38

© JAPI • september 2012 • VOL. 60

Review Article

Localizationism to Neuroplasticity---The Evolution of

Metaphysical Neuroscience
Sourya Acharya1, Samarth Shukla2, SN Mahajan3, SK Diwan4

Abstract
Neuroplasticity (also referred to as brain plasticity, cortical plasticity or cortical re-mapping) is the changing
of neurons, organization of their networks, and their function via new experiences. The brain consists of nerve
cells or neurons and glial cells which are interconnected, and learning may happen through changing of the
strength of the connections between neurons, by adding or removing connections, or by adding new cells.
“Plasticity” relates to learning by adding or removing connections, or adding cells. Contrary to the traditional
belief of neurolocalizationism, which states that each region of brain is dedicated for a particular type of activity,
neuroplasticity has struggled a long way and has created a safe niche in the neuroscientific hall of honor. Salute
to the neuroplasticians for their efforts to revolutionize the doctrine of neurology for the better understanding
of the remarkable powers of brain. This article is a brief attempt to fathom the mysterious and scientific ways
of neuroplasticity.

Introduction
T he traditional concept of localizationism was first proposed
by Paul Broca,1 in 1861, who dissected the brains of patients
died of strokes with motor aphasia and demonstrated that, a
part of the left frontal lobe is responsible for the problem which
was damaged in all. Hence the famous Broca’s area became
the first milestone of localizationism. Soon afterwards, Carl
Wernicke,2 localized another area responsible for language and
comprehension in the left superior temporal gyrus and inferior
parietal lobule, named after him as Wernicke’s area. Over
the next century the concept of “one function, one location,”
hypothesis dominated the field of neuroscience signifying that if
a part of brain dedicated for a specific task is damaged then brain
cannot reorganize itself to recover that lost function, because
brain is a hardwire.3,4
In 1868, Jules Cotard studied children who suffered early
massive brain diseases with damaged Broca’s areas and children
with absence of one hemesphere, found out that these children
can speak normally contrary to the one function, one location
hypothesis.5 Then came the great question, “Is the brain plastic
enough to reorganize its so called hardwired map, if necessary
when circumstances demand?.” Latter in 1876, Otto Soltmann,6
in his landmark experiment demonstrated that even if the
motor cortex of infant dogs and rabbits are removed, they are
still able to move. But unfortunately, these findings could never
emerge into limelight because of the exuberant dominance of
localizationist enthusiasm. The idea of neuroplasticity was first
proposed in 1892 by Santiago Ramón y Cajal 7 the proposer of
the neuron doctrine though the idea was largely neglected for the
next fifty years. In 1912 Grham Brown and Charles Sherrington
in their experiment showed that stimulating a particular point
in the cerebral cortex does not always initiate similar responses
so there is no point to point relationship between cortical motor
1
Associate Professor, Dept. of Medicine, 2Associate Professor, Dept.
of Pathology, 3Prof and Head, Dept. of Medicine, 4Professor, Dept.
of Medicine, JNMC/DMIMSU, Sawangi (Meghe), Wardha 442 004,
Maharashtra
Received: 21.04.2010; Revised: 04.09.2010; Accepted: 27.10.2010
map and a given movement.8 The first person to use the term
neural plasticity appears to have been the Polish neuroscientist
Jerzy Konorski. 9,10 During the 20th century, the consensus
was that lower brain and neocortical areas were immutable
in structure after childhood, meaning learning only happens
by changing of connection strength, whereas areas related to
memory formation, such as the hippocampus and dentate gyrus,
where new neurons continue to be produced into adulthood,
were highly plastic. This belief is being challenged by new
findings, suggesting all areas of the brain are plastic even after
childhood.11 Hubel and Wiesel had demonstrated that ocular
dominance columns in the lowest neocortical visual area, V1,
were largely unchangeable after the critical period (usually third
to eighth week of the life when the brain has to receive several
environmental stimuli so as to develop and function normally).12
Thanks to their research which was then incorporated in the
medical practice by operating on blind infants having congenital
cataracts giving them vision. Earlier it was thought that blind
by birth is blind forever. Critical periods also were studied with
respect to language; the resulting data suggested that sensory
pathways were fixed after the critical period. However, studies
determined that environmental changes could alter behavior and
cognition by modifying connections between existing neurons
and via neurogenesis. The brain is globally neuroplastic……!
Decades of research have now shown that substantial
changes occur in the lowest neocortical processing areas, and
that these changes can profoundly alter the pattern of neuronal
activation in response to experience. According to the theory of
neuroplasticity, thinking, learning, and acting actually change
both the brain’s physical structure (anatomy) and functional
organization (physiology) from top to bottom. Neuroscientists
are presently engaged in a reconciliation of critical period studies
demonstrating the immutability of the brain after development
with the new findings on neuroplasticity, which reveal the
mutability of both structural and functional aspects. A substantial
paradigm shift is now under way. Canadian psychiatrist Norman
Doidge has in fact stated that neuroplasticity is “one of the most
extraordinary discoveries of the twentieth century.”
Neuroplasticity basically refers to the brain’s natural ability
© JAPI • september 2012 • VOL. 60 39
across the lifespan to form new connections and change its
structure in response to experience. This means the brain
can change itself physically and functionally at any age to
compensate for injury and disease and to adapt to new situations
or changes in the environment. Whereas the brain was once
conceptualized as a machine, it could now be thought of as more
like clay, both malleable and vulnerable towards positive and
negative influences. Of course, there are limits to how much the
brain can change, reorganize, and heal, but these limits are not
as imposing as might be assumed. Indeed, harnessing the power
of neuroplasticity, people are fully recovering from massive
strokes and other head traumas, overcoming learning disabilities
to leap ahead in reading levels in a matter of months, rewiring
obsessive-compulsive behavior out of their brains, erasing the
pain of phantom limbs, restoring memory acuity and cognitive
processing during old age, learning to see without eyesight,
strengthening muscles just by thinking about them, meditating
to create eternal neurons that are conducive to compassion and
happiness, and on and on.
Brain Plasticity and Cortical Maps
Cortical organization, especially for the sensory systems,
is often described in terms of maps.13 For example, sensory
information from the foot projects to one cortical site and the
projections from the hand target in another site. As the result
of this somatotopic organization of sensory inputs to the
cortex, cortical representation of the body resembles a map
(or homunculus). The concept of mapping was first idealized
in 1930, by a neurosurgeon Dr. Wilder Penfield. 14 One of the
greatest discoveries Penfield made was the sensory and motor
brain maps, which like geographical maps are topographical
maps where the adjacent body parts are represented in the
brain adjacent to each other. This was a staunch localizationist
project. It was Michael Merzenich, known to be one of the world’s
leading researcher in neuroplasticity in his brillant experiments
documented that the shape of our brain maps changes on our
deeds over the course of our lives and the cortical maps are not
fixed and immutable….the brain constantly learns how to learn.15
In the late 1970s and early 1980s, several neuroplastician
groups began exploring the impacts of removing portions of
the sensory inputs usuing cortical maps as dependent variable.
They found that if the cortical map is deprived of its input it will
become activated at a later time in response to other, usually
adjacent inputs. Re-organization is not cortically emergent, but
occurs at every level in the processing hierarchy; this produces
the map changes observed in the cerebral cortex. Merzenich
and DT Blake16 used cortical implants to study the evolution
of plasticity in both the somatosensory and auditory systems.
Both systems showed similar changes with respect to behavior.
When a stimulus was cognitively associated with reinforcement,
its cortical representation strengthened and enlarged. In some
cases, cortical representations can increase two to threefold in
1–2 days at the time at which a new sensory motor behavior is
first acquired, and changes are largely finished within at most
a few weeks. Control studies show that these changes are not
caused by sensory experience alone: they require learning about
the sensory experience, and are strongest for the stimuli that are
associated with reward, and occur with equal ease in operant
and classical conditioning behaviors.
Fighting Phantoms—The Neuroplastic
Way
An interesting phenomenon involving cortical maps is the
incidence of phantom limbs. This is most commonly described
in people those who have undergone amputations in hands,
arms, and legs, but it is not limited to extremities. The phantom
limb feeling, which is thought1 to result from disorganization
in the brain map and the inability to receive input from the
targeted area, may be annoying or painful. These signals, being
functionally nonsense, were thought to be interpreted by the
brain as pain. The dominant theory for cause of phantom limbs
was irritation in the severed nerve endings. When a limb is
amputated, many severed and inflammed nerve endings are
terminated at the residual limb sending anomalous signals
to the brain. It is also theorized that phantom limb sensations
could be due to “crosswiring” in the somatosensory cortex,
which is located in the postcentral gyrus and which receives
input from the limbs and body. Incidentally, it is more common
after unexpected losses than planned amputations. There is a
high correlation with the extent of physical remapping and the
extent of phantom pain. As it fades, it is a fascinating functional
example of new neural connections in the human adult brain.
Neuroplastician of Indian origin, V.S Ramchandran, currently
director of The center for Brain and Cognition at the university
of California,USA, developed a “mirror box” for the treatment
of the phantom limb pains. Ramachandran reasoned that if
someone were to lose their right hand in an accident, they may
then have the feelings of a phantom limb because the input that
normally would go from their hand to the left somatosensory
cortex would be stopped. The areas in the somatosensory
cortex that are near to the ones of the hand (the arm and face)
will take over or “remap” this cortical region that no longer
has input. This remapping was first demonstrated through
magnetoencephalography (MEG), by showing that stroking
different parts of the face led to perceptions of being touched
on different parts of the missing limb.
A mirror box is basically an equipment which fools the brain
by showing the normal limb to the patient and making the patient
percieve it as if it were the lost limb. When an amputee places a
limb in the box, the reflection of the limb occupies the space in
which the amputated limb would normally be found. Amputees
sometimes report that their phantom limb is paralyzed;
Ramachandran obtained some evidence that the mirror box can
enable amputees to gain control over their missing limb, and
that it also alleviated phantom limb pain to some extent. Other
teams are investigating the use of virtual reality mirror boxes
for treating phantom limb pain.
Another explanation about the mirror box phenomenon
is in terms of an internal forward model, whereby the brain
predicts the sensory inputs which will occur as a result of
bodily movements. Thus, the predicted movement leads to the
sensation that the phantom limb is actually moving.
After a period of training the brain maps undergo plastic
changes and the phantom limbs dissappear. A lot of patients are
getting cured of their phantom symptoms by Ramchandran—
The so called” neurological illusonist.” In such patients fMRI
(functional MRI) scans reveal that the motor maps for the
phantom limbs increase, the shrinkage that accompanies the
amputation reverses and the motor and sensory maps of the
cerebral cortex normalize. Subsequently, the use of the mirror
box has been extended to rehabilitation of hemiparesis, due to
stroke and to rehabilition of spatial neglect . These extensions
40 © JAPI • september 2012 • VOL. 60
have met with moderate success, but further research is required
to evaluate their clinical effectiveness.17,18
Enriched Media Enhanses
Neuroplasticity and Plasticity Obeys
Laws of Quantum Physics!!!
Neuroplastician Mark Rosenzweig in his rat experiment
showed that Acetylcholine, the essential neurotransmitter
for learning was higher in the rats trained in difficult spatial
problems and was lower in those trained in simpler tasks.
Enriched environment stimulates cortical neurons to develop
new branches and also to strengthen existing branches. In
humans postmortem examination has revealed that education
increased the number of branches in neurons. It is believed
that practicing a new skill under right circumstances can
change billions of neural circuits in cortical maps---plasticity
rules from cradle to coffin ! Plastic change is a process which
indicates if cortical maps are changing then new connections
must have been forming among the neurons. Donald O. Hebb,
a behavioral psychologist in 1949, proposed that learning linked
neurons in new ways. When two neurons fire at the same time
repeatedly chemical changes occurs in both leading to more
stronger connection between the two. On the basis of this theory,
neuroscientist Carl Shatz summarized the basic doctrine of
plasticity----“Neurons that fire together wire together----Law
of association by simultaneity.” Quantum Physics teaches that
nothing is fixed, that there are no limitations, that everything is
vibrating energy. By understanding that everything is energy
in a state of potential and by applying the “Law of Attraction”
it seems prudent to justify that the energy of the brain has no
boundaries, it is constantly flowing in the fluidity of its neurons.
Neuroplasticity Begets Neuronal
Darwinism-----1
If the brain maps are mutable then there is a reason to hope
that people with learning disabilities, strokes, psychiatric
diseases and brain injuries might be able to change their defective
maps to new normal maps by getting their healthy neurons to
fire and wire together. This duty of forming new maps selects
the most able and healthy neurons by a competitive process
known as neuronal group selection theory, which was proposed
by neuroscientist Gerald Edelman—that for any new brain
activity the ablest group of neurons are selected-----a neuronal
Darwinism……!
The Neuronal Group Selection Theory
Three Major Parts
1. Anatomical connectivity in the brain occurs via selective
mechanical and chemical events that take place epigenetically
during development. This creates a diverse primary
repertoire by differential reproduction.
2. Once structural diversity is established anatomically, a
second selective process occurs during postnatal behavioral
experience through epigenetic modifications in the strength
of synaptic connections between neuronal groups. This
creates a diverse secondary repertoire by differential
amplification.
3. Reentrant signaling between neuronal groups allows
for spatiotemporal continuity in response to real-world
interactions.
Brain development depends on a variety of cell adhesion
molecules (CAMs) and substrate adhesion molecules (SAMs)
on cell surfaces which allow cells to dynamically control their
intercellular binding properties. This surface modulation
allows cell collectives to effectively “signal” as the group
aggregates, which helps govern morphogenesis. It is theorized
that cell proliferation, cell migration, cell death, neuron arbor
distribution, and neurite branching are also governed by similar
selective processes.
The concept of plasticity can be applied to molecular as well
as to environmental events.19 The phenomenon itself is complex
and can involve many levels of organization. To some extent
the term itself has lost its explanatory value because almost
any changes in brain activity can be attributed to some sort
of “plasticity”. Plasticity in more recent writing is frequently
described as a property of the central nervous system with
the term reorganization used to introduce the specific types
of changes observed including axonal sprouting, long-term
potentiation or the expression of plasticity related genomic
responses.
Concepts of Positive and Negative
Plasticity
Norman Doidge, following the lead of Michael Merzenich,
separates manifestations of neuroplasticity into adaptations that
have positive or negative behavioral consequences. For example,
if an organism can recover after a stroke to normal levels of
performance, that adaptiveness could be considered an example
of “positive plasticity”. An excessive level of neuronal growth
leading to spasticity or tonic paralysis, or an excessive release of
neurotransmitters in response to injury which could kill nerve
cells; this would have to be considered a “negative” plasticity.
In addition, drug addiction and obsessive-compulsive disorder
are deemed examples of “negative plasticity” as the synaptic
rewiring resulting in these behaviors is also highly maladaptive.
In a study, medical students brains were imaged during the
period when they were studying for their exams. In a matter of
months, the students’ gray matter increased significantly in the
posterior and lateral parietal cortex.20
One of the most interesting phenomena in positive plasticity
is the concept of Psychedelic plasticity. Psychedelics are drugs
whose primary action is to alter the cognition and perception of
the mind. Hallucinogens which target the 5-HT2A receptor can
influence cellular functioning via the activation of G proteins
and secondary messengers. The signaling pathways mediated
by the 5-HT2A receptor include the activation of PKC and MAPK,
protein kinases which energize enzymes to perform complex
cellular maintenance. The activation of PKC undoubtedly plays
an active role in the production and maintenance of long term
memory. Evidence shows that inhibiting PKC activation in the
cortex for as little as a few hours can cause the rapid erasure of
long-term memory associations. It is obvious that this kinase is
a fundamental part of memory formation and retention, and it
is not unreasonable to assume that drugs which stimulate PKC
activity may enhance or alter the processes of memory formation,
recall, retention, and plasticity.
Other research indicates that LSD activates intracellular
mechanisms to promote expression of genes responsible for
encoding c-Fos and Arc proteins, particularly in the pre-frontal
cortex (PFC). c-Fos is essential to cell proliferation, differentiation,
and cellular defense, while Arc (activity-regulated cytoskeleton-
associated protein) regulates the structure and plasticity of neural
© JAPI • september 2012 • VOL. 60 41
cytoskeleton architecture, the very scaffolding which maintains
neural shape and stability. By activating expression of c-Fos and
Arc proteins in PFC neurons, LSD may promote plasticity, cell
proliferation, cell repair, and synaptic generation in neurons
responsible for identity. Presumably any selective 5-HT 2A
agonist will produce similar results, making hallucinogenic
tryptamines primary candidates for cellular signal strengthening
and identity-based neuroplasticity.
Negative Plasticity; Depending on what is one’s goal in life
may differentiate the neuroplasticities as positive or negative
ones. In cases of sexual exhaustion the sufferers develop a
very negative neuroplasticity of the brain, which leads to
severe addiction to sexual activities, that when challenged
will create withdrawal symptoms, both physiological and
psychological. Sexual addiction is due to neuroplasticity of
the PVN (Hypothalamic paraventicular nucleus) where we
observe innervations of different nervous components and
systems - noradrenergic, oxytocinergic, adrenergic, autonomic,
dopamin, acetylcholine, glutamate, vagal, nitric oxidergic,
serotonin, and GABAergic. The nervous remodeling itself occurs
under the frequent stimulation of prostaglandin E2, oxytocin,
and norepinephrine. Norepinephrine activates certain cytokins
and protein kinases in the Locus ceruleus for prostaglandin
E2 production, which along with oxytocin causes arousal.
The enzyme dopamine beta-hydroxylase (increased by sex or
masturbation) constantly converts dopamine to norepinephrine
prompting constant sexual thoughts and arousal, leading to
addiction. Prostaglandin E2 if in excessive amounts is considered
extremely harmful. However, it is vital for the regulation of
the synaptic activity and plasticity, it actually accelerates the
neuroplasticity. Prostaglandin E2 is required for learning,
and memory. High levels of prostaglandin E2 also enhance
the cell membrane excitability and degrade the short term
memory and spatial navigation. In order to reverse the negative
neuroplasticity to a positive one, one must be self conscious
of what he is doing, and break the cycle of psychological and
physiological excitation by enhancing the proper modulation
on certain conversions.
The Pioneers and their Plastic Miracles
Paul Bach-y-Rita, the “father of sensory substitution and
brain plasticity” 21 developed BrainPort, a machine that “replaces
the vestibular apparatus and sends balance signals to the brain
from the tongue. This apparatus was first successfully tried
in a female patient with irreversible damage to the vestibular
apparatus. After she had used this machine for some time it
was no longer necessary, as she regained the ability to function
normally. Plasticity is the major explanation for the phenomena.
The patient’s vestibular system was “disorganized” and was
sending random rather than coherent signals, the apparatus
found new pathways around the damaged or blocked neural
pathways, helping to reinforce the signals that were sent by
remaining healthy tissues.
The second most important landmark Bach y Rita invented
was a device that allowed blind people to read, perceive
shadows, and distinguish between close and distant objects.22
This “machine was one of the first and boldest applications of
neuroplasticity.”1 The patient sat in an electrically stimulated
chair that had a large camera behind it which scanned the area,
sending electrical signals of the image to four hundred vibrating
stimulators on the chair against the patient’s skin. This device
was tried on six congenitally blind persons. Bach-y-Rita believed
in sensory substitution; if one sense is damaged, other senses can
sometimes take over. He thought skin and its touch receptors
could act as a retina (using one sense for another). In order for
the brain to interpret tactile information and convert it into visual
information, it has to learn something new and adapt to the new
signals. The brain’s capacity to adapt implied that it possessed
plasticity. He thought, “We see with our brains, not with our
eyes. Significant progress has been made in the development of
visual neuroprostheses to restore vision in blind individuals.
Appropriate delivery of electrical stimulation to intact visual
structures can evoke patterned sensations of light in those who
have been blind for many years. However, success in developing
functional visual prostheses requires an understanding of how
to communicate effectively with the visually deprived brain in
order to merge what is perceived visually with what is generated
electrically.
Michael Merzenich is a neuroscientist who has been one of
the pioneers of brain plasticity for over three decades. He has
made some of “the most ambitious claims for the field - that brain
exercises may be as useful as drugs to treat diseases as severe
as schizophrenia and that radical improvements in cognitive
functioning - how we learn, think, perceive, and remember are
possible even in the elderly.” Merzenich’s work was affected by
a crucial discovery made by David Hubel and Torsten Wiesel in
their work with kittens. The experiment involved sewing one eye
shut and recording the cortical brain maps. Hubel and Wiesel
saw that the portion of the kitten’s brain associated with the
shut eye was not idle, as expected. Instead, it processed visual
information from the open eye. This implied brain plasticity
during the critical period. However, Merzenich argued that
brain plasticity could occur beyond the critical period. Early
in his career Merzenich collaborated with a group of people to
develop the cochlear implant, which allows congenitally deaf
people to hear.23
An interest on neuroplasticity and nerve regeneration within
the auditory receptor and pathway has developed in recent years.
The receptor and the auditory pathway are controlled by highly
complex circuits that appear during embryonic development.
During this early maturation process of the auditory sensory
elements, we observe the development of two types of nerve
fibers: permanent fibers that will remain to reach full-term
maturity and other transient fibers that will ultimately disappear.
Both stable and transitory fibers however, as well as developing
sensory cells, express, and probably release, their respective
neuro-transmitters that could be involved in neuroplasticity.
Cell culture experiments have added significant information; the
in vitro administration of glutamate or GABA to isolated spiral
ganglion neurons clearly modified neural development. Nerve
regeneration and neuroplasticity have been demonstrated in
the adult auditory receptors as well as throughout the auditory
pathway. Neuroplasticity studies could prove interesting in
the elaboration of current or future therapy strategies (e.g.:
cochlear implants or stem cells), but also to really understand
the pathogenesis of auditory or language diseases (e.g.: deafness,
tinnitus, dyslexia, etc.) Studies have demonstrated that plasticity
is present in adult brains of postlingually deaf patients. In the
mature brain, auditory deprivation decreased neuronal activity
transiently in primary auditory and auditory-related cortices,
and, over time, functional reorganization likely takes place in
the auditory cortex. Plasticity is prominent in superior temporal
and anterior cingulate gyri in the sensory-deprived mature brain
and explains postimplantation improvement in patients with
cochlear implants.
Randy Nudo, a professor at The University of Kansas,
42 © JAPI • september 2012 • VOL. 60
is another important scientist in the field of brain plasticity
research. In his experiments he found that if a small stroke (an
infarction) is induced by impedance of blood flow to a portion of
a monkey’s motor cortex, the part of the body that responds by
movement will move when areas adjacent to the damaged brain
area are stimulated. In one study, intracortical microstimulation
(ICMS) mapping techniques were used in nine normal monkeys.
Some underwent ischemic infarction procedures and the others,
ICMS procedures. The monkeys with ischemic infarctions
retained more finger flexion during food retrieval and after
several months this deficit returned to preoperative levels.24 With
respect to the distal forelimb representation, “postinfarction
mapping procedures revealed that movement representations
underwent reorganization throughout the adjacent, undamaged
cortex.” Understanding of interaction between the damaged and
undamaged areas provides a basis for better treatment plans in
stroke patients.
The brain damage caused by a stroke may result in the loss
of cerebral function. However, the brain can use neuroplasticity
to adjust itself functionally, by reorganizing the cortical maps,
which contributes to the stroke recovery. The changes in the
cortex organization include an increase in the number and
density of dendrites, synapses and neurotrophic factors (these
are essentials for the survival of nervous cells). After damage has
been afflicted to the motor cortex, changes of activation in other
motor areas are observed. These changes can occur in homologue
areas of the non-affected hemisphere (which can substitute for
the lost functions) or in the intact cortex adjacent to the damage.
Thanks to these cortical reorganizations, which begins from one
to two days after the stroke, and can be extended for months, the
patients can recover, at least in part, the lost abilities.
Current research includes the tracking of changes that occur
in the motor areas of the cerebral cortex as a result of a stroke.
Thus, events that occur in the reorganization process of the brain
can be ascertained. Adult brains have the ability to change as a
result of injury but the extent of the reorganization ultimately
depends on the extent of the injury.
One of the most recent applications of neuroplasticity
involves work done by a team of doctors and researchers at
Emory University, specifically Dr. Donald Stein (who has been in
the field for over three decades) and Dr. David Wright. This is the
first experimental treatment in 40 years that has significant results
in treating traumatic brain injuries while also incurring no known
side effects and being cheap to administer. Dr. Stein noticed that
female mice seemed to recover from brain injuries better than
male mice. Also in females, he noticed that at certain points in the
estrus cycle females recovered even more. After lots of research,
they attributed this difference due to the levels of progesterone.
The highest level of progesterone present led to the fastest
recovery of brain injury in these mice. Progesterone is naturally
present in small but measurable amounts in the brains of males
and females. Human brain tissue is loaded with progesterone
receptors. Laboratory studies suggest that progesterone is
critical for the normal development of neurons in the brain
and exerts protective effects on damaged brain tissue. Based
on these observations they developed a treatment that includes
administering increased levels of progesterone injections to brain
injured patients. “Administration of progesterone after traumatic
brain injury (TBI) and stroke reduces edema, inflammation,
and neuronal cell death, and enhance spatial reference memory
and sensory motor recovery.”25 In their clinical trials, they had
a group of severely injured patients that after the three days of
progesterone injections there was a 60% reduction in mortality.25
Major advancements in the field of neuroplasticity have
enabled the development of novel techniques that do not require
expensive or invasive medicines or surgery. “The only goal of
rehabilitation in this context would be to teach the patient new
strategies to overcome those lost by the injury, and plasticity
would be defined by the extent to which such substitution is
possible. An increased understanding of plasticity of the brain
and spinal cord, and of behavior of innate modular mechanism
in intact and in injured systems, will likely assist in future
developments.”
Neuroplasticity in Cosmic
Consiousness
Richard Davidson a Harvard-trained neuroscientist at the
University of Wisconsin has led experiments in cooperation
with the Dalai Lama on effects of meditation on the brain.
26
The result was the scans that Prof. Davidson projected in
Dharamsala. They compared brain activity in volunteers who
were novice meditators to that of Buddhist monks who had
spent more than 10,000 hours in meditation. The task was to
practice “compassion” meditation, generating a feeling of loving
kindness toward all beings. In a striking difference between
novices and monks, the latter showed a dramatic increase in
high-frequency brain activity called gamma waves during
compassion meditation. Thought to be the signature of neuronal
activity that knits together far-flung brain circuits, gamma waves
underlie higher mental activity such as consciousness. The
novice meditators “showed a slight increase in gamma activity,
but most monks showed extremely large increases of a sort that
has never been reported before in the neuroscience literature,
suggesting that mental training can bring the brain to a greater
level of consciousness.
Using the brain scan called functional magnetic resonance
imaging, the scientists pinpointed regions that were active
during compassion meditation. In almost every case, the
enhanced activity was greater in the monks’ brains than the
novices’. Activity in the left prefrontal cortex (the seat of positive
emotions such as happiness) swamped activity in the right
prefrontal (site of negative emotions and anxiety), something
never before seen from purely mental activity. A sprawling
circuit that switches on at the sight of suffering also showed
greater activity in the monks. So did regions responsible for
planned movement, as if the monks’ brains were itching to go
to the aid of those in distress.
The study concluded that long-term Buddhist practitioners
can self-induce sustained electroencephalographic high-
amplitude gamma-band oscillations and phase-synchrony
during meditation. These electroencephalogram patterns differ
from those of controls, in particular over lateral frontoparietal
electrodes. In addition, the ratio of gamma-band activity (25-42
Hz) to slow oscillatory activity (4-13 Hz) is initially higher in the
resting baseline before meditation for the practitioners than the
controls over medial frontoparietal electrodes. This difference
increases sharply during meditation over most of the scalp
electrodes and remains higher than the initial baseline in the
postmeditation baseline. These data suggest that mental training
involves temporal integrative mechanisms and may induce
short-term and long-term neural changes.
Neuroplastic Rehabilitation
Constraint-Induced Movement Therapy (CIMT) is a
rehabilitation technique created by behavioral neuroscientist
© JAPI • september 2012 • VOL. 60 43
Edward Taub. Taub Therapy Clinic offers CIMT to patients who
have lost motor function in a limb due to a stroke, traumatic
brain injury (TBI), or brain surgery.27,28
 Programs at Taub Training Clinic involve therapy that
focuses on retraining the brain to stop relying primarily on the
unaffected limb and once again perform tasks with the affected
arm, hand, or leg. Practicing exercises with the affected limb
while restraining the normally functioning limb causes the
brain to rewire itself and relearn motor skills lost to neurologic
injury, thereby inhibiting the “learned nonuse” policy of the
brain. CIMT is most effective when begun at least 6 months
after a stroke or TBI and in people who have already completed
traditional rehabilitation. The recovery of functions of the limbs
which is promoted by plasticity is more difficult to occur, due
to a phenomenon known as “learned non use“. With the loss
of a brain area’s function, the body part that was linked to this
area is also affected and its mobility power is lost too. As the
patient cannot move his most affected limb, he compensate
this using the other limb. Thus, after a certain period, when the
damage effects aren’t present anymore and brain readaptations
happen, the movements could be recovered, but the patient
has already “learned” that the limb is no longer functional.
In the period following the stroke, a decrease in the extension
of the cortical representation areas is noticed for the affected
muscles: because they are not in use (aren’t working regularly),
its correspondent area in the brain is not stimulated. In a effort
to decrease or to recover from the “learned nonuse” effects, one
of the practices that have been used is the Constraint-Induced
Movement Therapy (CI-therapy) or forced use, which increases
the plastics changes that are favorable to the patient’s recovery.
This technique consists in the forced use of the affected arm
by the limited use of the non-affected arm. During a 10 to 15
days period, the patient’s non-affected arm is immobilized.
Consequently, many activities like dressing, eating, writing,
cooking, etc. can only be done by the affected arm, stimulating
the damaged cortex. In this period, the patient has a six daily
hours of physiotherapy training, doing repetitive tasks with the
affected arm. Due to this increased use of the affected arm, the
brain area connected to it is stimulated once again and occurs
an intense cortical reorganization. This reorganization increases
the representation area of this limb in the cortex and the motor
function ability is improved. So the CI-therapy can be considered
remarkably effective against the “learned nonuse”.
Between 55% and 75% of stroke survivors have lingering
disabilities that limit their ability to perform daily activities.
Until recently it was believed that stroke patients could regain
lost function only within a certain period (from the time of stroke
to 6 months afterwards) and that any remaining disability after
that time was unlikely to improve. Yet recent studies of CIMT
show that patients can make significant gains in movement,
strength, and coordination months and even years after the
original injury. For injuries to the upper extremity, patients
wear a special restraining mitt on their unaffected hand, which
encourages them use their injured limb. Typical exercises include
picking up or stacking small objects and practicing other tasks
that mimic the activities of daily living. Edward Taub, in his
experiments demonstrated that after a stroke the brain map for
an affected arm shrinks by about half. CIMT restores the motor
area of the brain to its normal size.29-31 Taub has applied CI
principles in a number of disorders including motor aphasia,32
and cerebral palsy with encouraging outcomes.CI therapy is now
being assessed in national trials throughout the united states.
Neuroplasticity in Psychiatry
Jeffrey M. Schwartz an American psychiatrist is one of the
world’s leading experts in neuroplasticity. He is a researcher
in the field of self-directed neuroplasticity. His major research
interest over the past two decades has been brain imaging/
functional neuroanatomy and cognitive-behavioral therapy
(CBT), with a focus on the pathological mechanisms and
psychological treatment of obsessive-compulsive disorder
(OCD).
Decades ago, he began to study the philosophy of conscious
awareness, the idea that the actions of the mind have an effect
on the workings of the brain. Jeffrey’s breakthrough work
in obsessive-compulsive disorder (OCD) provided the hard
evidence that the mind can control the brain’s chemistry. His
plasticity based treatment not only has helped people suffering
from OCD but instead it helps overcome worries, bad addictive
behaviours, substance abuse, compulsive sexual urges and so
on. In a beautiful and scientific way Norman Doidge, explains
the “Brain lock-unlock” mechanism in OCD patients. According
to this theory the OCD circuit consists of orbitofrontal cortex
(which detects the hypothetical mistakes), cingulate gyrus
(which reinforces the anxious and guilty feeling and compulses
the act) and the caudate nucleus (which normally makes our
thought flow from one to next). Positron Emission Tomography
(PET) scans of OCD patients show abnormal hyperactivity of
the orbitofrontal and cingulate gyrus and the caudate nucleus
is locked , so that the compulsive activity goes on. In Schwartz’s
neuroplastic approach the caudate nucleus is “unlocked” by
indulging the patient in some pleasure centric work which
releases dopamine and creates a new neural circuit which
competes with the old neural circuit overpowering it, and the
caudate nucleus fires normally and the compulsive thought
fades away.
A group of Scandinavian researchers showed that functional
neurons can, in fact, be generated in the adult human brain
in several distinct regions including the dentate gyrus of the
hippocampus and the subventricular zone. This process of
adult neurogenesis occurs throughout the lifespan and involves
proliferation of stem cells into neural progenitor cells of which
about 10% survive. The surviving cells differentiate into either
neurons or glia, and soon thereafter the newly formed dendrites
of the neurons receive glutamatergic input and join the ranks of
the existing neuronal network in structure and function.
Initially, the implication of hippocampal neurogenesis was
recognized for major depression and stress, in which magnetic
resonance imaging and postmortem studies documented
hippocampal atrophy. Subsequent research found that all
antidepressant drugs and electroconvulsive therapy stimulate
hippocampal neurogenesis, leading to a neuroplasticity model
for stress-related depression and its treatment. Furthermore,
mood stabilizers such as lithium and valproate, which are
widely used for the treatment of bipolar disorder, were also
found to have neuroprotective properties such as promotion
of neurogenesis and regeneration of cortical grey matter. These
findings are also important given the findings of atrophic brain
changes in recurrent bipolar disorder.
The relevance of neuroprotection to schizophrenia emerged
as recently as 2000, possibly because the first-generation
antipsychotics (FGAs) never gave a promising neurogenesis
signal in atrophic brain regions in schizophrenia such as the
cerebral cortex or the hippocampus. The main neuroplastic effect
associated with FGAs is an increase in caudate nucleus volume,
44 © JAPI • september 2012 • VOL. 60
which is considered an undesirable structural and functional
effect possibly associated with dopamine upregulation
and eventual tardive dyskinesia. The second-generation
antipsychotics (SGAs) do not induce caudate hyperplasia and
in fact may reverse it.
Pascual-Leone is a world leader in the development of
transcranial magnetic stimulation for application in cognitive
neuroscience and for therapeutic applications in neurology,
psychiatry and neurorehabilitation. Pascual-Leone’s research
aims at understanding the mechanisms that control brain
plasticity across the lifespan to be able to modify them for the
subject’s optimal behavioral outcome. Pascual-Leone combined
various brain imaging and brain stimulation methodologies
to establish a causal relationship and a precise chronometry
between regional brain activation and behavior, and used
noninvasive brain stimulation techniques to modulate brain
plasticity, suppressing some changes and enhancing others,
to gain a clinical benefit and behavioral advantage for a
given individual. Such non-invasive approaches can lead to
clinically relevant therapeutic effects in neuropsychiatry and
neurorehabilitation, and serve as proof-of-principle prior to
more invasive neuromodulatory interventions.33 Psychiatrist and
neuroplastic researcher, Kandel is one of the first who proposed
that as we learn, our individual neurons alter their structure
and start forming strong synaptic connections between them.
He was the first to demonstrate this hypothesis in relation to
long term memories in his experiment on sea snails for which
he received Nobel prize in 2000. In his landmark expeiment with
Aplysia (marine snail), he demonstrated that when the snail was
subjected to repeated unpleasant stimulus, its neuronal circuit
developed new synaptic connections and the snail developed a
kind of “learned fear” to the stimulus so that later on even if a
benign stimuli was given it reacted the same way as if it were
unpleasant. Along with fellow researcher James Schwartz, he
demonstrated that “Protein Kinase A” is the major chemical
which is responsible for the alteration of the genetic structure
of a neuron stimulating it to develop new strong synaptic
connections responsible for converting a short term memory to
long term memory. A single neuron for converting a short term
memory to a long term one can create as many as 1300 to 2700
new synaptic connections….a revolution in neuroplasticity.34-36
Sigmund Freud the veteran bishop of psychoanalysis proposed
four concepts of neuroplasticity. His first commandment was
“Neurons that fire together—wire together,” popularly known
as “Hebb’s Law” though he was the one who proposed it, in
1888,sixty years before Hebb. He stated that when two neurons
fire simultaneously this firing increases their association now
known as “the law of association”.
His second idea of neuroplasticity was that of the psychological
critical period which affects the sexual plasticity in latter life. If
anything goes wrong during this critical period in early life then
it affects the psychosexual development of an individual.37 The
third idea suggested that long term memories are not always
permanently engraved in the mind. A particular meaning of a
permanent memory can change depending on circumstantial and
developmental neuroplastic processing. Freud wrote that from
time to time memory traces are subjected to “a rearrangement
in accordance with fresh circumstances— a process called
retranscription.” 38 His forth idea depicts how unconcious
traumatic memories are trancribed to concious memories and
his patients are not actually viewing or remembering it as a bad
memory—they are “reliving” those memories in their minds.
He called this phenomena “transferences” which is neuroplastic
in nature.37 During transference, people turn into a ‘biological
time machine.’” A nerve is struck when someone says or does
something that reminds them of their past. This creates an
“emotional time warp” that transfers their emotional past and
their psychological needs into the present.
Neuroplasticity through Neurogenesis
Neurogenesis is the production of new neurons in the adult
brain. It is much more a process than an event. It is much more
than the division of a precursor cell. It involves multilevel
molecular decisions, including securing the survival of the
daughter cells. It entails also sending out the cellular processes
of dendrites and axons which form synapses with other cells.
A brain region which we call ‘neurogenic,’ can generate new
neurons. Neurogenic implies two events: the presence of
immature precursor cells from which new neurons can develop,
and, a microenvironment that is permissive for neurogenesis
to occur. In the adult mammalian brain there are two known
neurogenic regions: the hippocampus (which is a key area in
schizophrenia research) and the olfactory system.38-41 There are
numerous anecdotal reports of neurogenesis occurring in other
regions (e.g., the prefrontal cortex), but these have not passed
the stage of being anecdotal.
Stress, fear and anxiety may be the most salient negative
regulator of adult hippocampal neurogenesis. Research has
demonstrated that stress downregulates cell proliferation in
the hippocampal dentate gyrus and in the consecutive stages of
neuronal development. Prenatal stress has been demonstrated
to exert long-lasting negative effects on adult neurogenesis
and appears to reduce the baseline level of adult hippocampal
neurogenesis. It is also known that the negative effects of
even prolonged stress on adult hippocampal neurogenesis are
reversible. In short, as persons recover, their brains recover
from atrophic processes secondary to the cascading effects
of stress, e.g., excessive glutamate, calcium, cortisol, etc.
Psychosocial stress and social isolation significantly contribute
to the ‘negative’ symptoms. Severe mental illness has been
demonstrated to decrease cell proliferation in the hippocampus,
particularly in the dentate gyrus. Enriched environments and
physical exercise increase neurogenesis.42-43 It may be, that the
relation between stress and neurogenesis, follows an inverted
U curve, i.e., low stress causing neurogenesis, and high levels,
inhibiting neurogenesis. Depression is associated with disturbed
regulation of cortisol (as is bipolar disorder and schizophrenia).
Depression can be caused by prolonged anxiety and stress.
Stress also affects the number of sphere-forming cells that that
can be derived from the brain, which serves as an estimate of
the number of neural precursor cells in the subventricular zone
(SVZ).
Postnatal handling, calming affectionate contact (perhaps a
good case for adjunctive therapeutic massages in our socially
isolated patients), reversed the inhibitory effects of prenatal stress
on neurogenesis, i.e., increasing the number of sphere-forming
cells. In recent research, it has been demonstrated that, oxytocin,
which helps to consolidate bonding and affection ties between
caregivers and offspring, is anxiolytic in its effects. Nature
constantly reveals a wisdom, conserved across generations,
which has alerted us to the fundamental neurobiological basis
of the importance of affectionate contact, secure attachments,
compassion, etc.
Eminent swedish neuroplastic researchers Fredrick Gage and
Peter Eriksson discovered neuronal stem cells and they were
© JAPI • september 2012 • VOL. 60 45
able to isolate them from hippocampus. In their experiment
they injected these stem cells with a marker (BrdU), which
penetrates only new growing neurons in terminally ill subjects
and studied their brains after their death. They found new
growing baby neurons in the subjects hippocampus and termed
this phenomena “neurogenesis.” So that if possible neural stem
cells can cure diseases like Parkinsonism, MND, Alzheimer’s and
many psychiatric illnesses through neuroplasticity. 44
Recent researches have shown that as we age we tend to
perform cognitive activities in different lobes of brain from
those we use when young. This shift is another sign of plasticity.
Recent research also shows that the phenomena of lateralization
and hemispheric asymmetry becomes less effective or more
global with ageing that is the brain starts to reorganize and
decompensate for the normal loss. It has also been demonstrated
that physical and mental activity stimulates production of BDNF
(Brain derived nerve growth factor) which stimulates formation
of new synaptic connections redesigning the brain.45-46
The Plastic Ways: Jordan Grafman: An eminent neuroscientist
and chief of the Cognitive Neurosciences Section, National
Institute of Neurological Disorders and Stroke (NINDS), from
his researches proposed four types of neuroplasticity. 47
1. Map expansion: Activity induced neuroplastic changes.
2. Sensory reassignment: suggests that when one sense is
blocked, the respective cortical area starts processing for
other senses. For example in the blind the visual cortex can
receive inputs from another sense like touch.
3. Compensatory masquerade: reveals that there is more than
one alternative available for the brain to do a specific task.
4. Mirror region takeover: suggests that when one part
of hemisphere fails, then the same part of the opposite
hemisphere compensates and adapts for the same as best
as it can.48-49
Conclusion—The Quest Begins
Like the theory of relativity to quantum mechanics---- the
neuroscientists have brainstormed through the mysteries of
localizationism to neuroplasticity. As we have now started to
fathom further deep into the secrets of neuroscience, the more
we are learning about the nature’s ways of struggle for existence.
Concepts of neuroplasticity has opened a new horizon of
metaphysical approach to conventional neurology, and in time
to come…who knows neuroplasticity will rule and guide the
brain of a hypothetic supreme race.
Referrences
1. Broca, Paul. “Remarks on the Seat of the Faculty of Articulated
Language, Following an Observation of Aphemia (Loss of Speech)”.
Bulletin de la Société Anatomique, 1861;6:330–357.
2. Wernicke K (1995). “The aphasia symptom-complex: A psychological
study on an anatomical basis (1875)”. In Paul Eling. Reader in the
History of Aphasia: From (Franz Gall to). IV Amsterdam: John
Benjamins Pub Co. pp. 69–89. ISBN 90-272-1893-5.
3. Doidge, Norman. The Brain that Changes Itself: Stories of Personal
Triumph from the Frontiers of Brain Science. New York: Penguin
Group (USA) Incorporated, 2007.
4. Begley, Sharon. Train Your Mind, Change Your Brain: How a
New Science Reveals Our Extraordinary Potential to Transform
Ourselves. Ballantine Books, 2007.
5. Pearn J, Gardner-Thorpe C. Jules Cotard (1840-1889): his life and the
unique syndrome which bears his name. Neurology 2002;58:1400-3.
6. Finger S, Beyer T, Koehler PJ. Dr. Otto Soltmann (1876) on
development of the motor cortex and recovery after its removal in
infancy. Brain Res Bull 2000;53:133-40.
7. Cajal, S. Ramón y. La rétine des vertébrés. La Cellule 1892;9:121-133.
8. Graham Brown T, Sherrington CS. On the stability of a corticalpoint.
Proc R Soc Lond B Biol Sci 1912;85:250–277.
9. LeDoux, Joseph E. (2002). Synaptic self: how our brains become
who we are. New York, United States: Viking. p. 137. ISBN 0-670-
03028-7.
10. Konorski J. (1948). Conditioned reflexes and neuron organization.
Tr. from the Polish ms. under the author’s supervision. Cambridge
University Press. page 89 OCLC 14659990
11. Pasko Rakic. Neurogenesis in adult primate neocortex: an
evaluation of the evidence”. Nat Rev Neurosci 2002;3:65-71.
12. Hubel DH, Wiesel TN. The period of susceptibility to the
physiological effects of unilateral eye closure in kittens. J Physiol
1970;206:419-436.
13. Wall JT, Xu J, Wang X. Human brain plasticity: an emerging view of
the multiple substrates and mechanisms that cause cortical changes
and related sensory dysfunctions after injuries of sensory inputs
from the body. Brain Res Rev 2002;39:181-215.
14. Penfield W, Boldrey E. Somatic motor and sensory representation
in the cerebral cortex of man as studied by electrical stimulation.
Brain 1937;60: 389-443.
15. Paul RL, Merzenich M, H Goodman. “Representation of slowly
and rapidly adapting cutaneous mechanoreceptors of the hand
in Brodmann’s areas 3 and 1 of Macaca mulatta.”. Brain Research
1972;36:229–49. doi:10.1016/0006-8993(72)90732-9.
16. David T Blake, Marc A Heiser, Matthew Caywood, Michael
M Merzenich. Experience-Dependent Adult Cortical Plasticity
Requires Cognitive Association between Sensation and Reward.
Neuron 2006;52:371-381.
17. Ramachandran VS. Altschuler EL, Stone L et al. “Can mirrors
alleviate visual hemineglect?” Medical Hypotheses 1999;52:303-305.
18. Harvard University (2004, July 26). Scientists Pinpoint Molecules
That Generate Synapses. ScienceDaily. Retrieved July 13, 2008, from
http://www.sciencedaily.com/releases/2004/07/040726084801.htm.
19. Georgetown University Medical Center (2008, July 12). Learning
Suffers If Brain Transcript Isn’t Transported Far Out To End Of
Neurons. ScienceDaily. Retrieved July 13, 2008, from http://www.
sciencedaily.com /releases/2008/07/080710120503.htm.
20. Draganski et al. Temporal and Spatial Dynamics of Brain Structure
Changes during Extensive Learning. The Journal of Neuroscience
2006;26:6314-6317.
21. P.Bach-y-Rita. Sensory Plasticity. Acta Neurologica Scandinavica,
1967;43:417-26.
22. Remembering Leaders in the Field of Blindness and Visual
Impairment.” National Center for Leadership in Visual Impairment.
Salus University. 20 Nov. 2008.
23. BionicEar.com - Harmony Cochlear Implant by Advanced Bionics.
Advanced Bionics. 2009. Retrieved 2009-01-02.
24. Frost SB, Barbay S, Friel KM, Plautz EJ, Nudo RJ. Reorganization
of Remote Cortical Regions After Ischemic Brain Injury:A
Potential Substrate for Stroke Recovery. Journal of Neurophysiology
2003;89:3205-214.
25. Cutler SM, Stuart WH, Edward HP, Donald GS. Tapered
Progesterone Withdrawal Enhances Behavioral and Molecular
Recovery After Traumatic Brain Injury. Experimental Neurology
2005;195:423-29.
26. The Dalai Lama. “How Thinking Can Change the Brain”. source:
http://www.dalailama.com/news.112.htm
27. Taub E, Uswatte G, Bowman M, Delgado A, Bryson C, Morris D,
Mark VW. Use of CI therapy for plegic hands after chronic stroke.
Presentation at the Society for Neuroscience, Washington DC,
November 16,2005.
28. Taub E, Uswatte G, King DK, Morris D, Cargo JE, Chaterjee A. A
46 © JAPI • september 2012 • VOL. 60
placebo-controlled trial of constraint-induced movement therapy
for upper extremity after stroke. Stroke 2006;37:1045-49.
29. Taub E, Miller NE, Novack TA, Cook EW, Flemming WC,
Nepomuceno CS, Connell JS, CargoJE. Technique to improve
chronic motor deficit after stroke. Archives of Physical Medicine and
Rehabilitation 1993;74:347-54.
30. Lipert J, Miltner WHR et al; Motor cortex plasticity during
constraint-induced movement therapy in stroke patients.
Neuroscience Letters, 250:5-8.
31. Kopp B, Kunkel A, Taub E, et al; Plasticiy in the motor system related
to therapy induced improvement of movement after stroke. Neuro
Report 1999;10:807-10.
32. Pulvermuller F, Neininger B, Taub E, et al; Constraint induced
therapy of chronic aphasia after stroke. Stroke 2001;32:1621-26.
33. Pascual-Leone A and Hamilton R. 2001. The metamodal
organization of the brain. In C. Casanova and M. Ptito, eds. Progress
in Brain Research, Vol.134. San Deigo, CA: Elsevier Science, 427-45.
34. Kandel ER. From metapsychology to molecular biology:
Explorations into the nature of anxiety. American Journal of Psychiatry
1983;140:1277-93.
35. Control of Memory Formation Through Regulated Expression of
a CaMKII Transgene. Kandel E.R; Ibid; 2003,405.
36. Kandel ER, Schwartz JH, Jessel TM. Principles of neural science,
2000; 4th ed. New York: McGraw-Hill,1250.
37. Masson JM, trans. and ed. 1985. The complete letters of Sigmund
Freud to Wilhelm Fliess. Cambridge, MA: Harvard University Press,
207.
38. Levin F 2003. Psyche and brain: The biology of talking cures.
Madison, CT: International Universities Press.
The author has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate.
39. Eriksson PS, Perfilieva E, Gage FH et al; Neurogenesis in the adult
human hippocampus. Nature Medicine 1998;4:1313-17.
40. Van Praag H, Schinder BR, Gage FH et al; Functional neurogenesis
in the adult hippocampus. Nature 2002;415:1030-34.
41. Kempermann G, Gast D, Gage FH. Neuroplasticity in old age:
Sustained fivefold induction of hippocampal neurogenesis by long
term environmental enrichment. Annals of Neurology 2002;52:135-43.
42. van Praag H, Kempermann G, Gage FH. Running increases cell
proliferation and neurogenesis in adult mouse dentate gyrus. Nature
Neuroscience 1999; 2:266-70.
43. Peter S. Eriksson, Ekaterina Perfilieva, Thomas Björk-Eriksson,
Ann-Marie Alborn, Claes Nordborg, Daniel A. Peterson, Fred H.
Gage. Neurogenesis in the adult human hippocampus. Nature
Medicine 1998;4:1313-1317 doi:10.1038/3305
44. Springer MV et al. The relation between brain activity during
memory tasks and years of education in young and older adults.
Neuropsychology 2005;19:181-92.
45. Cabeza R. Hemispheric asymmetry reduction in older adults: The
HAROLD model. Psychology and Aging 2002;17:85-100.
46. Wilson RS et al. Participation in cognitively stimulating activities
and risk of incident Alzheimer’s disease. JAMA 2002;287:742-48.
47. Grafman J, Litvan I. 1999. Evidence of four forms of neuroplasticity.
In J. Grafman and Y. Christen, eds., Neuronal plasticity: Building
a bridge from the laboratory to the clinic. Berlin:Springer-Verlag,
131-39.
48. Grafman J. Conceptualizing functional neuroplasticity. Journal of
communication Disorders 2000;33:345-56.
49. Levin HS, Scheller J, Rickard T, Grafman J, Martinkowski K,
Winslow M, Mirvis S. Dyscalculia and dyslexia after right
hemispheric injury in infancy. Archives in Neurology 1996;53:88-96.