Neuromodulation: Technology at the Neural Interface

Received: December 5, 2016 Revised: February 19, 2017 Accepted: March 11, 2017

(onlinelibrary.wiley.com) DOI: 10.1111/ner.12604

State of the Art: Novel Applications for Deep

Brain Stimulation
Holly A. Roy, MRCS*†; Alexander L. Green, FRCS*†; Tipu Z. Aziz, FMedSci*†
Objectives: Deep brain stimulation (DBS) is a rapidly developing field of neurosurgery with potential therapeutic applications
that are relevant to conditions traditionally viewed as beyond the limits of neurosurgery. Our objective, in this review, is to high-
light some of the emerging applications of DBS within three distinct but overlapping spheres, namely trauma, neuropsychiatry,
and autonomic physiology.
Review Methods: An extensive literature review was carried out in MEDLINE, to identify relevant studies and review articles
describing applications of DBS in the areas of trauma, neuropsychiatry and autonomic neuroscience.
Results: A wide range of applications of DBS in these spheres was identified, some having only been tested in one or two cases,
others much better studied.
Conclusions: We have identified various avenues for DBS to be applied for patient benefit in cases relevant to trauma, neuropsy-
chiatry and autonomic neuroscience. Further developments in DBS technology and clinical trial design will enable these novel
applications to be effectively and rigorously assessed and utilized most effectively.

Keywords: Bladder control, brain injury, deep brain stimulation, depression, spinal cord injury
Conflict of Interest: The authors reported no conflict of interest.

INTRODUCTION
There has been a dramatic increase in the number of novel appli-
cations of deep brain stimulation (DBS) proposed and tested in
recent years. Running a basic Pubmed search using the search terms
“DBS” or “deep brain stimulation” and restricting the publication
year to 1995 revealed three English language papers describing DBS
in humans, two on DBS for pain (1,2), and one on DBS for Parkin-
son’s disease (PD) (3). Repeating the same search with the publica-
tion year restricted to 2005 produced a total of 206 English
language papers covering nine different subject categories relating
to DBS including PD and other movement disorders (109), DBS
methods including clinical and technological papers (51), neuropsy-
chiatry (13), pain (8), epilepsy (8), local field potentials and DBS relat-
ed neurophysiology (7), autonomic effects of DBS (3), trauma and
vegetative state (VS) (2), and neurodegenerative conditions other
than movement disorders (1), as well as four general papers which
did not fit into any of the above categories. Repeating the same
search again for publication year restricted to 2015 gave 601 English
language papers covering ten categories: PD and other movement
disorders (229), DBS methods including clinical and technological
papers (222), neuropsychiatry (66), pain (10), epilepsy (16), local field
potentials and DBS related neurophysiology (32), autonomic effects
of DBS (2), trauma and VS (0) and neurodegenerative conditions oth-
er than movement disorders (3), and general & ethical (21). The
growth in almost all subject areas is remarkable over the past two
decades. Improved neuroscience techniques including task-based
and resting state functional magnetic resonance imaging (fMRI),
high resolution diffusion tensor imaging and optogenetic techni-
ques are rapidly advancing both functional and neuroanatomical
this expansion, and with growth in the acceptability of DBS as a val-
id and important technology, a significant increase in the proposed
applications of DBS has occurred. Particularly encouraging is the
steady growth in technical and engineering-based studies which are
essential for equipping the field for progress. In this review, we
examine emerging areas where DBS is being actively explored, and
analyze some of the factors that may drive or restrict further devel-
opment for DBS as a whole. This is not intended to be an exhaustive
review but rather a discussion of some of the most interesting and
promising developments within the field shaped by our own inter-
ests and opinions about important areas of current and future
growth. These areas are grouped loosely into three general catego-
ries; trauma and acquired injury, neuropsychiatry and neurodegener-
ation, and autonomic. Our aim is to provide some background
context to each area under discussion and current evidence from
recent trials and case studies on outcomes. Established fields of DBS,
such as movement disorders, are outside the scope of this article.
Address correspondence to: Holly A. Roy, MRCS, Department of Functional Neu-
rosurgery, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3
9DU, UK. Email: roy.hollyann@gmail.com
* Nuffield Department of Surgical Sciences, Oxford University, Oxford, UK; and
†
Neurosurgery Department, Oxford University Hospitals, Oxford, UK
For more information on author guidelines, an explanation of our peer review
process, and conflict of interest informed consent policies, please go to http://
www.wiley.com/WileyCDA/Section/id-301854.html
Source(s) of financial support: Holly Roy was supported by the Medical Research
1

understanding of neurological and neuropsychiatric disorders. With Council UK.

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 ROY ET AL.
Trauma and Acquired Injury
Trauma is a common and devastating condition. In 2010, there
were 2.5 million traumatic brain injuries (TBIs) in the United States
alone, with the highest rate of deaths in the more than 65 and 15–
24-year age group (National Vital Statistics Mortality Data, Centres
for disease control and prevention). The incidence of TBI is set to
increase by 2020 (4) and there is growing interest in how to reduce
the rate of TBI and improve outcomes for sufferers. Moreover, as
many as three million people worldwide are living with disability fol-
lowing spinal cord injury (SCI) (5), including paralysis and loss of pel-
vic organ function. Most of the applications of DBS for traumatic
brain and spinal injury focus on restoring function in the damaged
brain or spinal cord by modulating behavior of circuits to compen-
sate for altered network activity following trauma, although some
techniques (6) are being developed to ameliorate the neurotoxic
effects of traumatic injury itself. Furthermore, DBS is being explored
as a treatment for other sequelae of traumatic injuries, such as neu-
ropathic pain following limb amputation or nerve avulsion, post-
traumatic tremor, and post-traumatic stress disorder (PTSD).
Traumatic Brain Injury
Due to advances in emergency care and neuro-critical care,
among other factors, survival rates after severe traumatic brain injury
are improving. However, one consequence of this is an increased
number of individuals with poor functional outcome including vege-
tative state (VS) (complete unawareness of self or surroundings with
no evidence of purposeful behavior) and minimally conscious state
(MCS) (definite behavioral evidence of consciousness). In a case
series of 25 subjects with post-traumatic VS, Cohadon et al. describe
“definite improvement” in 13 following centrum medianum-
parafascicularis complex DBS, but emphasize the fact that all of
these patients remained severely disabled and that some of the
improvement may have been unrelated to DBS (7). Yamamoto et al.
(2005) (8) report outcomes following DBS of the thalamic centro-
median parafascicular complex in 19 cases of VS and five cases of
MCS. They also describe DBS of the mesencephalic reticular forma-
tion (nucleus cuneiformis) in two cases of VS. A strong temporary
arousal response occurred at the onset of stimulation in all patients,
which was not associated with purposeful vocalization or activity. In
eight patients, emergence from the VS occurred. Furthermore, all
cases with MCS became able to communicate purposefully after
DBS. The main shortcoming of this study is the lack of a control or
comparison group, thus it is not clear to what extent DBS altered
the natural progression of selected patients, however, the results are
promising in that they are linked with a degree of improvement.
A case report published in 2007 describes significant improve-
ments associated with central thalamic DBS in cognitive behavioral
measures, oral function, and limb function in a patient with chronic
severe TBI and who was in MCS for six years with no earlier response
to other therapy (9). The patient was selected for the trial because
despite inability to communicate, fMRI revealed the existence of
bihemispheric cerebral language networks, suggesting that the neu-
ral systems required to support communication and language were
present, at least to some extent, and that lack of communication
could be due to global reduction in neuronal activity as a result of
damage to midbrain and thalamic structures. Of note, improve-
ments were not observed until a considerable period of time after
electrode implantation and onset of stimulation (160 days after
implantation).
In another trial, this time including four patients who had chronic
severe disabilities following TBI due to automobile crashes, but who
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were “awake, alert and able to follow commands,” the effect of
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nucleus accumbens/internal capsule DBS was tested (10). Post-hoc t-
tests after two years’ follow-up showed that there was an improve-
ment on the functional composite score (combining results from
the Mayo-Portland Adaptability Inventory-4 and the Functional Inde-
pendence Measure—essentially representing cognitive, emotional,
and self-care including mobility, toileting, transfers, and social cogni-
tion). The target (NAc/IC) was selected because of its extensive safe-
ty history due to use for other indications including obsessive
compulsive disorder (OCD), and because it is known to modulate
the behavior of frontal lobe networks which were thought to con-
tribute significantly to the deficits experienced by the TBI patients.
An additional target for DBS following traumatic brain injury has
been proposed based on animal studies. Stimulation of the septo-
hippocampal system after TBI improves spatial learning and restores
normal object exploration, particularly if the stimulation occurs in
the theta frequency band (11,12) or is delivered as theta burst stimu-
lation (13). Theta burst stimulation is thought to improve learning
either by inducing long-term potentiation or by evoking theta oscil-
lations, which facilitate memory formation (13). As far as we are
aware hippocampal stimulation has not been attempted in human
subjects following traumatic brain injury, although indirect stimula-
tion of the hippocampus during DBS for other indications has been
shown to have an effect on memory, such as in a case of high fre-
quency stimulation of the hypothalamic/fornix for obesity which
improved verbal memory via likely action on the hippocampus (14).
It is still early days for DBS purposed to improve brain function in
subjects following traumatic brain injury. The highly heterogeneous
nature of TBI makes subject and target selection for trial purposes
highly complex. However, existing results have shown that DBS may
bring benefits, especially for patients in MCS, and in the future,
potentially to those with specific cognitive impairments including
memory problems following TBI.
Spinal Cord Trauma
There has been an expansion of research into the use of neuro-
electric technologies to restore motor function after SCI. Around half
of spinal cord injuries are incomplete, meaning that some motor
and sensory function below the level of injury remains present (15).
The use of closed-loop stimulation systems to decode cortical (or
subcortical) signals about intended movement, and control move-
ments of a prosthesis (brain-machine interfaces) or trigger electrical
stimulation to drive a desired movement in peripheral organs such
as the limbs (functional electrical stimulation) is already a reality, as
demonstrated by the BrainGate system. The BrainGate consists of a
100-electrode array implanted into the motor cortex (M1). By decod-
ing neural signals within M1 the system can be activated by imag-
ined limb movements and used to control both a neural cursor and
basic movements of a prosthetic limb in patients with SCI (16).
Although the BrainGate and other similar systems for SCI do not
involve direct brain stimulation, the recording component often
involves invasive brain electrodes, and is therefore a close compan-
ion of DBS. Respiratory and lower urinary tract control driven by sub-
cortical sensors and developed based on autonomic research carried
out in the context of DBS may be possibilities for the future in the
field of SCI.
Furthermore, there is some evidence that DBS itself may poten-
tially be of therapeutic benefit following SCI. Low-frequency stimula-
tion of the nucleus raphe magnus (NRM) and the periaqueductal
grey area (PAG) after thoracic spinal contusion in rats has been
shown to reduce astrocytosis in the injured area (6,17), improve
white matter integrity and improve motor co-ordination and sensory
processing. The authors suggest that the NRM may be a “repair

control centre”; activated during traumatic injury and responsible
for releasing substances important for neurorepair. Whether or not
this target will prove beneficial for human subjects after SCI has not
yet been shown; nor whether the NRM also improves neuronal
repair in humans following traumatic brain injury, however these are
clearly avenues for future investigation.
Post-Traumatic Pain
Post-traumatic neuropathic pain can occur from a variety of trau-
matic aetiologies, commonly trauma during surgery (such as chronic
limb pain following amputation, or failed back surgery syndrome),
or an accident producing nerve trauma such as brachial plexus avul-
sion. Incidence of chronic pain in these groups can be as high as
76% in brachial plexus avulsion (18), 10–40% following lumbar disc
surgery (19–21) and 60% in the form of phantom pain after limb
amputation (22,23) producing a significant burden of disease. In a
proportion of these patients, the pain is refractory to pharmacologi-
cal therapy. DBS has been reported to be efficacious in a number of
cases of such medication-refractory traumatic pain syndromes.
Historically, DBS for chronic pain has been performed since the
1950s, and a number of more recent open-labeled studies have
demonstrated moderate efficacy. Recognized targets include the
ventral posterior lateral thalamic nucleus (VPL) and the periaqueduc-
tal grey/periventricular grey area (PAG/PVG). DBS for chronic pain,
including post-traumatic pain, has been reported by various groups.
For example, Rasche et al. (2006) (24) reported the results of a series
of 56 patients who received DBS for chronic pain, some of whom
had pain of traumatic origin, including 13 with failed back surgery
syndrome, 4 with phantom limb pain, and 12 with pain following
SCI. The best results were obtained for patients with failed back sur-
gery syndrome, where 9/13 experienced greater than or equal to
50% pain relief at long term follow-up (range 2–8 years for success-
ful outcomes). There was a mixed outcome for the small number of
subjects (n 5 4) with phantom limb pain. In this small group, all of
whom received VPL/PVG DBS, two out of four experienced more
than 50% pain relief, but one of these did not want to keep the DBS
system implanted. Better outcomes for DBS for phantom limb pain
were reported in a case series of 11 patients implanted with VPL
DBS for neuropathic limb pain (pain aetiology was either phantom
limb pain after amputation or deafferentation pain after brachial
plexus avulsion) (25). In this group, there was an improvement in
visual analogue score of 69.6 6 29.6% 12 months after surgery,
which was statistically significant. Another open label single centre
study reported improvements in 89% of amputees receiving DBS at
the VPL, PVG, or both for chronic neuropathic pain (26). However,
two US open-label trials to support application for FDA approval of
DBS for chronic pain were closed without the criterion for success of
therapy being met overall. The explanation for variability in trial out-
comes is not clear, however, important methodological differences
exist between trials in crucial issues of patient selection, preopera-
tive opioid reduction, and assessment of outcome. Blinding and
sham stimulation are generally absent from reports of DBS for
chronic pain and it seems important to have a trial in a selected aeti-
ology group incorporating these key methodological features. Fur-
ther efforts to evaluate the efficacy of DBS for post-traumatic pain in
specific patient groups in the hands of an experienced neurosur-
geon and multidisciplinary team, with carefully planned trial meth-
odology, is imperative.
Post-Traumatic Seizures
Post-traumatic seizures are an important complication of head
injury, and can be classified as immediate (occurring within 24 hours
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NOVEL APPLICATIONS FOR DBS
of injury), early (occurring between 24 hours and one week of inju-
ry), or late (occurring more than 7 days following injury). Late post-
traumatic seizures are often taken to indicate the presence post-
traumatic epilepsy (27). In a large US epidemiological study, the
five-year cumulative incidence of post-traumatic seizures was
reported to be 0.7, 1.2, and 10% (28) in mild, moderate and severe
head injuries respectively and more recent studies have reported
the cumulative prevalence of post-traumatic seizures to range
between 4 and 20.5% (27). Following traumatic brain injury, the risk
of developing epilepsy may be as much as 30 times higher than in
the general population, and the majority of patients who develop
post-traumatic epilepsy after TBI have drug-resistant epilepsy, which
means that they fail to respond to an adequate trial of more than
two appropriately selected anti-epileptic drugs (29). Brain stimula-
tion techniques, including DBS, are possible treatments that have
been investigated for drug-resistant epilepsy and may therefore be
an option for post-traumatic epilepsy. For example, for patients with
seizures originating in the temporal lobes, the double-blinded
SANTE trial (Stimulation of the Anterior Nucleus of the Thalamus for
Epilepsy) demonstrated significant benefits in terms of reduction in
seizure frequency (30). Although a dedicated trial of DBS for post-
traumatic epilepsy has not been published (to our knowledge) TBI
patients with drug-resistant epilepsy with a temporal lobe origin
may benefit from this treatment.
Acquired Brain Injury Tremor
DBS for tremor associated with acquired brain injury has been
reported in a number of case reports and small case series (31–34).
In one series of eight patients with tremor following acquired brain
injury either in the form of a haematoma, ischaemic stroke, or trau-
matic brain injury, DBS of the ventro-oralis posterior (VOP)/zona
incerta (ZI) region produced a mean tremor reduction of 80.75%,
based on the Bain tremor rating (31). The efficacy of this treatment
may be a result of activity within preserved white matter tracts
between the stimulation target and cortical areas responsible for
movement control (35).
Acquired Dystonia
While pallidal DBS is well established for primary dystonia, there is
relatively less work published regarding DBS for children with
acquired dystonias. These can occur as part of cerebral palsy, usually
secondary to perinatal brain damage due to hypoxic ischaemic
encephalopathy, periventricular leukomalacia, kernicterus, or basal
ganglia strokes (36). Small studies have reported modest but clear
improvements in selected paediatric patients with acquired dystonia
following pallidal DBS in terms of motor score (improvements in the
region of 30–40% have been reported), disability score and quality
of life (QOL) (37,38). Furthermore, a recent study described no nega-
tive effects on cognition but improved function on a perceptual rea-
soning test in a cohort of children following pallidal DBS for
secondary dystonia (39).
Aggression
Aggression and self-injurious behavior can occur following trau-
matic brain injury, and acquired brain injury secondary to birth anox-
ia. Several case reports of improvement in aggressive behavior
following DBS have been published (though not all subjects
described had a history of acquired or traumatic brain injury). DBS of
the amygdala and supra-amygdaloid projection system has been
described as leading to a remarkable improvement in self-injurious
behavior and autistic-spectrum symptoms in a 13-year old boy over
3
a 26 month follow-up period (40), while self-mutilating behavior
 ROY ET AL.
improved with DBS of the posterior hypothalamus in a woman
whose symptoms developed following severe TBI. Clinical improve-
ment in self-injurious behavior and autistic symptoms has also been
reported following NAc DBS (41) in a 14-year old.
Post-Traumatic Stress Disorder
PTSD is a disabling condition in which an individual who has had
a previously traumatic experience repeatedly reexperiences symp-
toms of trauma, often in the form of nightmares, intrusive thoughts,
and flashbacks, along with symptoms of avoidance, mood distur-
bance, hyperarousal, sleep impairment (42,43). In severe cases, suf-
ferers may be unable to have normal interpersonal interactions or
hold down a regular job due to the severity and intensity of flash-
backs and other PTSD symptoms. PTSD can be refractory to pharma-
cotherapy in up to 30% of patients (44). The development of PTSD is
likely to involve both fear and memory neurocircuitry (43) including
the amygdala, which is involved in creating an association between
a stimulus and fear. The amygdala is also central to the process of
extinction, whereby a stimulus no longer evokes a fear reaction.
Both fear conditioning and extinction are influenced by inputs from
the medial prefrontal cortex (45). DBS within the right amygdala of
the rat has been shown to reduce hypervigilance to a trauma-
associated object relative to sham DBS and paroxetine, despite par-
oxetine being more effective at reducing generalized anxiety (46).
Following these observations, in a single subject with severe PTSD,
amygdala DBS targeted to the basolateral nucleus of the amygdala
produced a remarkable improvement in nightmare intensity and
sleep quality (45). It is likely that further studies of DBS in PTSD will
follow in the future.
Neuropsychiatry and Neurodegeneration
There has been an intense increase in the interest in the use of
DBS for the treatment of neuropsychiatric conditions. These disor-
ders involving mood, memory, personality, and behavior are major
challenges for the medical profession and often refractory to phar-
macotherapy, thus representing an important avenue for the devel-
opment of DBS.
Treatment Resistant Depression
For over a decade, treatment resistant depression (TRD), defined
as the presence of major depressive disorder and failure to respond
to at least four different classes of antidepressant (including aug-
mentation with lithium, anticonvulsants, atypical antipsychotics, and
antidepressants) electroconvulsive therapy and evidence-based psy-
chotherapy, has been investigated for its responsiveness to DBS. A
number of neuroanatomical DBS targets have been described
including the ventral capsule/ventral striatum (VC/VS), the subcal-
losal cingulate (47), the nucleus accumbens (NAc) (48,49), the anteri-
or limb of the capsula interna (ALIC) (50), the medial forebrain
bundle, the inferior thalamic peduncule and the lateral habenula
(51,52). Generally, response to DBS is taken to be equal to or more
than 50% improvement in the Hamilton Depression Rating Score
(HDRS), while remission is taken to be a score of “nondepressed” on
the HDRS scale. The stimulation target associated with the most
extensively reported outcomes is probably the subcallosal cingulate,
otherwise known as the subgenual cingulate or Brodmann’s area 25
(53). Reasons for initial interest in this area as a target included
observations that reduced metabolic activity in this region was
reported in patients with major depressive disorder who responded
to antidepressant therapy, but not those who were unresponsive to
antidepressant therapy (54,55). Furthermore, the subgenual cingu-
4
late appeared to be connected to a number of other important
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regions linked with depression (56). In small open label trials, DBS of
the subcallosal cingulate was indeed shown to be safe and effica-
cious (57–59). Furthermore, an open label trial including a sham lead
in phase also showed good results (60), and ongoing DBS in patients
with successfully treated TRD appears to protect against remission
(61). However, the BROADEN trial, an important controlled, blinded
trial of subcallosal DBS for TRD carried out by St Jude Medical was
discontinued, as it failed a futility test, raising important questions
about the efficacy of the treatment and the best way to assess
outcome.
DBS of the VC/VS has also been investigated with apparent bene-
ficial effects (62) and no major adverse neuropsychological out-
comes (63), however, this too is associated with a discontinued
clinical trial, again due to perceived lack of efficacy of the treatment
compared with sham stimulation (64).
Despite apparent lack of efficacy in the large industry sponsored
trials, research continues to identify an optimal stimulation target
for depression and refine outcomes for existing targets. Alternative
targets which are actively under investigation include DBS at the
inferior thalamic peduncle (ITP) and median forebrain bundle (52),
while DBS of the NAc has shown positive long-term responses in
a small number of patients (49), with 5 out of 11 patients classified
as responders to treatment at 12 months (65), a finding which
remained stable at four years’ follow-up.
Interestingly, vagus nerve stimulation (VNS) for the adjuctive
treatment of chronic or recurrent depression in adults failing to
respond to at least four appropriate and adequate antidepressants
has been approved by the US FDA since 2005 (66). Stimulation of
the left vagus nerve, initially carried out for epilepsy and approved
for the treatment of epilepsy in 1997, was noted to have a positive
effect on mood (67) and was therefore trialled as a treatment for
depression. Although an initial review of trials concluded that there
was no significant difference in effect between VNS and placebo
(68), a subsequent analysis of controlled clinical trials comparing
VNS 1 treatment as usual (TAU) with TAU only found that response
rates at 96 weeks were 14% for VNS 1 TAU, and only 4% for TAU
alone, and that overall, 32% of people with depression responded
to VNS 1 TAU (66). Although there do not appear to be any trials
directly comparing DBS and VNS for depression, published out-
comes of controlled trials of DBS for depression appear to be at least
comparable to VNS, with response rates reported by controlled trials
of DBS ranging from 20 to 70% (52,64), the main limitation with this
data being that only a minority of published trials on DBS for
depression are controlled. Other options could include combining
VNS with DBS, or indeed improving patient selection using neuroim-
aging or genetic testing to personalize treatment and maximize
beneficial outcomes from therapy.
Obsessive Compulsive Disorder
OCD is a disabling psychiatric disorder which has a prevalence of
around 2–3% (69). It is associated with unwanted ideas, images, and
compulsions, which lead to the performance of repetitive and ste-
reotyped mental or behavioral acts. Of the population diagnosed
with OCD, 10% may be completely medication refractory, and as
many as 10–40% may remain severely disabled despite treatment
(70–73). Historically, lesional surgery such as cingulotomy and anteri-
or capsulotomy has been a last-resort option for patients with
severe refractory OCD, but the procedure is irreversible and associat-
ed with a risk of adverse effects (74). OCD is thought to be associat-
ed with neural circuit abnormalities in cortico-striato-thalamo-
cortical loops that implicate the thalamus, striatum and amygdala,
and cortical regions including the prefrontal cortex, dorsolateral

prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, and
the ventromedial prefrontal cortex (74). High frequency DBS, aimed
at modulating activity within this circuit, was first described in 1999
(75), and in 2009, the US FDA released a humanitarian device
exemption for DBS for OCD (http://www.fda.gov/NewsEvents/News-
room/PressAnnouncements/ucm149529.htm), based on evidence
from 26 patients with severe, medication refractory OCD, across 4
sites who had on average 40% symptom reduction over more than
a 12-month period. A number of targets have been trialled including
the ALIC, the nucleus accumbens, ventral caudate, ventral capsule
and ventral striatum (VC/VS), the STN and the ITP, and successful
outcomes may be linked to a reduction in high preoperative fronto-
striatal connectivity (76). A recent meta-analysis of studies of DBS for
OCD (77) included data from 31 studies (116 patients), of which six
studies (45 patients) were double blind sham controlled studies. The
meta-analysis found that there was a global improvement on the
Yale-Brown Obsessive Compulsive Scale of 45.1%, global response
of 60% and that the incidence of severe adverse effects was less
than for the comparable ablative techniques, capsulotomy or cingu-
lotomy. Although follow-up durations differed between studies, all
of the trials that included a sham stimulation arm reported a signifi-
cant benefit resulting from active stimulation compared with sham
stimulation (77). Adverse effects included intracranial haemorrhage
in three patients, five patients with infections of the scalp or abdom-
inal wound, which were controlled with antibiotics, and one tonic-
clonic seizure. Hypomanic symptoms were the most common
adverse effect (n 5 23) and some autonomic side effects were also
described including eneuresis (n 5 3), weight changes (n 5 6), sleep
difficulties (n 5 4), flushing (n 5 12), dizziness and nausea (n 5 7).
Interestingly although many studies did not report QOL outcomes,
those which did provide this data appeared to show that QOL mea-
sures continued to improve years after the implantation of DBS and
that QOL improvements were seen even in those patients who were
classified as nonresponders. This important finding could easily have
escaped unnoticed if study design had been limited to narrow out-
come criteria or short follow-up durations.
Tourette’s Syndrome
Tourette’s syndrome is a neuropsychiatric condition that affects
roughly 1% of the population globally (73). It develops in childhood
and is associated with multiple motor tics and also vocal tics. There
is also a high incidence of comorbid neuropsychiatric conditions
such as ADHD, OCD, and deliberate self-injury behaviors. Although
the neural basis of Tourette’s syndrome is not fully understood, one
hypothesis implicates dysfunctional striatal circuitry whereby the
globus pallidus interna (Gpi) and substantia nigra pars reticulata
(SNr) receive excessive inhibition, resulting in thalamic disinhibition
and the resultant brief motor tic (78,79). Based on this concept, a
number of targets have been investigated including the thalamic
centromedian-parafascicular complex (CM/Pf) which receives output
from basal ganglia circuits (79), the subthalamic nucleus, the nucleus
accumbens and the GPi. In a study which included 18 patients with
up to six years’ follow-up, Porta et al (2012) (80) reported a signifi-
cant improvement in tics as well as reduced incidence of OCD and
depression after CM/Pf DBS. More recently, a randomized double
blind cross-over trial of GPi DBS reported a significant improvement
in tics during the on stimulation blinded phase of the trial relative to
the off-stimulation phase (81), and a further improvement in the
incidence of tics and an improvement QOL measures during the
open label phase. Only one study has attempted to compare the
CM thalamic and GPi targets in terms of both tic reduction and
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improvement of psychiatric co-morbidities and this study found the
GPi to be the most advantageous in this regard (82).
Alzheimer’s Disease
Although Alzheimer’s disease (AD) has been traditionally viewed
as a structural disorder with clear pathological features, there are
associated functional changes, including deficits in memory and
cognition. It is a possibility that functional deterioration could be
reversed or slowed by DBS to enhance performance in selected
functional circuits. The basal forebrain cholinergic nucleus basalis of
Meynert (NBM) has been proposed as a potential DBS target for AD,
as reduction in cholinergic transmission is closely implicated in the
disease process. An initial study comprising a four-week double-
blind sham-control phase followed by an 11-month open label peri-
od demonstrated response in 4 out of 6 subjects at 12-month fol-
low-up, with stable or even improved cognition as assessed by the
Alzheimer’s disease assessment scale (83). The same group also
reported positive outcomes after implanting NBM DBS in two AD
patients at an earlier disease stage (84). Although the mechanism
underlying the benefits of NBM is not clear, there may be a direct
role of acetylcholine in reducing the deposition of beta amyloid in
the cortex. An alternative target for AD that has also been investigat-
ed is the fornix/hypothalamus. A phase I trial of DBS in the fornix/
hypothalamus (electrodes were implanted in the hypothalamus but
also made contact with the anterior border of the fornix) in six
patients with mild AD demonstrated a turnaround in the pattern of
reduced glucose utilization relative to controls typically seen in AD,
and a reduction in the rate of decline in mini mental state (MMSE)
score (85). Furthermore, in a different report describing the same
patient cohort, improved functional connectivity in fronto-temporo-
parieto-striatal-thalamic and fronto-temporo-parieto-hippocampal
networks were observed at 12 months post DBS and metabolic
changes in related cortical regions correlated with better memory,
cognitive, and QOL outcomes (86). At one-year follow-up, hippo-
campal atrophy was also significantly less in the DBS group than in
a matched AD group who did not receive DBS (87). The long-term
follow-up and safety outcomes from this cohort will be of great
interest.
Huntington’s Disease
Huntington’s disease is a genetic neurodegenerative disorder
with features that include motor and neuropsychiatric symptoms.
DBS of the GPi has been shown to have mixed effects—while being
beneficial for chorea, its value for cognitive and other motor mea-
sures may be limited according to an open label study of seven sub-
jects with genetically confirmed Huntington’s disease (88). Similar
conclusions were drawn in a recent study of GPi DBS in three
patients with Huntington’s disease (89) leading to the suggestion
that selection criteria of subjects for future GPi DBS in Huntington’s
should include severe chorea, to maximize the risk-benefit ratio for
surgery.
Addiction, Obesity, and Eating Disorders
“Limbic” circuits have been targeted in the search for DBS for
addiction and eating disorders. As the brain’s “reward centre,” the
NAc is thought to be a promising target for DBS for addiction, and
has been was shown to have a significantly reduced volume relative
to controls in male heroin addicts (90). Case reports have described
cessation of addiction in heroin addiction (91,92) and alcohol addic-
tion (93) following NAc DBS, and in a long-term follow-up study,
Muller et al. reported outcomes for five patients who underwent
5
DBS of the NAc for alcohol addiction. Of these, all patients reported
 ROY ET AL.
complete absence of cravings for alcohol and two out of five
became completely abstinent at long-term follow-up, while the oth-
er three significantly reduced their alcohol intake (94).
Anorexia nervosa is a potentially life-threatening eating disorder,
associated with a fear of weight gain and “refusal to maintain a
body weight at or above the minimally normal weight for age and
height” (DSM-IV). In a phase I prospective study of six patients with
chronic anorexia nervosa, Lispman et al. (2013) (95) reported
improved BMI in three patients at three months post surgery and
improvements in mood and affective symptoms in four subjects.
There was one serious adverse event reported in the trial (a seizure
thought to be due to severe metabolic derangements during pro-
gramming). PET imaging showed a reduction in cingulate, medial
frontal, and insular metabolic activity and increase in parietal lobe
activity after treatment. A case report also describes improved BMI
in a single patient after DBS of the subgenual cingulate for anorexia
nervosa (96). DBS of the Nac (97,98) and furthermore, VC/VS has
been shown to be beneficial in a patient with anorexia nervosa and
symptoms of OCD (99).
Morbid obesity has also been a subject of interest in relation to
DBS. The costs and risks of bariatric surgery are not negligible and
various neural stimulation targets for obesity treatment have been
described, including the lateral hypothalamus and ventral hypothal-
amus, important centres for the control of appetite and feeding
behavior, and the NAc based on evidence that dysregulation of
reward circuitry is involved in obesity (100,101). There is limited pub-
lished evidence about the outcome of DBS for obesity in humans:
Whiting et al (2013) (102) published a small series of three patients
and described DBS of the lateral hypothalamus as safe, with “weight
loss trends” observed when monopolar stimulation was specifically
set at contacts demonstrated to increase metabolic rate. A single
subject was treated with bilateral hypothalamic electrodes (14) with
no effect on weight, and further trials are underway.
Autonomic
The autonomic nervous system (ANS) is involved in the regulation
of physiologic and homeostatic parameters relating particularly to
the visceral organs and the coordination of physiological responses
to threat. Blood pressure and heart rate, respiration, pupillomotor
reactivity, sexual function, gastrointestinal secretions and motility,
and urine storage and micturition are all under a degree of ANS con-
trol. Many autonomic functions are maintained via peripheral ner-
vous system feedback loops, often with a central nervous system
component. Collectively, the network of brain areas involved in
maintaining and regulating the ANS is known as the “central auto-
nomic network” and important progress in our understanding of the
anatomy and function of the CAN in the human have been made in
recent years due to developments in neuroimaging techniques
(103,104). Modulation of activity within the CAN at specifically
selected anatomic targets, using DBS, offers a possible means of
altering or modifying autonomic functions, and carefully observed
studies of autonomic side effects arising from DBS for other indica-
tions, have made it possible to experimentally test the effects of
DBS on the ANS (105). Emerging patterns of autonomic changes fol-
lowing DBS have implications for sufferers of a range of cardiovascu-
lar (106–109), respiratory (110,111), gastrointestinal (112), and
genitourinary disorders (113–116) that implicate ANS functioning. It
may be that DBS in the future can be applied as a treatment for vari-
ous disorders involving elements of the ANS, including intractable
hypertension, as suggested by Patel et al. (2011) (109), orthostatic
6
hypotension (107), severe reversible airway disease (110), or urge
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V Neuromodulation 2017; ••: ••–••
incontinence (117). In addition, in patients with conditions that pro-
duce symptoms in multiple systems under autonomic control, such
as PD, significant improvements in autonomic symptoms have been
reported following DBS of certain targets, such as the STN (118),
which means that STN may become a target of preference in PD
patients with significant autonomic symptomatology. Finally, DBS
may prove a viable treatment option for patients with primary dys-
autonomias, autonomic dysreflexia, or for conditions associated with
catastrophic autonomic system involvement such as sudden unex-
pected death in epilepsy. The scope is vast and for patients with
severe and life-threatening or life-impairing disturbances of the ANS,
the risks of DBS may be acceptable when weighed against the
symptoms and implications of their condition.
Furthermore, there is close integration between the ANS and oth-
er neural functions such as emotion and cognition (119), and thus
brain regions that are known to be important for autonomic control
are also implicated in emotional functions, such as the amygdala in
fear conditioning and PTSD.
Ongoing Trials for Novel Indications
Although we have attempted to discuss many novel applications
of DBS in this review, it is impossible to cover each with adequate
attention given the rapid rate of growth within the field. The clinical
trials registry currently lists a number of other important indications
with trials recruiting, including schizophrenia, vocal tremor, tinnitus
and pain, and autonomic dysreflexia in SCI.
TRIALS AND TECHNOLOGY: THE KEY TO
PROGRESS
Technological innovation has underpinned and paralleled devel-
opments in the clinical applications of DBS. In this final section, we
discuss some important factors involved in recent and future devel-
opments including animal models, trials, and technology.
One of the critical factors that has both enabled and restrained
development of DBS technology is animal models. Lack of a compa-
rable animal model certainly slows progression of research while
availability of a good animal model, for example as in the case of
PD, enables lesion/stimulation targets to be tested and verified
before human trials of DBS begin (120,121). Animal models for other
conditions, particularly neuropsychiatric, are less optimal but never-
theless still important for advancing knowledge about the condition.
Coupling of animal models with powerful techniques such as opto-
genetics have been particularly useful in selecting and refining cer-
tain stimulation targets (122,123).
Clinical trials are essential for establishing a new indication for
DBS, demonstrating efficacy of anatomical targets and stimulation
parameters for given patient groups. Anatomical sites for DBS that
have the support of clear trial evidence are most likely to receive
health authority approval, licensing, and funding. However, for ethi-
cal and practical reasons, DBS trials can be difficult to run, and this
can therefore represent a major hurdle in the development of the
field. One explanation for the challenging nature of DBS trials is that,
as described above, animal models for neuropsychiatric conditions
are not always adequate. This means that questions about precise
targeting, stimulation parameters, and patient selection often have
to be answered through human studies, which in some circumstan-
ces is ethically questionable. However, improvements in structural
and functional MRI (124), along with parallel developments in MEG,
EEG, and intracranial recordings using subdural grids and implanted
DBS electrodes, have greatly increased our ability to determine

effective targets by highlighting aberrant circuit activity in different
conditions. We believe that including a “control” design, either by
using an N-of-1 paradigm (125) or by incorporating a sham stimula-
tion arm (126), ensuring double-blinding wherever possible (9),
using a well-selected range of primary and secondary outcome mea-
sures including QOL (127) and ensuring a long follow-up duration
(77) are all important elements to the ideal trial.
Noninvasive and less-invasive neuromodulation techniques have
been evolving and developing alongside DBS and should not be
ignored by DBS enthusiasts. For example, repetitive transcranial
magnetic stimulation, which uses an electromagnetic coil placed
against the skull to generate local electrical currents within brain tar-
get regions has been shown to have significant benefits for patients
with major depressive disorder (128), while transcranial direct cur-
rent stimulation has been shown to improve motor outcomes fol-
lowing stroke (129) and epilepsy (130). Again, the possibilities of
combining noninvasive treatments with DBS, or for predicting
response to DBS, are exciting.
Ethical and financial issues must also be addressed. Ethical deci-
sions will be ever more challenging as DBS technology develops
and is applied to an increasing spectrum of mental and neurological
disorders, including those in which the patients’ capacity to consent
to treatment is limited or absent. Device manufacturers, who seek to
develop enhanced technology while maintaining profits must con-
tinue to operate in a competitive market where no single manufac-
turer has the monopoly over clinical decisions and where there is a
drive to keep costs reasonable to be able to treat more patients
who need DBS.
Stereotactic and functional neurosurgery has been characterized
by innovative thinking in the past (131). New ideas and innovations
will inevitably change the nature of the field in the future. For exam-
ple, adaptive stimulation for PD has been shown to be clinically
more effective and more energy efficient than continuous DBS (132),
and intermittent DBS is also being investigated for conditions with
noncontinuous symptomatology, such as Tourette syndrome (73).
Neural oscillations are being studied to identify pathological signa-
tures, such as the beta band in PD and the theta band in TRD (133)
and furthermore, directional DBS lead types are becoming available
which permit greater flexibility over the shape of the volume of acti-
vated tissue to avoid unwanted side effects due to current spread to
adjacent white matter tracts (134).
Finally, in addition to advancements in DBS technology that will
improve the efficiency and effectiveness of DBS, and the range of
conditions that can be treated, we anticipate changes in technology
that will allow systems to become easier to program and use. For
example, systems that can be programmed remotely will enable
changes to be made without the patient travelling to clinic to physi-
cally meet a member of the DBS team. Developments such as these,
in combination with improved efficiency and longer battery life,
may make DBS technology more accessible including to those in
less economically developed countries, where at the moment, high
treatment costs and poor access to tertiary centres makes DBS an
unrealistic option for many people who would benefit from it.
Authorship Statements
Tipu Aziz and Alexander Green contributed to the conception
and design of the article. Holly Roy contributed to the conception
and design and drafting of the article. Tipu Aziz reviewed the article
critically for important intellectual content. All authors gave final
permission for the version to be published.
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
NOVEL APPLICATIONS FOR DBS
How to Cite this Article:
Roy H.A., Green A.L., Aziz T.Z. 2017. State of the Art:
Novel Applications for Deep Brain Stimulation.
Neuromodulation 2017; E-pub ahead of print.
DOI:10.1111/ner.12604
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