default-mode in one hemisphere is kept more vigilant to wake the
sleeper up as a night watch upon detection of deviant stimuli. The regional
interhemispheric asymmetric sleep in a novel environment may play a similar protective
role to that in marine mammals and birds.632
The interhemispheric asymmetry of sleep depth associated with the FNE was found in the
default-mode network (DMN) involved with spontaneous internal thoughts during wakeful
rest. 633,634 The degree of asymmetry was signicantly correlated with the sleep-onset
latency, which reects the degree of difculty of falling asleep and is a critical measure for
the FNE. Furthermore, the hemisphere with reduced sleep depth showed enhanced
evoked brain response to deviant external stimuli. Deviant external stimuli detected by the
less-sleeping hemisphere caused more arousals and faster behavioural responses than
those detected by the other hemisphere. These lines of evidence are in accord with the
hypothesis that troubled sleep in an unfamiliar environment is an act for survival over an
unfamiliar and potentially dangerous environment by keeping one hemisphere partially
more vigilant than the other hemisphere as a night watch, which wakes the sleeper up
when unfamiliar external signals are detected. (Tamaki et al, Idem)
In the case of MDL, this becomes more significant because of her autism spectrum disorder
which adds another dimension to that of the basic unfamiliar environment. Also, her
anxiety will promote further troubled sleep or failure to fall asleep as she is probably afraid
of possibilities like nocturnal enuresis and fear generated by dreams.
Sumpter et al studied subjects who had suffered moderate-severe pediatric traumatic brain
injury (TBI). Significantly more sleep problems were parent-reported. There was no
evidence of circadian rhythm disorders, and daytime napping was not prevalent.
Moderate-severe pediatric TBI was associated with sleep inefficiency in the form of sleep
onset and maintenance problems. This preliminary study indicates that clinicians should be
aware of sleep difficulties following pediatric TBI, and their potential associations with
cognitive and behavioral problems in a group already at educational and psychosocial

632

Tamaki, M; Bang, JW; Watanabe, T & Yuka Sasaki, Y. Night Watch in One Brain Hemisphere
during Sleep Associated with the First-Night Effect in Humans. Current Biology 26, 15 May 9,
2016.

633

Mason, M.F., Norton, M.I., Van Horn, J.D., Wegner, D.M., Grafton, S.T., & Macrae, C.N.
Wandering minds: the default network and stimulus-independent thought. Science 315, 393
395; 2007.

634

Raichle,M.E.; MacLeod,A.M.; Snyder, A.Z.; Powers,W.J.; Gusnard, D.A.; & Shulman, G.L. A
default mode of brain function. Proc. Natl. Acad. Sci. USA 98, 67668; 2001.

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risk. Where concerted action has not been given to this problem and this has not been part
of a care plan it can be a difficulty for parents and carers as well as the subject. 635
Soehner et al, have examined the prevalence and functional consequences of severe
insomnia symptoms in mood and anxiety disorders. The presence of at least one insomnia
symptom in the past year was associated with significantly greater days of impairment
across all WHO-DAS 636 domains for respondents with comorbid disorders. For those with
anxiety disorders only, insomnia symptoms were associated with more days of impairment
across all domains except self-care. Also, for those with mood disorders only, insomnia
symptoms were associated with significant impairment in all domains except mobility and
self-care.637
Taylor et al, in their study of insomnia, used empirically validated insomnia diagnostic
criteria to compare depression and anxiety in people with insomnia and people not having
insomnia. Previous research had shown that there was a strong relationship existing
between insomnia, depression, and anxiety; where insomnia may be a risk factor. However,
the exact nature of this relationship had remained unclear because previous studies had
varied definitions of insomnia and sometimes did not control for confounds. 638
Further, none of the studies discussed above attempted to ruleout underlying sleep
disorders and many did not attempt to rule out medical causes of the insomnia, depression,
or anxiety. This is important considering that depression, anxiety, and insomnia can all be
caused or at least exacerbated by other medical or psychiatric disorders. By not excluding
or controlling for underlying organic sleep disorders and medical conditions, it is highly likely
participants with comorbid insomnia were included in the earlier analyses, again possibly
making the prevalence rates inaccurate for people with primary insomnia. The results of
this study show that there are clearly a large proportion of people with insomnia who show
clinically significant depression and anxiety. Due to the possible reciprocal relationship of
these disorders, more effort needs to be focused on explicating the exact nature of the
relationship and finding ways to intervene. (Idem)
Sleep deprivation also causes memory deficits. Recent research shows that five hours of
sleep deprivation leads to a loss of connectivity between neurons in the hippocampus, a
region of the brain associated with learning and memory. It is proposed that changes in
the connectivity between synapses structures that allow neurons to pass signals to each
other can affect memory. To study this further, the researchers examined the impact of
brief periods of sleep loss on the structure of dendrites, the branching extensions of nerve
cells along which impulses are received from other synaptic cells, in the mouse brain. Lack
of sleep is a common problem and it has severe consequences for health, overall
wellbeing, and brain function. 639

635

Sumpter RE; Dorris L; Kelly T & McMillan TM. Pediatric sleep difficulties after moderate-severe
traumatic brain injury. J Int Neuropsychol Soc. 2013 Apr 22:1-6.

636

The World Health Organization Disability Assessment Schedule

637

Soehner, AM & Harvey, AG. Prevalence and Functional Consequences of Severe Insomnia
Symptoms in Mood and Anxiety Disorders: Results from a Nationally Representative Sample.
Sleep, Vol. 35, No. 10, 2012.

638

Taylor DJ; Lichstein KL; Durrence HH et al. Epidemiology of insomnia, depression and anxiety .
Sleep 2005;28(11): 1457-1464.

639

Havekes, R; Park, AJ; Tudor, JC; Luczak, VG; Hansen, RT; Ferri, SL; Bruinenberg, VM;
Poplawski, SG; Day, JP; Aton, SJ; Radwaska, K; Meerlo, P; Houslay,MD; Baillie, GS & Abel, T.
Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in
hippocampal area CA1. eLife, doi: 10.7554/eLife.13424; 2016.

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Many people report getting sick when they don't get enough sleep. Gharib et al took
blood samples from 11 pairs of identical twins with different sleep patterns and discovered
that the twin with shorter sleep duration had a depressed immune system, compared with
his or her sibling. The authors show is that the immune system functions best when it gets
enough sleep. Seven or more hours of sleep is recommended for optimal health. 640
They found that a lot of existing data showed that curtailing sleep for a limited time in the
laboratory setting can increase inflammatory markers and activate immune cells.
However, little was known about the effects of longstanding short sleep duration under
natural conditions. This study employed "real world" conditions and showed for the first time
that chronic short sleep shuts down programs involved in immune response of circulating
white blood cells.
The results are consistent with studies that show when sleep deprived people are given a
vaccine, there is a lower antibody response and if you expose sleep deprived people to a
rhinovirus they are more likely to get the virus. This study provides further evidence of the
importance of sleep to overall health and well-being particularly to immune health. (Idem)

Wakefulness and sleep are dynamic states during which brain functioning is modified and
shaped. Sleep loss is detrimental to many brain functions and results in structural changes
localized at synapses in the nervous system. Areal et al reviewed some of the latest
observations of structural changes following sleep loss in some vertebrates and insects. They
emphasized that these changes are region-specific and cell type-specific and that, most
importantly, these structural modifications have functional roles in sleep regulation and
brain functions. They also considered selected mechanisms driving structural modifications
occurring with sleep loss. They concluded that overall, recent research highlights that
extending wakefulness impacts synapse number and shape, which in turn regulate sleep
need and sleep-dependent learning/memory. 641
An equally important implication of these experiments is that the short-term effects of brain
lesions may be very different from the long-term effects. Consequently, the many lesion
experiments which still focus almost exclusively on short-term effects may provide an
incorrect view of the functions subserved by various parts of the brain. This is particularly
true when the lesions produce impairment of or a reduction in any function.
There is an emerging consensus that sleep plays a vital role in recalibrating the emotional
functioning of the brain 642, 643 . Without sufficient sleep, there appears to be a reduction in

640

SA Gharib et al. Transcriptional Signatures of Sleep Duration Discordance in Monozygotic

Twins. Sleep, January 2017 DOI: 10.1093/sleep/zsw019.

641

Areal, CC; Simon C. Warby, SC & Mongrain, V. Sleep loss and structural plasticity. Current
Opinion in Neurobiology Volume 44, June 2017, Pages 17 (Neurobiology of Sleep). Online in
advance of publication.

642

Walker, MP & Van Der Helm, E. Overnight therapy? The role of sleep in emotional brain
processing. Psychol. Bull., 135 (2009), pp. 731748.

643

Walker, MP. The role of sleep in cognition and emotion. Ann. N. Y. Acad. Sci, 1156 (2009), pp.
168197.

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emotional regulation capacities and a loss of perceptual sensitivity to cues that provide
critical emotional information about the external environment and internal milieu 644 .
Emotional processing is particularly sensitive to sleep deprivation, but research on the topic
has been limited and prior studies have generally evaluated only a circumscribed subset of
emotion categories. Killgore et al evaluated the effects of one night of sleep deprivation
and a night of subsequent recovery sleep on the ability to identify the six most widely
agreed upon basic emotion categories. 645 Sleep deprivation was associated with
significantly reduced accuracy for identifying the expressions of happiness and sadness in
the morphed faces.
Blair has shown that human survival has long depended on the ability to accurately read
and infer the emotional states of others. Because the face communicates the physical and
affective condition, motivation, and potential intentions of those in close proximity, it
provides a crucial source of information about factors that could affect survival and
wellbeing, including the presence or absence of danger, the availability of resources, the
needs of others, and the potential for social inclusion and affiliation.646
The work of Killgore and Blair is important in the case of MDL because her neuropathology
reduces her ability to understand facial expressions and loss of sleep must cause more
problems in that area. [See pages 110-116]

The Chemistry of Sleep

Knowledge about the chemical nature of the
brainstem neurons increased dramatically in the early 1960s when the Swedish anatomists
Kjell Fuxe and Anica Dahlstrom demonstrated that the pons harboured neurons whose
widely branching axons distributed two chemical substances throughout the brain.
Neurons for each chemical were located in their own defined area of the pons (such an
area is called a nucleus). The neurons of the midline raphe nuclei were the main source of
the neurotransmitter serotonin (5-hydroxy-tryptamine), and the neurons of the nucleus locus
coeruleus, a major source of the neurotransmitter norepinephrine. Both were known to be
neurotransmitters that tended to inhibit the cells they contacted. But because of their
widespread and diffuse distribution and the long course of their action they came to be
called neuromodulators, indicating that they set the response mode of the brain rather
than conveying sensory or motor data. Serotonin and norepinephrine belong to a class of
substances called biogenic amines; hence, neurons that release these two
neurotransmitters are referred to as aminergic. Because these two substances were known
to play an important role in the control of the cardiovascular and gastrointestinal systems,
they were immediate and strong candidates for a central role in controlling the state of the
brain. It was as if the brain had its own nervous system, a brain within a brain as it were. 647
Another neurotransmitter, called acetylcholine, was also suspected to play a role in sleep.
Unlike serotonin or norepinephrine, acetylcholine is excitatory; that is, it causes cells to fire.

644

Goldstein-Piekarski, AN; Greer, SM; Saletin, JM & Walker, MP. Sleep Deprivation Impairs the
Human Central and Peripheral Nervous System Discrimination of Social Threat. J. Neurosci., 35
(2015), pp. 1013510145.

645

Killgore, WDS; Balkin, TJ; Angela M. Yarnell, AM & Capaldi, VF. Sleep deprivation impairs
recognition of specific emotions. Neurobiology of Sleep and Circadian RhythmsAvailable
online 21 January 2017. In Press, Accepted Manuscript.

646

Blair, RJ. Facial expressions, their communicatory functions and neuro-cognitive substrates;
Philos. Trans. R. Soc. Lond. B. Biol. Sci., 358 (2003), pp. 561572.

647

Hobson, JA. Sleep. Scientific American Library: HPHLP; New York, 1989.

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Neurons that release acetylcholine are called cholinergic and cells that respond to it are
called cholinoceptive.
The dominant theory of the brain mechanisms of sleep had been developed by Jouvet
and his colleagues. Basically, Jouvet's theory depicts two brain stem sites that are
anatomically and neuro-chemically distinct: one controls slow wave sleep and the other
controls REM sleep. Jouvet observed that damage to the brain stem raphe complex
produced insomnia. The raphe complex was shown to be the site of origin of many of the
forebrain serotonin neurons. Drugs which reduced serotonergic function also produced
insomnia. These data formed the core of a raphe-serotonergic theory of slow-wave
sleep648.
It was also reported that damage to the brain stem locus coeruleus eliminated REM sleep.
The locus coeruleus was shown to be the site of origin of many of the forebrain noradrenalin
neurons. Drugs which reduced noradrenergic function tended to eliminate REM sleep. All
of these data suggest that sleep-wakefulness cycles are far more neuro-chemically
complex than was originally believed.
Having previously emphasized the role of acetylcholine in REM sleep, Jouvet proposed in
1967 649 that the brainstem exerted its control of non-REM sleep via serotonin and of REM
sleep via norepinephrine. The idea was that each neurotransmitter caused a different state
via its influence on neurons throughout the brain. These latter two conclusions, though
based on solid pharmacological data, have not been confirmed by physiological or by
biochemical studies, but Jouvet's earlier postulate that acetylcholine enhances REM sleep
has been fully confirmed.
If, as Jouvet's work had clearly indicated, there were both a clock and a trigger for the
periodic REM sleep episode in the pons, it should be possible to identify specific neurons in
both. Using the microelectrode technique, Hobson and McCarley found that some cells
turned on and others turned off in REM sleep (Hobson, 1989, Idem). The REM-off cells were
the real surprise, because they were the very neurons in the raphe and locus coeruleus that
Jouvet's pharmacological studies had predicted should be on. The REM-on cells did not
release serotonin or norepinephrine but did possibly release acetylcholine.

_____________________

WORKING MEMORY AND COGNITION

MD L s workin g m em ory h as b een s e riou s l y af f ec ted
by her brain injury both In terms of th e structures
th at wer e d am aged an d th e f ai lu r e of s om e
deve lopm en t al pro ces s es th at f ol lo wed; ad ded to
this are the problems th at h ave accrued due to th e

648

Jouvet, M. Sleep and Altered States of Consciousness (edit. by Kety, S. S., Evarts, E. V., and
Williams, H. L.), 86 (Williams and Wilkins, Baltimore, 1967).

649

Jouvet, M. Sleep and Altered States of Consciousness (edit. by Kety, S. S., Evarts, E. V., and
Williams, H. L.), 86 (Williams and Wilkins, Baltimore, 1967).

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l ack of n o rm al s oc i al c on t ac ts wi th h er pe ers du rin g
childh ood.
I t is im po rt an t th er ef or e t o u n ders t an d t h e w ay in
which
working
memory
af f e cts
our
cogn itive
proc es s es an d h ow MD L s def ici ts in th is are a af f e c t
h er em o tion al lif e an d c om m u n ic ation abili ty as a
res u l t of d am ag e t o h er p ref ron t al c or te x an d i ts
con n e ct ion s t o o th e r br ain are as .

Working Memory

Working memory is a form of short-term memory that

is often exemplified by the times when information is being held on line for the purpose of
performing computations on it (analogous to a mental scratch pad). Fuster650,651 provided
the first detailed account of the role of working memory in prefrontal processes. He
describes the role of the prefrontal cortex as that of integrating temporally distributed
information, a complex process which he attributed partly to short-term working memory.
Contrasting this view with supervisory attentional system-like executive accounts of
prefrontal function652, he writes: The prefrontal cortex would not superimpose a steering or
directing function on the remainder of the nervous system, but rather, by expanding the
temporal perspectives of the system, it would allow it to integrate longer, newer, and more
complex structures of behaviour. Thus, frontal damaged patients, in whom the SAS is
damaged, are no longer able to exert goal-directed control over their actions but simply
respond to stimuli.
The overall goal of cognitive neuroscience as a discipline is to determine the biological
basis of the mind. As an interdisciplinary discipline that has evolved from both
neuroscience and psychology, cognitive neuroscientists consume data derived from each
of these disciplines in their attempt to advance cognitive theory as well as determine how
the brain implements cognitive function. Advances made in understanding the cognitive
and neural basis of working memory provide examples of this synergy. DEsposito suggests
that future studies must continue to consider both cognitive and neural data. 653 Research
thus far suggests that working memory can be viewed as neither a unitary nor a dedicated
system. A network of brain regions, including the PFC, is critical for the active maintenance
of internal representations that are necessary for goal-directed behaviour. Thus, working
memory is not localized to a single brain region but probably is an emergent property of the
functional interactions between the PFC and the rest of the brain.
Goldman-Rakic654 has proposed a working-memory account of frontal lobe function on the

650

Fuster JM. The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal
Lobe. New York: Raven Press, 1980.

651

Fuster JM. The prefrontal cortex and temporal integration, in Jones EG, Peters A (eds):
Cerebral Cortex: Vol 4. Association and Auditory Cortices. New York: Raven Press; 1985.

652

Supervisory attentional system (SAS) a loosely defined collection of brain processes that
are responsible for planning, cognitive flexibility, abstract thinking, rule acquisition, initiating
appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory
information.

653

DEsposito, M. From Cognitive to neural models of working memory. In Driver, J; Haggard, P; &
Shallice, T. Mental Processes in the Human Brain. OUP, New York; 2007

654

Goldman-Rakic PS. Circuitry of primate prefrontal cortex and regulation of behavior by

representational memory, in Plum F, Mountcastle V (eds): Handbook of Physiology, The
Nervous System: V. Bethesda, MD: American Physiological Society, 1987.

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basis of extensive research with non-human primates. Building on the well-established relationship between the prefrontal cortex and delayed-response tasks, she argues that the
prefrontal cortex is responsible for maintaining information (representational memory)
that is later used to guide action. Funahashi and colleagues655,656 have carried out a
variety of lesion studies and single-unit recording studies to establish the role of prefrontal
cortex in working memory, primarily with monkeys trained to perform spatial workingmemory tasks.
Neuro-imaging studies in humans657,658,659,660 suggest that similar working-memory processes
are located pre-frontally in the human brain. Goldman-Rakic (1987, idem) has suggested
that the association between prefrontal cortex and working memory can, in principle,
explain a range of human cognitive impairments following focal frontal lesions as well as
other non-focal pathologies affecting prefrontal cortex. The proposal that working memory
impairment could underlie the range of cognitive changes seen after prefrontal damage
first found direct support in the work of Cohen and Servan-Schreiber661.
Working-memory accounts of prefrontal function are favoured for a number of reasons662:
First, they are parsimonious, in that working-memory theories contain only the individual
processing components needed to perform the task without needing a central executive
(such as the SAS) to coordinate these components (and to serve as the locus of damage
when explaining patient behaviour).
Second, they have proven capable of explaining a wider range of seemingly disparate
impairments than other non-executive theories (Cohen, 1992 idem) & 663.
Third, they are supported by a wealth of evidence from monkey neurophysiology and, increasingly, from neuro-imaging studies in humans. For instance, Fougnie and Marois have
found that the hallmark of both visual attention and working memory is their severe
capacity limit. People can attentively track only about four objects in a multiple object

655

Funahashi S; Bruce CJ & Goldman-Rakic PS. Mnemonic coding of visual space in the
monkey's dorsolateral prefrontal cortex. J Neurophysiol 61:331349,1989.

656

Funahashi S; Bruce CJ & Goldman-Rakic PS. Dorsolateral prefrontal lesions and oculomotor
delayedresponse performance: Evidence for mnemonic scotomas. J Neurosci 13:14791497, 1993.

657

Cohen J; Forman S & Braver T, et al. Activation of prefrontal cortex in a nonspatial working
memory task with functional MRI. Hum Brain Mapping 1:293-304, 1994.

658

D'Esposito M; Shin RK & Detre JA, et al. Object and spatial working memory activates
dorsolateral prefrontal cortex: A functional MRI study. Soc Neurosci Abstr 21:1498, 1995.

659

D'Esposito M; Detre J & Alsop D, et al. The neural basis of the central executive system of
working memory. Nature 378:279-281, 1995.

660

Jonides J; Smith E & Koeppe R, et al. Spatial working memory in humans as revealed by PET.
Nature 363:623-625, 1993.

661

Cohen JD & Servan-Schreiber D. Context, cortex, and dopamine: A connectionist approach

to behavior and biology in schizophrenia. Psychol Rev 99:4577,1992.

662

Kimberg, DY; DEsposito, M & Farah, MJ. Frontal Lobes: Cognitive and Neuropsychological
Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology.
McGraw-Hill, New York, 1997.

663

Kimberg DY & Farah MJ. A unified account of cognitive impairments following frontal lobe
damage: The role of working memory in complex, organized behavior. J Exp Psychol Gen
122:411-428, 1993.

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tracking (MOT) task and can hold only up to four objects in visual working memory (VWM).
It has been proposed that attention underlies the capacity limit of VWM.
They tested this hypothesis by determining the effect of varying the load of a MOT task
performed during the retention interval of a VWM task and comparing the resulting dualtask costs with those observed when a VWM task was performed concurrently with another
VWM task or with a verbal working memory task. Instead of supporting the view that the
capacity limit of VWM is solely attention based, the results indicated that VWM capacity is
set by the interaction of visuospatial attentional, central amodal, and local task-specific
sources of processing.664
Fourth, they suggest a way of resolving what is perhaps the central problem of the neuropsychology of the frontal lobe function the paradox of dissociable impairments with an
unintuitive compelling family resemblance.
If we assume that working memory is compartmentalized in the prefrontal cortex according
to what is being represented in memory (for which evidence exists), then performance in
different tasks can be impaired or spared depending on which types of working memory
have been damaged. Nevertheless, according to working-memory accounts, there is an
underlying commonality among the tasks sensitive to prefrontal damage namely, their
dependence on working memory. 665

Buffers

A critical component of Baddeleys working memory model is the existence

of verbal mid-spatial storage buffers666. The cognitive concept of a buffer translated into
neural terms would propose that temporary retention of task-relevant information requires
transfer of that information to a part of the brain that is dedicated to the storage of
information. Presumably, such buffers are analogous to a computers RAM, which serves as
a cache for information transferred from the hard drive that is processed by a CPU.
Consistent with this interpretation of a working memory buffer, many descriptions of
cognitive models of working memory refer to the information being in or out of working
memory.

664

Fougnie, D. & Marois, R. Distinct Capacity Limits for Attention and Working Memory.
Psychological Science. 6; V17; 2006 pp 526-534.

665

Kimberg, DY; DEsposito, M & Farah, MJ. Frontal Lobes: Cognitive and Neuropsychological
Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology.
McGraw-Hill, New York, 1997.

666

Baddeley, A. Working memory. New York, NY: Oxford University Press; 1986.

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Relation of Specialized Short-Term Buffers,

Long-Term Explicit Memory and Working Memory.
Stimuli processed in different specialized systems (such as sensory,
spatial, or language systems) can be held simultaneously in short-term
buffers. The various short-term buffers provide potential inputs to
working memory, which can deal most effectively with only one of the
buffers at a time. Working memory integrates information received
from short-term buffers with long-term memories that are also
activated.
For example, in a recent review of working memory, Repovs & Baddeley667 state that, the
function of the articulatory rehearsal process is to retrieve and rearticulate the contents
held in this phonological store and in this way to refresh the memory trace. Further, while
speech input enters the phonological store automatically, information from other modalities
enters the phonological store only through recoding into phonological form, a process
performed by articulatory rehearsal. Later, the authors refer to, focal shifts of attention to
memorized locations that provide a rehearsal-like function of maintaining information
active in spatial working memory. Thus, one question that neuro-scientific data can
address regarding how the brain implements working memory processes is whether such
buffers or storage sites exist in distinct parts of the brain to support the active maintenance
of task-relevant information.
A cognitive model of working memory, put forward by Cowan668,669 proposes that the,
contents of working memory are not maintained within dedicated storage buffers, but

667

Repovs, G. & Baddeley, A. The multi-component model of working memory: explorations in

experimental cognitive psychology. Neuroscience 139, 5-2; 2006.

668

Cowan, N. Evolving conceptions of memory storage, selective attention, and their mutual
constraints within the human information processing system. Psycho I. Bull. 104, 163-171; 1988.

669

Cowan, N. An embedded-process model of working memory. In Models of working memory:

mechanisms of active maintenance and executive control (eds A. Miyake & P. Shah), pp. 62101. Cambridge, UK: Cambridge University Press; 1999.

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rather are simply the subset of information that is within the focus of attention at a given
time. He describes an embedded-processes model where working memory comes from
hierarchically arranged faculties comprising long-term memory, the subset of working longterm memory that is currently activated and the subset of activated memory that is the
focus of attention. These ideas are similar to that put forth by Anderson670 who referred to
working memory as those representations currently at a high level of activation. Thus, taskrelevant representations are not in working memory, but they do have levels of activation
that can be higher or lower. After use, for example, representations may be temporarily
more active or primed. In this formulation, working memory does not have a size, or
maximum number of items, as a structural feature. Instead, performance on working
memory tasks is determined by the level of activation of relevant representations, and the
discriminability of activation levels between relevant and irrelevant representations 671 .
Again, in neural terms, Cowans or Andersons cognitive model of working memory would
predict that information that is represented throughout the brain is not transferred to an
independent buffer or storage site, but rather that temporary retention of task-relevant
information is mediated by the activation of the neural structures that represent the
information being maintained or stored (for a further discussion of these and related ideas,
see Ruchkin, et al 672. In other words, the temporary retention of a face, for example, would
require activation of cortical areas that are involved in the perceptual processing of faces.
From a neuroscience perspective, it is counter-intuitive that all temporarily stored
information during goal-directed behaviour requires specialized dedicated buffers. Clearly,
there could not be a sufficient number of independent buffers to accommodate the
infinite types of information that need to be actively maintained to accommodate all
potential or intended actions.
For instance, in a system with only two buffers, such as verbal and visuo-spatial, how would
the retention of odours or tactile sensations, which cannot always be recoded into verbal
or visuo-spatial representations, be accomplished? More recently, an additional episodic
buffer has been proposed to be a store capable of multi-dimensional coding that allows
the binding of information to create an integrated episode673 . However, even with the
addition of this buffer, Baddeleys working memory model cannot accommodate storage
of all possible types of information processed by the human brain (it is important to note,
however, that this was not probably the original intent of his model).
Alternatively, in Cowans proposal, which does not rely on the concept of specialized
dedicated storage buffers, active maintenance or storage of task-relevant representations
could be implemented with a neural system where memory storage occurs in the very
same brain circuitry that supports the perceptual representation of information. Such a
neural system presumably would be more flexible and efficient than one that transfers
information back and forth between dedicated storage buffers. Obviously, there is still work
to be done to test these competing hypotheses.

670

Anderson, J. R. The architecture of cognition. Cambridge, MA: Harvard University Press; 1983.

671

Kimberg, D. Y., D'Esposito, M. & Farah, M. J. Cognitive functions in the prefrontal cortexworking memory and executive control. Curro Dir. Psychol. Sci. 6, 185-192; 1997.

672

Ruchkin, D. S., Grafman, J., Cameron, K. & Berndt, R. S. Working memory retention systems: a
state of activated long-term memory. Behav. Brain Sci. 26, 709-728, discussion 728-777; 2003.

673

Baddeley, A. The episodic buffer: a new component of working memory? Trends Cogn. Sci. 4,
417423; 2000

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The influence of memory on perception is an example of what cognitive scientists
sometimes call top-down processing, which contrasts with the build-up of perceptions from
sensory processing, known as bottom-up processing.
Working memory, in short, sits at the crossroads of bottom-up and top-down processing
systems and makes high-level thinking and reasoning possible. Stephen Kosslyn, a leading
cognitive scientist, puts it this way:
Working memory ... corresponds to the activated information in long-term memories, the
information in short-term memories, and the decision processes that manage which
information is activated in the long-term memories and retained in the short-term memories ...
This kind of working memory system is necessary for a wide range of tasks, such as performing
mental arithmetic, reading, problem-solving and . . . reasoning in general. All of these tasks
require not only some form of temporary storage, but also interplay between information that
is stored temporarily and a larger body of stored knowledge674.

How, then, does working memory work in the brain? Studies conducted in the 1930s by C.F.
Jacobsen provide the foundation for our understanding of this problem675. He trained
monkeys using something called the delayed response task. The monkey sat in a chair and
watched the experimenter put a raisin under one of two objects that were side by side. A
curtain was then lowered for a certain amount of time (the delay) and then the monkey
was allowed to choose. In order to get the raisin, the monkey had to remember not which
object the raisin was under but whether the raisin was under the left or the right object.
Correct performance, in other words, required that the monkey holds in its mind the spatial
location of the raisin during the delay period (during which the playing field was hidden
from view). At very short delays (a few seconds), normal monkeys did quite well, and
performance got predictably worse as the delay increased (from seconds to minutes).
However, monkeys with damage to the prefrontal cortex performed poorly, even at the
short delays. On the basis of this and research that followed, the prefrontal cortex has
come to be thought of as playing a role in temporary memory processes, processes that we
now refer to as working memory.
Previously attention has been drawn to the role of the medial prefrontal cortex in the
extinction of emotional memory. In contrast, it is the lateral prefrontal cortex that has most
often been implicated in working memory. The lateral prefrontal cortex is believed to exist
only in primates and is considerably larger in humans than in other primates676. It is not
surprising that one of the most sophisticated cognitive functions of the brain should involve
this region.
In recent years, the role of the lateral prefrontal cortex in working memory has been studied
extensively by the laboratories of Joaquin Fuster at UCLA and Pat Goldman-Rakic at
Yale.677,678,679,680 Both researchers have recorded the electrical activity of lateral prefrontal

674

Kosslyn, SM., and Koenig, O. Wet mind: The new cognitive neuroscience; New York:
Macmillan; 1992.

675

Jacobsen, CE; & Nissen, HW. Studies of cerebral function in primates: IV. The effects of frontal
lobe lesions on the delayed alternation habit in monkeys. Journal of Comparative and
Physiological Psychology 23, 101-12; 1937.

676

Preuss, TM. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered.
Journal of Cognitive Neuroscience 7, 1-24; 1995.

677

Fuster, JM. The prefrontal cortex. New York: Raven; 1989).

678

Goldman-Rakic, PS. Circuitry of primate prefrontal cortex and regulation of behavior by

representational memory. In Handbook of physiology. Section 1: The nervous system. Vol. 5:
Higher Functions of the Brain, F. Plum, ed. (Bethesda, MD: American Physiological Society, pp.
373-417; 1987.

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neurons while monkeys performed delayed response tasks and other tests requiring shortterm storage. They have shown that cells in this region become particularly active during
the delay periods. It is likely that these cells are actively involved in holding on to the
information during the delay.

Prefrontal Cortex and Working Memory

There is now a critical mass of studies

that find lateral Prefrontal Cortex (PFC) activity in humans during delay tasks. (See Curtis &
DEsposito681) For example, in a functional magnetic resonance imaging (fMRI) study using
an oculomotor delay task identical to that used in monkey studies, it was observed that not
only the frontal cortex activity during the retention interval but also the magnitude of the
activity, correlated positively with the accuracy of the memory-guided saccade that
followed later.
This relationship suggests that the fidelity of the actively maintained location is reflected in
the delay-period activity682. Thus, the existence of persistent neural activity during blank
memory intervals of delay tasks is a powerful empirical finding, which lends strong support
for the hypothesis that such activity represents a neural mechanism for the active
maintenance or storage of task-relevant representations.
The necessity of the PFC for the active maintenance of task-relevant representations has
been demonstrated by studies that have found impaired performance on delay tasks in
monkeys with selective lesions of the lateral PFC 683,684 .
However, monkey physiology studies recording from other brain areas and human fMRI
studies of working memory have also found that the PFC is not the only region that is active
during the temporary retention of task-relevant information. For example different brain
regions are involved during the performance of the oculomotor delayed response task.
Specifically, different brain regions were active depending on whether the task required
the temporary maintenance of retrospective (e.g. past sensory events) or prospective (e.g.
representations of anticipated action and preparatory set) codes.
This study demonstrated not only that many different brain regions exhibit persistent neural
activity during active maintenance of task-relevant information, but also that a unique
network of brain regions are recruited depending on the type of information being actively
maintained. The fMRI data also support the notion that even within the domain of spatial
information, separable neural mechanisms are engaged for the active maintenance of
motor plans versus spatial codes. Moreover, given that the task only required the

679

Goldman-Rakic, PS. Working memory and the mind. In Mind and brain: Readings from
Scientific American magazine, W. H. Freeman, ed. (New York: Freeman), pp. 66-77; 1993.

680

Wilson, FAW; Scalaidhe, SP; & Goldman-Rakic, PS. Dissociation of object and spatial
processing domains in primate prefrontal cortex. Science 260, 1955-58; 1993.

681

Curtis, C. E. & D'Esposito, M. Persistent activity in the prefrontal cortex during working memory.
Trends. Cogn. Sci. 7,415423; 2003.

682

Curtis, C. E., Rao, V. Y. & D'Esposito, M. Maintenance of spatial and motor codes during
oculomotor delayed response tasks. J. Neurosci. 24, 3944-3952; 2004.

683

Bauer, R. H. & Fuster, J. M. Delayed-matching and delayed-response deficit from cooling

dorsolateral prefrontal cortex in monkeys. Q. J. Exp. Psychol. B 90, 293-302; 1976.

684

Funahashi, S., Bruce, C. J. & Goldman-Rakic, P. S. Dorsolateral prefrontal lesions and

oculomotor delayed-response performance: evidence for mnemonic "scotomas". J. Neurosci.
13, 1479-1497; 1993.

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oculomotor system, it is probable that distinct neural circuitry will be recruited when the
motor act involves other modalities, such as speech or limb output685 .
Thus, this is the first piece of evidence that the concept of specialized buffers (for, say,
verbal versus spatial information) may not map adequately onto neural architecture.
Rather, the findings appear more consistent with a system in which active maintenance
involves the recruitment of the same circuitry that represents the information itself, with
different circuits for different types of spatial information (e.g. visual versus oculomotor).
Similar findings exist when the visual component of working memory is investigated with
neuro-scientific methods. For example, in another fMRI study686 , the participants were
asked to learn a series of faces, houses and face-house associations and they were
scanned while performing a delayed match-to-sample (DMS) and delayed paired associate (DPA) task with these stimuli.
Results showed that delay-period activity within category-selective inferior temporal subregions reflected the type of information that was being actively maintained the fusiform
gyrus showed enhanced activity when participants maintained previously shown faces on
DMS trials, and when subjects recalled faces in response to a house cue on DPA trials.
Likewise, the para-hippocampal gyrus showed enhanced activity when participants
maintained previously shown houses on DMS trials and when they recalled houses in
response to a face cue on DPA trials.
These fMRI findings are consistent with several monkey neuro-physiological studies which
have also shown that temporal lobe neurons exhibit persistent stimulus-selective activity in
tasks requiring the active maintenance of visual object information across short delays
687,688,689. Again, like spatial and motor codes, active maintenance of visual stimuli is
mediated by the activation of cortical regions that also support processing of that
information, perceptual in this case.
Neuro-scientific studies of verbal working memory, which has been most extensively studied
by behavioural methods; (Vallar & Shallice, provide a similar view regarding the neural
mechanisms underlying working memory690 ). Consistently, performance on tasks that tap
the phonological loop, as conceptualized by Baddeley, engage a set of brain regions
that are thought to be involved in phonological processing. For example, using functional
neuro-imaging techniques during verbal working memory tasks, the left inferior parietal

685

Hickok, G., Buchsbaum, B., Humphries, C. & Muftuler, T. Auditory-motor interaction revealed
by fMRI: speech, music, and working memory in area Spt. J. Cogn. Neurosci. 15, 673-682;
2003.

686

Ranganath, C., Cohen, M. X., Dam, C. & D'Esposito, M. Inferior temporal, prefrontal, and
hippocampal contributions to visual working memory maintenance and associative memory
retrieval. J. Neurosci. 24, 3917-3925; 2004.

687

Miyashita, Y. & Chang, H. S. Neuronal correlate of pictorial short-term memory in the primate
temporal cortex. Nature 331,68-70; 1988.

688

Miller, E. K., Li, L. & Desimone, R. Activity of neurons in anterior inferior temporal cortex during a
short-term memory task. J. Neurosci. 13, 1460-1478; 1993.

689

Nakamura, K. & Kubota, K. Mnemonic firing of neurons in the monkey temporal pole during a
visual recognition memory task. J. Neurophysiol. 74, 162-178; 1995.

690

Vallar, G. & Shallice, T. Neuropsychological impairments of short-term memory. Cambridge,

UK: Cambridge University Press; 1990.

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lobe, posterior inferior frontal gyrus (Brocas area), premotor cortex and the cerebellum are
typically activated691,692 .
However, is this network of brain regions also responsible for the active maintenance of
non-phonological language representations (e.g. lexical-semantic)? For visual word
recognition, a functionally specialized processing stream is thought to exist within inferior
temporal cortex, representing visual words at increasingly higher levels of abstraction along
a posterior-to-anterior axis. 693
Intracranial electrophysiological recordings, for example, (Nobre et al 694 ) show that
posterior inferior temporal cortex differentiates letter strings from non-linguistic complex
visual objects. Brain activity in more anterior inferior temporal cortical regions, in contrast,
distinguishes words from non-words and is affected by the semantic context of words,
indicating that anterior inferior temporal cortex holds more elaborate linguistic
representations (see also Marslen-Wilson & Tyler 695 and Patterson 696).
To demonstrate that there is distinct neural circuitry supporting the active maintenance of
non-phonological language representations, DEsposito 697 explored the role of language
regions within the left infero-tempora1 cortex (ITC) that are involved in visual word
recognition and word-related semantics. Using fMRI, he first localized a visual word form
area within inferior temporal cortex area and then demonstrated that this area was
involved in the active maintenance of visually presented words during a delay task. 698
Specifically, he found that this area was recruited more for the active maintenance of
words than pseudo-words (i.e. orthographically legal and pronounceable non-words).
Maintenance of pseudo-words should not elicit strong sustained activation in such brain
regions, as no stored representations pre-exist for these items. These results suggest that
verbal working memory may be conceptualized as involving sustained activation of all
relevant pre-existing cortical language (phonological, lexical or semantic) representations.
If working memory maintenance processes reflect the prolonged activation of the same
brain regions that support online processing, evidence for cortical activity in the absence of
stimuli should be evident not only in association cortex but also within primary cortical

691

Paulesu, E., Frith, C. D. & Frackowiak, R. S. The neural correlates of the verbal component of
working memory. Nature 362,342-345; 1993

692

Awh, E., Jonides, J., Smith, E. E., Schumacher, E. H., Koeppe, R. A. & Katz, S. Dissociation of
storage and rehearsal in verbal working memory: evidence from PET. Psycho I. Sci. 7, 25-3;
1996.

693

Cohen, L. & Dehaene, S. Specialization within the ventral stream: the case for the visual word
form area. Neuroimage 22,466476; 2004.

694

Nobre, A. C., Allison, T. & McCarthy, G. Word recognition in the human inferior temporal lobe.
Nature 372, 260-263; 1994.

695

Marslen- Wilson, W D. & Tyler, L. K. Morphology, language and the brain: the decompositional
substrate for language comprehension. Phil. Trans. R. Soc. B 362, 823-836; 2007.

696

Patterson, K. The reign of typicality in semantic memory. Phil. Trans. R. Soc. B 362, 813-821;
2007.

697

D'Esposito, M. From cognitive to neural models of working memory. Phil. Trans. R. Soc. B. 29
May 2007; vol. 362 no. 1481 761-772

698

Fiebach, C. J., Rissman, J. & D'Esposito, M. Modulation of infero-temporal cortex activation

during verbal working memory maintenance. Neuron 51, 251-261; 2006.

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regions. This indeed is the case as such effects have been observed in primary olfactory 699,
visual 700,701 and auditory cortex.702,703 Thus, the neuro-scientific data presented here is
consistent with most, if not all, neural populations being able to retain information that can
be accessed and kept active over several seconds, via persistent neural activity in the
service of goal-directed behaviour.
Baddeleys original advance (Idem, 1986) was to move us from the concept of short-term
memory that accounted only for the storage of representations, to the concept of working
memory as a multi-component system that allows for both storage and processing of
temporarily active representations. Likewise, Logie704 considered working memory as a
mental workspace that cannot only hold but is also able to manipulate activated
representations.
If working memory is defined as simultaneous storage and processing, then these tasks
would probably be considered to assess short-term memory rather than working memory.
Thus, it is probably fair to say that the concept of working memory as a non-unitary system
that allows for both storage and processing has gained popular acceptance. However,
less progress has been made regarding the neural mechanisms underlying the processing
component of working memory as compared with the storage component705 (although
see Petrides706).
DEsposito also proposes (Idem) that any population of neurons within primary or unimodal
association cortex can exhibit persistent neuronal activity, which serves to actively maintain
the representations coded by those neuronal populations. Areas of multimodal cortex,
such as PFC and parietal cortex, which are in a position to integrate representations
through connectivity to unimodal association cortex, are also critically involved in the

699

Zelano, c., Bensafi, M., Porter, J., Mainland, J., Johnson, B., Bremner, E., Telles, C., Khan, R. &
Sobel, N. Attentional modulation in human primary olfactory cortex. Nat. Neurosci. 8, 114-120;
2005.

700

Klein, I., Paradis, A. L., Poline, J. B., Kosslyn, S. M. & Le Bihan, D. Transient activity in the human
calcarine cortex during visual-mental imagery: an event-related fMRI study. J. Cogn.
Neurosci. 12(Suppl. 2), 15-23; 2000.

701

Singer, W. & Gray, C. M. Visual feature integration and the temporal correlation hypothesis.
Annu. Rev. Neurosci. 18,555-586; 1995.

702

Calvert, G. A., Bullmore, E. T., Brammer, M. J., Campbell, R., Williams, S. C., McGuire, :P. K.,
Woodruff, P. W, Iversen, S. D. & David, A. S. Activation of auditory cortex during silent
lipreading. Science 276, 593-596; 1997.

703

Kraemer, D. J., Macrae, C. N., Green, A. E. & Kelley, W M. Musical imagery: sound of silence
activates auditory cortex. Nature 434,158.; 2005.

704

Logie, R. H. Visuo-spatial working memory. Hove, UK: Erlbaum; 1995.

705

DEsposito, M. From Cognitive to neural models of working memory. In Driver, J; Haggard, P; &
Shallice, T. Mental Processes in the Human Brain. OUP, New York; 2007

706

Petrides, M. Frontal lobes and working memory: evidence from investigations of the effects of
cortical excisions in nonhuman primates. In Handbook of neuropsychology, vol. 9 (eds F.
Boller & J. Grafman), pp. 59-84. Amsterdam, The Netherlands: Elsevier Science B.Y; 1994.

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active maintenance of task-relevant information (see also Burgess et al 707 ; Stuss &
Alexander708.
Miller & Cohen 709 have proposed that in addition to the recent sensory information,
integrated representations of task contingencies and even abstract rules (e.g. if this object
then this later response) are also maintained in the PFC. This is similar to what Fuster710 has
long emphasized, namely that the PFC is critically responsible for temporal integration and
the mediation of events that are separated in time but contingent on one another. In this
way, the PFC may exert control in that the information it represents can bias the posterior
unimodal association cortex in order to keep neural representations of behaviourally
relevant sensory information activated when they are no longer present in the external
environment711,712,713,714.
In a real world example, when a person is looking at a crowd of people, the visual scene
presented to the retina may include a myriad of angles, shapes, people and objects.
However, if that person is a police officer looking for an armed robber escaping through the
crowd, some mechanism of suppressing irrelevant visual information while enhancing taskrelevant information is necessary for an efficient and effective search. Thus, neural activity
throughout the brain that is generated by input from the outside world may be differentially
enhanced or suppressed, presumably from top-down signals emanating from integrative
brain regions such as PFC, based on the context of the situation. Thus, in this formulation,
the processing component of working memory is that the control of actively maintained
representations within primary and unimodal association cortex stems from the
representational power of multimodal association cortex, such as the PFC, parietal cortex
and/or hippocampus.
If the PFC, for example, stores the rules and goals, then the activation of such PFC
representations will be necessary when behaviour must be guided by internal states or
intentions. As Miller & Cohen715 elegantly state, putative top-down signals originating in
PFC may permit the active maintenance of patterns of activity that represent goals and
the means to achieve them. They provide bias signals throughout much of the rest of the
brain, affecting visual processes and other sensory modalities, as well as systems responsible

707

Burgess, P. W, Gilbert, S. J. & Dumontheil, I. Function and localization within rostral prefrontal
cortex (area 10). Phil. Trans. R. Soc. B 362,887-899; 2007.

708

Stuss, D. T. & Alexander, M. P. Is there a dysexecutive syndrome? Phil. Trans. R. Soc. B 362, 901915; 2007.

709

Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev.
Neurosci. 4, 167-202; 2001.

710

Fuster, J. The prefrontal cortex: anatomy, physiology, and neuropsychology of the frontal
lobes. New York, NY: Raven Press; 1997.

711

Fuster, J. M. Cortical dynamics of memory. Int. J. Psychophysiol. 35, 155-164; 2000.

712

Ranganath, C., Cohen, M. X., Dam, C. & D'Esposito, M. Inferior temporal, prefrontal, and
hippocampal contributions to visual working memory maintenance and associative memory
retrieval. J. Neurosci. 24, 3917-3925; 2004.

713

Miller, B. T. & D'Esposito, M. Searching for "the top" in top-down control. Neuron 48, 535-538;
2005

714

Postle, B. R. Delay-period activity in the prefrontal cortex: one function is sensory gating. J.
Cogn. Neurosci. 17, 1679-1690; 2005.

715

Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev.
Neurosci. 4, 167-202; 2001.

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for response execution, memory retrieval, emotional evaluation, etc. The aggregate effect
of these bias signals is to guide the flow of neural activity along pathways that establish the
proper mappings between inputs, internal states and outputs needed to perform a given
task.
Computational models of this type of system have created a PFC module (e.g. OReilly et
al716.) that consists of rule units whose activation leads to the production of a response
other than the one most strongly associated with a given input. Thus, this module is not
responsible for carrying out input-output mappings needed for performance. Rather, this
module influences the activity of other units whose responsibility is making the needed
mappings (e.g. Cohen et al717 ). Thus, there is no need to propose the existence of a
homunculus (e.g. central executive) in the brain that can perform a wide range of
cognitive operations which are necessary for the task at hand.
DEsposito has used a delay task to directly study the neural mechanisms underlying topdown modulation by investigating the processes involved when participants were required
to enhance relevant and suppress irrelevant information718 . During each trial, participants
observed sequences of two faces and two natural scenes presented in a randomized
order.
The tasks differed in the instructions informing the participants how to process the stimuli:
(i)

remember faces and ignore scenes,

(ii)

remember scenes and ignore faces, or

(iii)

passively view faces and scenes without attempting to remember them.

In each task, the period in which the cue stimuli were presented was balanced for bottomup visual information, thus allowing us to probe the influence of goal-directed behaviour on
neural activity (top-down modulation). In the two memory tasks, the encoding of the taskrelevant stimuli requires selective attention and thus permits the dissociation of physiological
measures of enhancement and suppression relative to the passive baseline.
There appears to be at least two types of top-down signal, one that serves to enhance
task-relevant information and another that serves to suppress task-relevant information. It is
well documented that the nervous system uses interleaved inhibitory and excitatory
mechanisms throughout the neuro-axis (e.g. spinal reflexes, cerebellar outputs and basal
ganglia movement control networks). Thus, it may not be surprising that enhancement and
suppression mechanisms may exist to control cognition.719,720 By generating contrast via

716

O'Reilly, R. C., Noelle, D. C., Braver, T. S. & Cohen, J. D. Prefrontal cortex and dynamic
categorization tasks: representational organization and neuro-modulatory control. Cereb.
Cortex 12, 246-257; 2002.

717

Cohen, J. D., Dunbar, K. & McClelland, J. L. On the control of automatic processes: a parallel
distributed processing account of the Stroop effect. Psychol. Rev. 97, 332-36; 1990.

718

Gazzaley, A., Cooney, J. W., McEvoy, K., Knight, R. T. & D'Esposito, M. Top-down
enhancement and suppression of the magnitude and speed of neural activity. J. Cogn.
Neurosci. 17, 1-11. 2005.

719

Knight, R. T., Staines, W R., Swick, D. & Chao, L. L. Prefrontal cortex regulates inhibition and
excitation in distributed neural networks. Acta. Psychol. (Amst) 101, 159-178; 1999.

720

Shimamura, A. P. The role of the prefrontal cortex in dynamic filtering. Psychobiology 28, 207218; 2000.

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both enhancements and suppressions of activity magnitude and processing speed, topdown signals bias the likelihood of successful representation of relevant information in a
competitive system.
Though it has been proposed that the PFC provides a major source of the types of topdown signals that DEsposito has described, this hypothesis largely originates from
suggestive findings rather than direct empirical evidence. However, a few studies lend
direct causal support to this hypothesis (see also Vuilleumier & Driver721 ).
Clearly, there are other areas of multimodal cortex such as posterior parietal cortex, and
the hippocampus, that can also be the source of top-down signals. For example, the
hippocampus has been proposed to be specialized for rapid learning of arbitrary
information which can be recalled in the service of controlled processing. Moreover, input
from brainstem neuro-modulatory systems probably plays a critical role in modulating goaldirected behaviour. For example, the dopaminergic system probably plays a critical role in
cognitive control processes. (DEsposito, idem 2007 & Stuss DT, idem 2007)
The contribution of the lateral prefrontal cortex to working memory is still being explored.
However, considerable evidence suggests that the lateral prefrontal cortex is involved in
the executive or general purpose aspects of working memory. For example, damage to
this region in humans interferes with working memory regardless of the kind of stimulus information involved. (Fuster, 1989, Idem) &722.
Further, brain imaging studies in humans have shown that a variety of different kinds of
working memory tasks result in the activation of the lateral prefrontal cortex.723,724,725,726 In
one recent study, for example, subjects were required to perform a verbal and a visual task
either one at a time or at the same time727. The results showed that the lateral prefrontal
cortex was activated when the two tasks were performed together, thus taxing the
executive functions of working memory, but not when the tasks were performed separately.
The lateral prefrontal cortex is ideally suited to perform these general purpose working
memory functions. It has connections with the various sensory systems (like the visual and
auditory systems) and other neocortical systems that perform specialized temporary
storage functions (like spatial and verbal storage) and is also connected with the
hippocampus and other cortical areas involved in long-term memory (Fuster, idem, 1989;

721

Vuilleumier, P. & Driver, J. Modulation of visual processing by attention and emotion: windows
on causal interactions between human brain regions. Phil. Trans. R. Soc. B 362, 837-855; 2007.

722

Petrides, M. Frontal lobes and behaviour. Current Opinion in Neurobiology 4, 207-11; 1994.

723

Petrides, M; Alivsatos, B; Meyer, E; & Evans, AC. Functional activation of the human frontal
cortex during the performance of verbal working memory tasks. Proceedings of the National
Academy of Sciences USA 90, 878-82; 1993.

724

Jonides, J; Smith, EE; Keoppe, RA; Awh, E; Minosbima, S; & Mintun, M.A. Spatial working
memory humans as revealed by PET. Nature 363, 623-25; 1993.

725

Grasby, PM; Firth, CD; Friston, KJ; Bench, C; Frackowiak, RSJ; & Dolan, RJ. Functional mapping
of brain areas implicated in auditory-verbal memory function. Brain 116, 1-20; 1993.

726

Swartz, BE; Halgren, E; Fuster, JM; Simpkins, E; Gee, M; & Mandelkern, M. Cortical metabolic
activation in humans during a visual memory task. Cerebral Cortex 5,205-14; 1995.

727

D'Esposito, M; Detre, J; Alsop, D; Shin, R; Atlas, S; & Grossman, M. The neural basis of the
central executive system of working memory. Nature 378,279-81; 1995.

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Goldman-Rakic, 1987, idem)&728,729. In addition, it has connections with areas of the cortex
involved in movement control, allowing decisions made by the executive to be turned into
voluntarily performed actions (Fuster, idem, 1989; Goldman-Rakic, 1978, idem). Recent
studies have begun to show how the lateral prefrontal cortex interacts with some of these
areas. However, the best understood are the interactions with temporary storage buffers in
the visual cortex.
Cortical visual processing begins in the primary visual area located in the occipital lobe (the
rear-most part of the cortex). This area receives visual information from the visual thalamus,
processes it, and then distributes its outputs to a variety of other cortical regions. Although
the cortical visual system is enormously complex730, the neural pathways responsible for two
aspects of visual processing are fairly well understood. These involve the determination of
what a stimulus is and where it is located.731,732 The what pathway involves a
processing stream that travels from the primary visual cortex to the temporal lobe and the
where pathway goes from the primary cortex to the parietal lobe.
Goldman-Rakic and colleagues recorded from cells in the parietal lobe where pathway
during short-term memory tests requiring the temporary remembering of the spatial location
of visual stimuli. They found that cells there, like cells in the lateral prefrontal cortex, were
active, suggesting that they were keeping track of the location, during the delay.
(Goldman-Rakic, 1987, idem)
The parietal and frontal regions in question are anatomically interconnected the parietal
area sends axons to the prefrontal region and the prefrontal region sends axons back to
the parietal area. These findings suggest that the parietal lobe visual area works with the
lateral prefrontal cortex to maintain information about the spatial location of visual stimuli in
working memory. Similarly, Robert Desimone found evidence for reciprocal interactions between the visual areas of the temporal lobe (the what pathway) and the lateral prefrontal
cortex in studies involving the recognition of whether a particular object had been seen
recently733. The maintenance of visual information in working memory thus appears to
crucially depend on interactions between the lateral prefrontal region and specialized
areas of the visual cortex.
LeDoux suggests that this involvement of specialized short-term buffers in the sensory
systems and a general-purpose working memory mechanism in the prefrontal cortex is a
very complicated system. The prefrontal cortex itself seems to have regions that are
specialized, at least to some degree, for specific kinds of working memory functions. Such
findings, however, do not discredit the notion that the prefrontal cortex is involved in the

728

Reep, R. Relationship between prefrontal and limbic cortex: A comparative anatomical

review. Brain, Behavior and Evolution 25, 5-80; 1984.

729

Uylings, HBM; & van Eden, CG. Qualitative and quantitative comparison of the prefrontal
cortex in rat and in primates, including humans. Progress in Brain Research 85, 31-62; 1990.

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Van Essen, DC. Functional organization of primate visual cortex. In Cerebral cortex, A. Peters
and E. G. Jones, eds. (New York: Plenum), pp.259-328; 1985.

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Ungerleider, LG; & Mishkin, M. Two cortical visual systems. In Analysis of visual behavior, D. J.
Ingle, M. A. Goodale, and R. W. Mansfield, eds. Cambridge: MIT Press, pp. 549-86; 1982.

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Ungerleider, LG; & Haxby, J. What and where in the human brain. Current Opinion in
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general-purpose or executive aspects of working memory since only some cells in these
areas play specialized roles. Interactions between the general-purpose cells in different
areas may coordinate the overall activity of working memory. It is thus possible that the
executive functions of the prefrontal cortex might be mediated by cells that are distributed
across the different prefrontal subsystems rather than by cells that are collected together in
one region. (LeDoux, 1998, idem)
The pathway from the specialized visual areas tells the prefrontal cortex what is out there
and where it is located (bottom-up processing). The prefrontal cortex, by way of
pathways back to the visual areas, primes the visual system to attend to those objects and
spatial locations that are being processed in working memory (top-down processing).
These kinds of top-down influences on sensory processing are believed to be important
aspects of the executive control functions of working memory.
Recent studies, especially by Goldman-Rakic and associates, have raised questions about
the role of the prefrontal cortex as a general purpose working memory processor. (Wilson
et al, 1993; Idem) For example, they have found that different parts of the lateral prefrontal
cortex participate in working memory when animals have to determine what a visual
stimulus is as opposed to where it is located, suggesting that different parts of the
prefrontal cortex are specialized for different kinds of working memory tasks. While these
findings show that parts of the prefrontal cortex participate uniquely in different short-term
memory tasks, they do not rule out the existence of a general-purpose workspace and a
set of executive functions that coordinate the activity of the specialized systems, especially
since the tasks studied did not tax the capacity of working memory in a way that would
reveal a limited capacity system.
Studies that have taxed the system, like imaging studies in humans, suggest that neurons in
the lateral prefrontal cortex are part of a general-purpose working memory network. At the
same time, it is possible, given Goldman-Rakic's findings that the general-purpose aspects
of working memory are not localized to a single place in the lateral prefrontal cortex but
instead are distributed over the region. That this may occur is suggested by the fact that
some cells in the specialized areas of the lateral pre-frontal cortex participate in multiple
working memory tasks. (Petrides, 1994, Idem)
There is also evidence that the general purpose functions of working memory involve areas
other than the lateral prefrontal cortex. For example, imaging studies in humans have
shown that another area of the frontal lobe, the anterior cingulate cortex, is also activated
by working memory and related cognitive tasks. (DEsposito, et al, 1995, Idem) &734,735

734

Corbetta, M; Miezin, FM; Dobmeyer, S; Shulman, GL; & Petersen, SE. Selective and divided
attention during visual discriminations of shape, color, and speed: Functional anatomy by
positron emission tomography. Journal of Neuroscience 11, 2383-2402; 1991.

735

Posner, M; & Petersen, S. The attention system of the human brain. Annual Review of
Neuroscience 13, 25-42; 1990.

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Relation of the "What" and "Where" Visual Pathways to Working Memory.

Visual information, received by the visual cortex, is distributed to cortical areas
that perform specialized visual processing functions. Two well-studied specialized functions are those involved in object recognition (mediated by the
what pathway) and object location (mediated by the where pathway). These
specialized visual pathways provide inputs to the prefrontal cortex (PFC), which
plays a crucial role in working memory. The specialized systems also receive
inputs back from the PFC, allowing the information content of working memory
to influence further processing of incoming information. Leftward-going arrows
represent bottom-up processing and rightward-going ones top-down
processing.

Like the lateral pre-frontal cortex, the anterior cingulate region receives inputs from the
various specialized sensory buffers, and the anterior cingulate and the lateral pre-frontal
cortex are anatomically interconnected. (Fuster, 1989, Idem) &736. Moreover, both regions
are part of what has been called the frontal lobe attentional network, a cognitive system
involved in selective attention, mental resource allocation, decision making processes, and
voluntary movement control737. It is tempting to think of the general purpose aspects of
working memory as involving neurons in the lateral prefrontal and anterior cingulate regions
working together.
One other area of the prefrontal cortex, the orbital region, located on the underneath side
of the frontal lobe, has emerged as important as well. Damage to this region in animals
interferes with short-term memory about reward information, about what is good and bad at
the moment 738, and cells in this region are sensitive to whether a stimulus has just led to a

736

Goldman-Rakic, PS. Topography of cognition: Parallel distributed networks in primate

association cortex. Annual Review of Neuroscience 11, 137-56; 1988.

737

Posner, M. Attention as a cognitive and neural system. Current Directions in Psychological

Science 1, 11-14; 1992.

738

Gaffan, D; Murray, EA; & Fabre-Thorpe, M. Interaction of the amygdala with the frontal lobe
in reward memory. European Journal of Neuroscience 5, 968-75; 1993.

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reward or punishment 739,740,741. Humans with orbital frontal damage become oblivious to
social and emotional cues and some exhibit sociopathic behaviour. 742 This area receives
inputs from sensory processing systems (including their temporary buffers) and is also
intimately connected with the amygdala and the anterior cingulate region. The orbital
cortex provides a link through which emotional processing by the amygdala might be
related in working memory to information being processed in sensory or other regions of the
neocortex.
There is still much to be learned about working memory and its neural basis. It is not clear,
for example, whether both the temporary workspace and the executive functions are
actually located in the frontal cortex. It is possible that the prefrontal areas do not store
anything but instead just control the activity of other regions, allowing the activity in some
areas to rise above the threshold for consciousness and inhibiting the activity of the others.
In spite of the fact that we still have much to learn, the researchers in this area have made
considerable progress on this very tough, and very important, problem. (LeDoux, Idem,
1998
This very complicated span of neural activity is carried out in our brains without us having to
think about it consciously. However, with subjects like MDL, who have damage to some of
the areas involved, it can be seen why there is a failure of certain cognitive and social skills
and it is important to portray these difficulties as being influenced by her brain damage and
not by lack of intellect.
From the extensive research noted above there can be no doubt that MDLs behavioural
symptoms stem to a great extent from damage to the frontal lobes. It can also be
understood just how difficult it is to predict how MDLs brain damage affects the processing
of information and to what extent the deficiencies of her working memory adds to these
problems. Consider as individuals there is not a conscious understanding from moment
to moment of how our brains are dealing with the constant flow of information. We only
know such things as a lack of comprehension and a failure of memory; these events occur
in what we consider to be a brain that is working normally. If our brains do not work as well
today as they did say a year ago, then we have the ability to compare the two phases of
our life. MDL has to cope with a disabled brain without any knowledge of what the situation
would be if it hadnt been damaged. Even if changes have taken place in her brain since
the original injury, she does not have the ability to know why or even to question why.

_______

739

Thorpe, SJ; Rolls, ET; & Maddison, S. The orbitofrontal cortex: Neuronal activity in the behaving
monkey. Experimental Brain Research 49, 93-115; 1983.

740

Rolls, ET. Neurophysiology and functions of the primate amygdala. In The amygdala:
Neurobiological aspects of emotion, memory, and mental dysfunction, J. P. Aggleton, ed.
(New York: Wiley-Liss), pp. 143-65; 1992.

741

Ono, T & Nishijo, H. Neurophysiological basis of the KliiverBucy syndrome: Responses of

monkey amygdaloid neurons to biologically significant objects. In The amygdala:
Neurobiological aspects of emotion, memo,); and mental dysfunction, J. P. Aggleton, ed.
(New York: Wiley-Liss), pp. 167-90; 1992.

742

Damasio, A. Descartes error: Emotion, reason, and the human brain. New York:
Grosset/Putnam; 1994.

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PERVASIVE DEVELOPMENT DISORDERS

The category of pervasive developmental disorder (PDD) was introduced to classification
systems in 1980 when it became clear that autism was not a psychotic disorder and could
no longer be classified with the childhood psychoses. The term was coined to reflect the
full range of IQs in autism, the selective nature of the deficits, and the severity of their
impact on adaptive function. The PDD diagnostic category is stipulated for disorders characterized by specific qualitative impairments in social interactions, verbal and nonverbal
language and their use for communication, symbolic and imaginative play, and abstract
reasoning and related complex behaviour. Impairments are selective i.e.,
disproportionate to age and IQ expectations and also have distinctive qualitative
characteristics. (Minshew, 1997, Idem)
It has been said that people with autism suffer from a lack of central coherence, the
cognitive ability to bind together a jumble of separate features into a single, coherent
object or concept743. Ironically, the same can be said of the field of autism research, which
all too often seems a fragmented tapestry stitched from differing analytical threads and
theoretical patterns. Defined and diagnosed by purely behavioural criteria, autism was first
described and investigated using the tools of behavioural psychology. More recent years
have added brain anatomy and physiology, genetics, and biochemistry, but results from
these new domains have not been fully integrated with what is known about autistic
behaviour. The unification of these many levels of analysis will not only provide therapeutic
targets for prevention and remediation of autism but can also provide a test case for
theories of normal brain and cognitive development. Autism research therefore has much
to learn from and much to offer to the broader neuroscience community. 744
There has been little clinical consideration given to the possibility of early brain damage
being a possible cause of autism spectrum disorder. 745
A variety of other more subtle or nonspecific abnormalities-ranging from delayed motor
development and hyperactivity to relative insensitivity to pain, sound sensitivity, and exaggerated fears-are often also present but are 'considered minor or peripheral features. From
the beginning it was clear that there were disorders other than autism in this category, but
the capacity for differentiating and defining them was essentially non-existent. The
classification and criteria for these disorders remain in evolution. (Minshew, 1997, Idem)
Clinically, autism is defined by a triad of deficits comprising impaired social interaction,
impaired communication, restricted interests, and repetitive behaviours. Although in some
cases speech never develops fully or never develops at all; in other cases, speech may be
present but so inflexible and unresponsive to context that it is unusable in normally paced
conversation. Often, speech is limited to echolalia or confined to narrow topics of expertise
in which discourse can proceed without conversational interplay. The communicative
impairment extends also to nonverbal signals such as gaze, facial expression, and gesture.
Elison et al have found that Infants at seven months of age who go on to develop autism
are slower to reorient their gaze and attention from one object to another when

743

Frith U. Autism: explaining the enigma. Oxford: Blackwell; 1989.

744

Belmonte, MK; Allen, G; Beckel-Mitchener, A; Boulanger, LM; Carper, RA; & Webb, SJ. Autism
and Abnormal Development of Brain Connectivity. Journal of Neuroscience, October 20,
2004 24(42):9228 9231

745

Challoner, A. Abnormal Brain Structure and Autism.

http://www.scribd.com/doc/9635846/Abnormal-Brain-Structure-and-Autism-

167 | P a g e

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compared to seven-month-olds who do not develop autism, and this behavioral pattern
is in part explained by atypical brain circuits. The study concluded that atypical visual
orienting is an early feature of later emerging autistic spectrum disorder and is associated
with a deficit in a specific neural circuit in the brain. These findings suggest that sevenmonth-olds who go on to develop autism show subtle, yet overt, behavioral differences
prior to the emergence of the disorder. They also implicate a specific neural circuit, the
splenium of the corpus callosum, which may not be functioning as it does in typically
developing infants who show more rapid orienting to visual stimuli. 746
There also may be a connection between this disturbance noted in the splenium in autistic
spectrum disorder and what may be earlier brain damage. Damage that accounts for
permanent cognitive impairment in patients with mild traumatic brain injury (mTBI) can be
shown by diffusion tensor imaging to involve diffuse axonal injury. It has also been
suggested that the thalamus may play an important role in the development of clinical
sequelae in mTBI. By variously altered diffusion tensor imaging- and diffusional kurtosis
imaging-derived measures, this is shown in the thalamus and the internal capsule. In
addition to these regions, patients examined more than 1 year after injury also show similar
differences in the splenium of the corpus callosum and the centrum semiovale. Cognitive
impairment was correlated in this research with mean kurtosis in the thalamus and the
internal capsule. These findings suggest that combined use of diffusion tensor imaging and
diffusional kurtosis imaging provides a more sensitive tool for identifying brain injury. In
addition the authors suggest that mean kurtosis in the thalamus might be useful for early
prediction of permanent brain damage and cognitive outcome. 747
Social behaviours, too, are beset by a lack of flexibility and rapid coordination. Children
with autism do not coordinate attention between objects of mutual interest and the other
people, who may be interested in them, often engage in parallel play at the edge of a
group rather than joining in cooperative play, and do not engage in pretend play. Intense
and narrowly focused interests tend to concentrate on systems748 that operate
deterministically and repeatably according to tractable sets of rules, whether these are
abstract and complex systems such as computers or role-playing games or very concrete
and simple systems such as toilets or washing machines.
Critical to identifying the causal factors of autism, and key to its relevance to normal
development, is the recognition that autism is actually the extreme of a spectrum of
abnormalities. Milder phenotypes on this spectrum include Asperger syndrome749 in which
language is relatively unimpaired, and the Broader Autism Phenotype in which
characteristic cognitive traits are present sub-clinically750. The combination of this broad

746

Elison, JT; Piven, J & Schultz, RT. Atypical brain circuits may cause slower gaze shifting in
infants who later develop autism. American Journal of Psychiatry (3/20/2013).

747

Grossman, EJ; Ge, Y; Jensen, JH; Babb, JS; Miles, L; Reaume, J; Silver, JM; Grossman, RI &
Inglese, M. Thalamus and Cognitive Impairment in Mild Traumatic Brain Injury: A Diffusional
Kurtosis Imaging Study. J Neurotrauma. 2012 Sep; 29(13):2318-27. doi: 10.1089/neu.2011.1763.

748

Baron-Cohen, S. The extreme male brain theory of autism. Trends Cogn Sci 6:248 254; 2002.

749

Wing, L. Aspergers syndrome: a clinical account. Psychol Med 11:115129; 1981.

750

Dawson, G.; Webb, S.; Schellenberg, GD; Dager, S; Friedman, S; Aylward, E & Richards, T.
Defining the broader phenotype of autism: genetic, brain, and behavioural perspectives.
Dev Psychopathol 14:581 611; 2002.

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variation of phenotypes and a 6090% concordance rate in identical twins751 suggests a
large number of genetic and environmental biasing factors752.
In addition to the central coherence paradigm, autism has been variously characterized as
a deficit of executive function 753, complex information processing 754, theory of mind 755,
and empathy.756
Each of these theories is a valid description of many aspects of the autistic syndrome but
each, in answering unsolved questions at one level of explanation, introduces them at
another. Recent attempts at a theoretical synthesis have focused on abnormal neural
connectivity, and, superficially, there seems some disagreement as to whether this
abnormality involves a surfeit757,758 or a deficit759,760 of connectivity. The picture is
complicated by the fact that the term connectivity admits more than a single meaning.
Conceptually, we can differentiate local connectivity within neural assemblies from longrange connectivity between functional brain regions. On another axis, we can also
separate the physical connectivity associated with synapses and tracts from the
computational connectivity associated with information transfer. Physically, in the autistic
brain, high local connectivity may develop in tandem with low long-range connectivity
(Just et al., Idem, 2004), perhaps as a consequence of widespread alterations in synapse
elimination and/or formation761.
Furthermore, indiscriminately high physical connectivity and low computational
connectivity may reinforce each other by failing to differentiate signal from noise,
(Rubenstein and Merzenich, Idem 2003); Belmonte et al., Idem 2004) (See Figure below).

751

Bailey, A; Le Couteur, A; Gottesman, I; Bolton, P; Simonoff, E; Yuzda, E & Rutter, M. Autism as a

strongly genetic disorder: evidence from a British twin study. Psychol Med 25:6377; 1995

752

Muhle, R; Trentacoste, SV & Rapin I. The genetics of autism. Pediatrics 113:e472 e486; 2004.

753

Ozonoff, S; Pennington, B & Rogers, SJ. Executive function deficits in high-functioning autistic
individuals: relationship to theory of mind. J Child Psychol Psychiatry; 32:10811105; 1991.

754

Minshew, NJ; Goldstein, G & Siegel DJ. Neuropsychologic functioning in autism: profile of a
complex information processing disorder. J Int Neuropsychol Soc 3:303316; 1997.

755

Baron-Cohen S; Leslie AM. & Frith U. Does the autistic child have a theory of mind?
Cognition 21:37 46; 1985.

756

Baron-Cohen, S. The extreme male brain theory of autism. Trends Cogn Sci 6:248 254; 2002.

757

Rubenstein, JL & Merzenich, MM. Model of autism: increased ratio of excitation/inhibition in

key neural systems. Genes Brain Behav 2:255267; 2003.

758

Belmonte, MK & Baron-Cohen, S. Normal sibs of children with autism share negative frontal
but not positive sensory abnormalities: preliminary evidence from fMRI during processing of
visual distractors. Soc Neurosci Abstr 30:582.10; 2004.

759

Brock, J; Brown, CC; Boucher, J & Rippon, G. The temporal binding deficit hypothesis of
autism. Dev Psychopathol 14:209 224; 2002.

760

Just, MA; Cherkassky, VL; Keller, TA & Minshew, NJ. Cortical activation and synchronization
during sentence comprehension in high-functioning autism: evidence of underconnectivity.
Brain 127:18111821; 2004.

761

Sporns, O; Tononi, G & Edelman, GM. Theoretical neuroanatomy: relating anatomical and
functional connectivity in graphs and cortical connection matrices. Cereb Cortex 10:127141;
2000.

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This model is consistent not only with the impairments in higher-order cognition described by
the diagnostic triad but also with impairments of motor coordination762, perceptual
abnormalities such as high visual motion coherence thresholds763 and broad tuning of
auditory filters764, abnormal growth within regions of local but not long-range white-matter
projections765, and the substantial co-morbidity of epilepsy with autism766 (Ballaban-Gil and
Tuchman, 2000).
Although MDL sometimes appears to show signs of autistic spectrum disorder (ASD), it has
been shown that damage to specific areas of the brain can produce symptoms that mimic
some of those of autism. 767
As IQ declines in autism, abstract reasoning falls disproportionately, whereas immediate
recall and visuo-spatial ability are usually preserved. The predictable outcome with
increasing severity of such a profile is mental retardation with an unusual preservation of
memory for details and visuo-spatial ability and unusually poor adaptive behaviour relative
to IQ. (Minshew, 1997, Idem)
It is obvious that MDL does not show these characteristics and she does not have the
symptoms of classical autism. However, it will have been noted that some of the
neurological deficits that MDL does have and that have arisen from her initial brain damage
are comparable to some characteristics of ASD. Neurological studies in autism have
demonstrated predominant deficits in abstract reasoning and problem solving abilities;
higher-order language abilities and complex memory abilities.

Neurophysiology of Autism

The neurophysiology of autism is largely a research

issue, aside from the clinical usefulness of brain stem auditory evoked potentials in assessing
hearing. One summary of this literature has emphasized the occurrence of hearing loss in
this population and has advocated vigorous evaluation of hearing status. 768
Neurophysiologic functioning in autism has been demonstrated to be characterized by
abnormalities in cognitive potentials with preservation of early and middle latency potentials. From a patho-physiologic perspective, this profile implicates complex cognitive
processes and higher brain regions. A recent study of eye movement physiology in autism
has revealed a similar profile with prominent abnormalities in cortically controlled eye
movements subserved by frontal and parietal circuitry and intact basic and reflex eye

762

Teitelbaum, P; Teitelbaum, O; Nye, J; Fryman, J & Maurer, RG. Movement analysis in infancy
may be useful for early diagnosis of autism. Proc Natl Acad Sci USA 95:1398213987; 1998.

763

Milne, E; Swettenham, J; Hansen, P; Campbell, R; Jeffries, H & Plaisted, K. High motion

coherence thresholds in children with autism. J Child Psychol Psychiatry 43:255263; 2002.

764

Plaisted, K; Saksida, L; Alcantara, JI & Weisblatt, EJL. Towards an understanding of the

mechanisms of weak central coherence effects: experiments in visual configural learning and
auditory perception. Philos Trans R Soc London B Biol Sci 358:375386; 2003.

765

Herbert, MR; Ziegler, DA; Makris, N; Filipek, PA; Kemper, TL; Normandin, JJ; Sanders, HA;
Kennedy, DN & Caviness Jr, VS. Localization of white matter volume increase in autism and
developmental language disorder. Ann Neurol 55:530540; 2004.

766

Ballaban-Gil, K & Tuchman R. Epilepsy and epileptiform EEG: association with autism and
language disorders. Ment Retard Dev Disabil Res Rev 6:300 308; 2000.

767

Challoner, A. Abnormal Brain Structure and Autism.

http://www.scribd.com/doc/9635846/Abnormal-Brain-Structure-and-Autism-

768

Klin A. Auditory brainstem responses in autism: brain stem dysfunction or peripheral hearing
loss. J Autism Dev Dis 23:15-35, 1993.

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movements subserved by sub-cortical and posterior fossa structures. (Minshew, 1997, Idem)
From long observation of MDLs behaviour and assessment of her attributes and limitations it
is clear that the above description by Minshew and Klin does not bear any resemblance to
MDL.

Neuropathology of Autism

The description of the neuropathology of autism 769

has been limited to the examination of a small number of cases and to clinical pathology
methods. Quantitative measurements of cell number and structure volume are notably
lacking. The neuro-pathologic abnormalities described in autism are subtle overall and
consist of a 100- to 200-g increase in brain weight in most cases and histologic
abnormalities in the limbic system and cerebellum.
In the small, compact grey matter structures of the limbic system, the neurons were
immature in appearance and exhibited a truncation in dendritic tree development. In
addition, there was an increase in cell-packing density, which appeared to be the
consequence of a decrease in the neuropil. In the cerebellum, there was a decrease in
Purkinje and granule cells throughout the hemispheres but greatest in neocerebellar
regions. These findings have been of major importance in providing definitive, evidence of
the neurologic basis of autism and have characterized it as a disorder of neuronal
organization.
More recent research by Belmonte et al has involved work on abnormal neural
connectivity and used it to show explanatory framework within which genetic and neuropathological findings on autism may be unified with neuroanatomy, neurophysiology, and
behaviour. Communication between these levels of analysis promises a greater
understanding of mechanisms underlying both normal and pathological development of
neural and cognitive systems and has the potential to render a multiplicity of experimental
and theoretical approaches more coherent. 770

Autism and Anxiety

Studies exploring the relationships of anxiety with autism771,772

and the amygdala in autism773 led to the conclusions that:
1. the amygdala is not essential for social behaviour;
2. pathology of the amygdala may not be the basis for impaired functioning in autism;
and
3. impairments of amygdala functioning in autism may produce effects through
influencing fear and anxiety that are commonly co-morbid in autism, and that in
turn might exacerbate other causes of social impairment.

769

Bauman ML & Kemper TL. Neuroanatomic observations of the brain in autism, in Bauman ML,
Kemper TL (eds): The Neurobiology of Autism. Baltimore: Johns Hopkins University Press, 1994,
pp 86-101.

770

Belmonte, MK; Allen, G; Beckel-Mitchener, A; Boulanger, LM; Carper, RA; & Webb, SJ. Autism
and Abnormal Development of Brain Connectivity. Journal of Neuroscience, October 20,
2004 24(42):9228 9231

771

Muris P, Steerneman P, Merckelbach H, Holdrinet I, Meesters C. Comorbid anxiety symptoms

in children with pervasive developmental disorders. J Anxiety Disord. 1998;12:387-393.

772

Gillott A, Furniss F, Walter A. Anxiety in high-functioning children with autism. Autism.

2001;5:277-286.

773

Thomas KM, Drevets WC, Dahl RE, et al. Amygdala response to fearful faces in anxious and
depressed children. Arch Gen Psychiatry. 2001;58:1057-1063.

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In another set of studies, 774,775,776 in which primates had amygdala lesions placed shortly
after birth, (as opposed to studying lesions made in mature animals), Amaral established
that the amygdala was not necessary for gaining or acquiring social knowledge in the first
place.
Data were also presented about a patient who had an Urbache Wiethe syndrome with
bilateral lesions of the amygdala. This interesting patient was referenced as extensively
studied by Adolphs and colleagues.777,778,779 This patient was impaired in her ability to
recognise fearful faces, yet she could easily perceive happiness or other emotions in faces.
Of note, she otherwise lived a normal life, which is remarkable for someone without an
amygdala. The conclusion from this case and others suggests that the amygdala is not
essential for normal social behaviour and that damage in this area does not necessarily
lead to autistic behaviour.

Patho-physiology of Autism

The patho-physiology of the clinical syndrome

of autism is controversial, with multiple different hypotheses as to the central neuropsychologic deficit and central nervous system localization. Regardless of differences,
current theories propose a primary deficit in higher-order cognitive abilities and localization
at the neural systems level or at multiple levels of the neuraxis. The predominant theories
propose a core deficit in executive functions780, control of attention781, or complex information processing782. Localizations proposed for these deficits include frontal systems,
frontal cortex-parietal cortex-neocerebellar vermis, and generalized involvement of
neocortical systems, respectively.

It can be seen that damage to these areas post-natally may produce autistic-type deficits.
It is said that treatment of autism and similar disorders involves primarily an environmental
and behavioural approach, as there are no medications with demonstrated efficacy
against the primary deficits in autism. Academic intervention should employ a model that
is the converse of the traditional learning disability approach, with a particular emphasis on

774

Amaral DG. The primate amygdala and the neurobiology of social behavior: implications for
understanding social anxiety. Biol Psychiatry. 2002;51:11-17.

775

Prather MD, Levenex P, Mauldin-Jourdain ML, et al. Increased social fear and decreased fear
of objects in monkeys with neonatal amygdala lesions. Neuroscience. 2001;106:653-658.

776

Emery NJ, Capitanio JP, Mason WA, Machado CJ, Mendoza SP, Amaral DG. The effects of
bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca
mulatta). Behav Neurosci. 2001;115:515-544.

777

Adolphs R, Tranel D, Damasio AR. The human amygdala in social judgment. Nature. 1998;
393): 470-474.

778

Adolphs R, Tranel D, Damasio H, Damasio A. Impaired recognition of emotion in facial

expressions following bilateral damage to the human amygdala. Nature. 1994;372:669-672.

779

Adolphs R, Tranel D, Damasio H, Damasio AR. Fear and the human amygdala. J Neurosci.
1995; 15:5879-5891.

780

Ozonoff S; Strayer DL & McMahon WM, et al. Executive function abilities in autism: An
information processing approach. J Child Psychol Psychiatry 35:659-685, 1994.

781

Courchesne E; Townsend JP & Akshoomoff NA, et al. A new finding: Impairment in shifting
attention in autistic and cerebellar patients, in Broman SH, Grafman J (eds): Atypical Deficits
in Developmental Disorders: Implications for Brain Function. Hillsdale, NJ: Erlbaum, 1994, pp
101-317.

782

Minshew NJ; Goldstein G & Siegel DJ. Profile of neuropsychologic functioning in autism: A
generalized disorder of complex information processing. J Int Neuropsychol Soc. 3, 303-316;
1997.

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interpretative and problem-solving deficits. (Minshew, 1997, Idem)

Behaviour Modification in Autism

Firstly, in terms of behaviour modification,

which is the mainstay of treatment, several guidelines are essential to the successful
application of such techniques to individuals with pervasive developmental disorders. The
underlying principle is the recognition that autism and the pervasive developmental
disorders directly involve the very skills that are the basis of adaptive function in society and
thus the capacity for adapting to real life. Thus, these individuals should not be expected
to adapt to the environment but rather the environment should be adapted to them.
Secondly, staff should be highly familiar with the deficits in autism and their behavioural
manifestations, so that these individuals are not expected to do things that involve their
deficits and that odd behaviour which is not hindering the individuals function is accepted
as hard-wired rather than targeted for change because it looks odd to others.
Difficulty in coping with the presence of others and with change and ritualistic obsessive
compulsive behaviour are the sources of most undesirable behaviour. Thus, if a behaviour
problem develops, the social demands and amount of change occurring in the
environment at the time need to be assessed to determine if they exceed the individual's
usual tolerance limits. Rituals that do not interfere with function should generally be
respected as a means of coping with change.

_______

THE NEURO-BEHAVIOURAL EXAMINATION OF CHILDREN

With any neurological/behavioural/competence-based assessment of MDL, there has to
be a continuous reference to and reliance on determining what is her age norm for any
tasks and this must of necessity begin with a realisation that her brain injury occurred at the
age of five/six months.
From that, there has to be an understanding of what her developmental milestones were
together with her behavioural and neurological characteristics up to the age of say 18
years. To this one must add the impact of trauma that she has received including
environmental, emotional and physical events so that adjustments can be made to aid
the discovery of what, for her, is an age-appropriate level of assessment; and it may not be
equal across all areas.
Thus it may be (say) age four for some assessments and age twelve for others. There will be
very few areas, if any, that will allow assessors to view her as an adult in terms of her
neurological development especially in relation to communication, emotion and many
practical capabilities and these include social relationships.

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As Denckla writes783, Apart from such (assessment) tests or tasks themselves, for each of
which there is a rationale, there is an aspect of evaluation that goes beyond the term
examination and is indispensable to developmental mental status; this is the history and
description of the patient by parents and teachers. Of course, this is shared with all of
behavioural neurology, since the literal confines of examination cannot sample complex
social, vocational, and communal behaviours relevant to any patient's mental status. For
the developmental clinic, however, the need to collect and interpret parent- and teacherderived data relates with urgency to decisions about certain diagnostic entities that are
shared by professional colleagues in psychiatry and education. Whatever our
neurologically based intellectual qualms about some of these diagnoses, service to the
patients demands that data considered to be the basis of these entities be included in the
neurobehavioral assessment.
Beyond attempts to document "syndromes" that overlap entities recognizable to the
schools and clinics where treatment is carried out, the neurobehavioral examination is free
to describe the strengths and weaknesses of each patient. Rarely is "localization" or classic
brain-behaviour correlation the purpose of the evaluations. Explanation of the cluster of
deficits or the profile, consistent with established knowledge of brain organization, helps to
legitimize educational approaches or accommodations. Sometimes brain-based explanations even serve to clarify prognosis. At the very least, brain-based explanations usually
help to avoid irrational or harmful treatments and, for those patients mature enough to
attempt to understand themselves, self-knowledge and insight are the not inconsiderable
benefits. (Idem)
Sumowski and colleagues have shown that higher intellectual enrichment (estimated with
education) reduces the negative effect of TBI on cognitive outcomes and thereby supports
the cognitive reserve hypothesis in persons with TBI. They believe that future work is
necessary to investigate whether intellectual enrichment can build cognitive reserve as a
rehabilitative intervention in survivors of TBI.784
It is the failure of professionals to understand these complex issues and there relevance to
the examination and assessment of MDL, that she has suffered from incorrect assessments
during the whole of her life. The effect of those failures is cumulative with each successive
incorrect assessment/diagnosis feeding further diversity and thereby failing to find the
correct diagnosis for her condition. That is compounded most severely when it is
considered that some of these incorrect diagnoses have subsequently involved the use of
psychotropic medication to purportedly relieve conditions from which she was not suffering.
MDLs sole neuropsychological assessment in her adult years was conducted by the
assessor alone, having never met her before and he disallowed a parent from being
present. This egregious error is used as an example of what not to do when making a
pragmatic assessment. From Dencklas approach (see above), it can be seen just how
important are the features of her outline of how a neurological assessment should be
carried out.

783

Denckla, MB. The Neurobehavioral Examination in Children. In Feinberg, T E & Farah, M J.

Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997

784

Sumowski JF; Chiaravalloti N; Krch D; Paxton J & Deluca J. Education attenuates the
negative impact of traumatic brain injury on cognitive status. Arch Phys Med Rehabil. 2013
Dec;94(12):2562-4

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Denckla stresses that what is included in the evaluation is multi-determined. To be unkind,
one could call the menu of what is included, a hodgepodge; to be generous, one could
call it eclectic and pragmatic. It is not a fixed battery; it changes with conceptual and
data driven shifts in the current relevant literatures. For example, there is convergent
consensus that phonologic coding skills are the basis for reading acquisition. The inclusion
of direct norm-referenced measures of phoneme segmentation, phonologic memory, and
reading (decoding) nonsense words became standard in the learning disability-oriented
workup. Depending on the chief complaint, which varies somewhat from patient to
patient and age group to age group, only a core is invariant; but a certain set of mental
status constructs is assessed flexibly, on an individualized basis. As Sumowski reminds us,
"Don't assault (patients) with your battery." It will be perfectly obvious and recognizable to
any professional trained to engage in the mental status examination that the
developmentalist surveys language, attention, memory, visual perception, and
(emphatically) motor skills. (Idem)
There is an interesting neurological evaluation to be made from how a subject holds a
pencil or a knife and fork. The way these items are grasped indicates the level of motor
control. In MDLs case it is clear that (at present) she has less control over the proximal
positions of her fingers and is therefore less able to write or draw effectively or to use a knife
and fork to her best advantage. Her control has reverted to a primitive ulnar grasp that
controls movement by the forearm rather than more distally.
It is very much an undermining of MDLs control and of her wellbeing and her self-perceived
worth, that she finds herself unable to do the things with her fingers that once she could do.
As this is a deterioration from her previous abilities, it could be argued that she has
regressed neurologically and one might ask is that an organic remission or is it to do with
the long-term medication to which she has been subjected?
During MDLs childhood there was no attempt made to assess her through paediatric
neurology. This, despite the fact that she was seen five or six times a year by a neurologist
from the age of four to eighteen. Of course it has to be recognised that in the 1960s, brain
science was still almost in its infancy when it came to understanding atraumatic injuries
such as MDLs. There were some scientific papers available on the subject from about
1965, but the science is not well-documented until the 1980s. As a result MDLs
consultations were almost entirely monitoring exercises (and that probably to assess how
her parents were coping) and there was never any attempt to assess her neurological
deficiencies. There were occasional attempts to see how she was writing and drawing and
some of these documents were filed. It is clear from hindsight that the lack of knowledge of
this type of brain injury led to a less than satisfactory outcome for MDL. Instead there was a
steady transference to what was then called the mental handicap service and that led
almost sine qua non to the psychiatric service and then because that didnt understand
the brain injury, onwards to psychotropic medication from the age of ten years.

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AFTERWORD
All those who have researched human neurology have discovered the
inherent complexity of the brain and its interlocking functions. There remains
controversy in some areas and this may continue as no two brains are alike
and no one persons experience of learning is the same as that of another.
In reviewing this updated neurology research it may help to throw some
light on how the deficiencies of MDLs mental processes can happen but it
does not necessarily do more than indicate that her behaviour is bound up
in the differences from normal that occur in her brain and that her problems
will relate to failures in her neuronal processing.
For those who have been able to see a deeper meaning, it will be clear that
none of her damaged areas of brain can be repaired and that the kindest
and most caring approach to those problems is to create an environment in
which she can find comfort, happiness and a minimum of stress.
_______

BIBLIOGRAPHY
Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill,
New York, 1997
Pennington BF. Diagnosing Learning Disorders: A Neuropsychological Framework. New
York: Guilford, 1991.
Atrens, D. & Curthoys, I. The Neurosciences and Behaviour: An Introduction. Academic
Press, Sydney, Australia; 1982.

___________

ADDENDUM
As a result of very recent behavioural brain research some interesting findings have been
published. The highlights of these are:

Experimental diffuse TBI causes thalamic neuron pathology and astrocyte activation
that persists up to 1 month

Onset of neuron pathology and glial activation occurs with dynamic changes in
neuron morphology

Histopathological changes in the presence of preserved cytoarchitecture support

circuit reorganization

Histopathological changes coincide with previously published changes in circuit

function and behaviour.

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TBI-induced persisting histopathology indicates prolonged reparative processes

rather than rapid recovery.
Thalamic dysfunction has been implicated in overall chronic neurological dysfunction after
traumatic brain injury (TBI), however little is known about the underlying histopathology. In
experimental diffuse TBI (dTBI), we hypothesize that persisting histopathological changes in
the ventral posteromedial (VPM) nucleus of the thalamus is indicative of progressive circuit
reorganization. Since circuit reorganization in the VPM impacts the whisker sensory system,
the histopathology could explain the development of hypersensitivity to whisker stimulation
by 28 days post-injury; similar to light and sound hypersensitivity in human TBI survivors.785

785

Thomas, TC; Oglea, SB; Rumneyd, MB; Mayd, HG; Adelsona, D. & Lifshitza, J. Does time heal
all wounds? Experimental diffuse traumatic brain injury results in persisting histopathology in
the thalamus. Behavioural Brain Research; Original Research Article. In Press, Accepted
Manuscript, Available online 29 December 2016.

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