Deep Brain Stimulation

for Psychiatric Disorders

-An Update
Presenters : Dr. Mahendra P. Sharma
Dr. Naveen Anand
Senior Resident : Dr. Anish Shouan
Chairperson : Dr. S.M. Singh
 Outline of Part 1

What is Deep Brain Stimulation(DBS)

Functional and Stereotactic Neurosurgery
Road To Deep Brain stimulation(DBS)
Why DBS
How it is done and its advantages
Indications
Side effects
 What is DBS?
Electrical pulses are delivered to specific brain
areas through implanted electrodes and a pulse
generator.
Type of Neuromodulation which is done through
Functional Stereotactic surgery
Different from other stimulation measures:
Vagus nerve stimulation - stimulation is done
to brain through the Vagus nerve
rTMS and Transcranial direct current
stimulation (TDCS) Stimulation is through
Scalp
(CTP 10th Edition)
 Functional and Stereotactic Neurosurgery

Functional Neurosurgery: The surgical destruction or chronic modulation of

a part of the brain as treatment of a physiological or psychological disorder
Theres no demonstrable lesion unlike that in the neurological diseases
(Read and Greenberg, 2009)

Stereotactic Surgery - Locating targets of surgical interest within the brain

relative to an external frame which allows the locations in brain to be more
precisely identied
(Galloway and Maciunas, 1990)
Road to Deep Brain Stimulation (DBS)
1930s - Egas Moniz performed the
1980s- DBS introduced as an rst frontal lobotomy
effective treatment in PD 1940s - Freeman and Watts
1990s- Because of side-effects of performed frontal lobotomies in US
psychotropic medications and
availability of safer techniques of
surgery, role of DBS in psychiatry
studied by Nuttin et als DBS
study on treatment refractory1950s- With the invention of
OCD psychotropic drugs and their broad
application, the interest for surgery
waned
- 1st evidence of DBS for Psychiatric
disorder. Faced with immense Criticism

(Schlapfer TE and Bewernick BH, 2010)

 Why Deep Brain Stimulation

Serious side effects of Psychosurgery

Irreversibility of Psychosurgery
As DBS was perceived as reversible and because stereotactic ablative
surgery for psychiatric illness suffered from the legacy of the lobotomy era,
DBS became a legitimate and acceptable tool for surgical treatment of
psychiatric illnesses
(Hariz M., 2012)
 Components of Deep Brain Stimulation

Three Major Components

Implanted pulse generator (IPG)- battery
powered neurostimulator, which sends
electrical pulses to the brain to interfere with
neural activity at the target site
Lead- coiled wire with electrodes placed in
the target sites of brain
Extension- insulated wire that connects the
Lead to the IPG, which is placed
subcutaneously below the clavicle or in some
cases, the abdomen
(Eljamel S, 2013)
 Procedure

All three components are surgically

implanted into the body
A hole about size of quarter is drilled in
the skull and the electrode inserted
IPG and Extension are then installed
Brief (0.06 milliseconds) pulses
administered continuously at high
frequency (>100 Hz)
(CTP 10th Edition)
Asleep DBS

Done with help of

intraoperative imaging via
CT/MRI machine
Obviates the need for
intraoperative
physiological and awake
monitoring
 Study to compare Sleep DBS with Awake DBS

Inclusion criteria included patient number >15, report of precision

While
and/or DBSoutcomes
clinical under general anaesthesia
data, and may lead
at least 6 months oftofollow-up
Therelower
wereoverall complication
145 studies, rates(Especially
16 of which were under general
Intracerebral haemorrhage and infection) , awake
anaesthesia
DBS may lead
No significant to lessintreatment-induced
difference mean operating time side effects
Asleep DBS optimises lead placement by taking advantage of
However There
intraoperative were
imaging, no significant
tighter differences
blood pressure controlinand
clinicalpatient
decreased motor movement
outcomes between the two techniques.

(Allen L Ho et al., 2017)

 Cost and Recovery Time in DBS

Costs about Rs 11 lakhs in India (In US around Rs 45 Lakhs)

After surgery, swelling of the brain tissue, mild disorientation and sleepiness
can be experienced
After 24 weeks, there is a follow-up to remove sutures, turn on the
neurostimulator and program it
The batteries in the pulse generator must be replaced every three to five
years
Done with a small incision as an outpatient procedure
http://www.dheerajbojwani.com/deep-brain-stumulation-therapy-low-cost
advantages-India.html
 Advantages of DBS

Clinical effects can be achieved without irreversible lesioning

Brain activity can be changed in a direct, controlled manner
Opportunity to continuously adjust stimulation variables for each patient in
order to optimize therapy
Patient can turn off stimulation immediately if side effects occur
Is the only neurosurgical method that allows blinded studies for therapy
control
(Cleary et al., 2015)
 1st Instance of DBS in Psychiatry

Experimental neuromodulation via brain electrodes was first tried in

patients with psychiatric disorders during the 1950s by Robert G. Heath,
Russel R. Monroe and Walter A. Mickle
Stimulated the electrode placed in Amygdaloid nucleus of patient of
Schizophrenia
Stimulation of Amygdaloid nucleus was associated with strong emotional
response
(Health G. et al., 1955)
 Testing Protocol in DBS

Baseline:
Psychiatric
Medical
Full Neuropsych
MRI

3 Months 6 Months 12 Months

Psychiatric Psychiatric Psychiatric
Part Neuropsych Part Neuropsych Full Neuropsych
PET PET PET

Nuttin B et al., 2014

 Neuropsychological Evaluation

Frontal / Executive Functions

Information Processing Speed
Learning and Memory
Manual Motor Skills
Emotional Processing

Nuttin B et al., 2014

 Proposed Mechanism of Action of DBS

Depolarisation blockade of current dependent ion channels leading to a

functional lesion of the surrounding tissue
(Beurrier C et al., 2001)
Exhaustion of the neurotransmitter pool or synaptic inhibition
(Dostrovsky JO et al.,2000; Zucker RS, Regehr WG
2002)
Neural activation in the stimulated areas
(Jech R et al., 2001)
 Factors affecting effect of DBS on Neurons

Physiological properties of the surrounding brain tissue

Geometric conguration of the electrode as well as the distance and
orientation of the neuronal elements towards the electrode
(Kringelbach ML et al., 2007)

Stimulation parameters (frequency, amplitude, pulse width, duration)

Nonlinear relationship between stimulus duration (pulse width) and
amplitude (voltage/current)
(Ranck JB Jr 1975)
 Selection of Stimulation Parameters for DBS

Several challenges to selection of optimal stimulation parameters for DBS:

Large number of degrees of freedom in stimulus parameters and electrode
geometries
Variability and uncertainty in electrode positioning
Commonly used DBS parameters are 60130 Hz, 60200
Unknown effects
s pulse width,of stimulation
and 210 volt
Complexity and diversity of responses to DBS
(Kuncel A.M. and Grill W.M.,2004)

Most of the stimulation parameters are vague and involve turning

parameters up until the effects are desirable or side effects occur
(Krack et al.,2002)
 Changes with DBS

Depression Alzheimers Disease

(Mayberg et al., 2005; Laxton et al., 2010)

 What is DBS used for?
Approved as a treatment for:
Parkinsons Disease
Essential Tremor
Dystonia
Obsessive Compulsive Disorder (OCD) (Under Humanitarian Device
Exemption)
Investigational use in:
Major Depressive Disorder (MDD)
Tourette Syndrome
Addiction
Anorexia Nervosa
Schizophrenia, Autism, Anxiety disorders
(Graat et al., 2017)
Use of DBS In OCD
 Neurocircuitry model of OCD

Dysfunctions in a network connecting the cortex and basal ganglia

Overactivation of the direct pathway of the cortico-striatal- thalamic-
cortical loop
Changes in orbitofrontal cortex, anterior cingulate cortex and caudate
nucleus
(Baxter LR 1990; Baxter LR et al., 2001)
 Neurocircuitry model of OCD

Hyperactivity of the CSTC-circuit in OCD is most likely mediated by

decreased serotonin levels and increased levels of striatal dopamine
(Perani et al., 2008; Simpson et al., 2003)

Therapeutic effects for OCD might be mediated by restoring prefrontal

serotonergic neurotransmission by DBS
(Van Dijk et al., 2012)
DBS RCT in OCD
 Sub-thalamic Nucleus Stimulation in Severe OCD
Author Methodology Procedure Result
Mallet L et 10-month time period N=16 YBOCS score after stimulation was
al., 2008 significantly much lower than the score after
Crossover, double-blind, Target Site- Sub sham stimulation (mean [SD], 198 vs. 287;
(New multi-center study
There might Thalamic
be reductionP = 0.01)
in the
England
symptoms Nucleus
of severe forms of OCD
Journal of Assessing the efficacy and GAF score was significantly higher (5614 vs.
but it is associated with a
Medicine) safety of stimulation of the 438, P = 0.005)
substantial
subthalamic nucleus risk of serious adverse
events No effect on depression, and anxiety

15 serious adverse events, including 1

intracerebral haemorrhage and 2 cases of
infection
Deep Brain Stimulation of Nucleus Accumbens in Treatment Resistant OCD
Author Methodology Procedure Result
Huff et al., 12-month time period N=10 Mean Y-BOCS scores decreased
2010 signicantly from 32.2 (4.0) at baseline to
Double-blind sham- Target Site- 25.4 (6.7) after 12 months (p = 0.012)
(Clinical controlled crossover
Evenstudy
thoughNucleus Five out
the benefit within theof ten patients showed a decrease
Neurology rst year Accumbens
is lower compared of more
withthan 25%
and 3 months of DBS followed One patient showed a decrease in Y-BOCS
other studies, unilateral stimulation
Neurosurgery by 3 months of sham severity greater than 35%
of NAC still shows a marked benet
) stimulation, or vice versa Depression, global functioning and quality
and then DBS was in 50% of the patients of life improved within one year
continued unblinded for all In contrast, anxiety, global symptom
patients severity and cognitive function showed no
signicant changes
 Deep Brain Stimulation of Nucleus Accumbens in Treatment Refractory
OCD
Author Methodology Procedure Result
Denys et al., Double-blind sham- N=16 In the open phase, the mean Y-BOCS
2010 controlled crossover study score decreased by 46%, from 33.7 at
Target Site- baseline to 18.0 after 8 months
(Arch. Of Open 8-month treatment Nucleus 9 of 16 patients were responders, with a
General Bilateral
phase, followed by a deep brain stimulation
Accumbens of
mean Y-BOCS score decrease of 23.7, or
the nucleus accumbens may
Psychiatry) double-blind crossover 72%be an
effective and safe treatment
phase with randomly for
In the sham-controlled phase (n=14), the
assigned 2-weektreatment-refractory
periods OCD mean Y-BOCS score difference
of active or sham between active and sham stimulation
stimulation, ending with was 8.3 or 25%
an open 12-month Depression and anxiety decreased
maintenance phase significantly(difference of score of 11.3
and 12.1 respectively in active vs sham)
 Meta-analysis on OCD

Total studies- 31 with N=116 patients

Target areas of the ventral internal capsule/ventral striatum, the Nucleus
accumbens, Subthalamic nucleus, Anterior limb of the Internal Capsule and
Inferior Thalamic Peduncle
Most published studies focus their
Global percentageattention
of Y-BOCSon reduction was estimated
symptom reductionat 45.1% and global
percentage of responders
after DBSat 60.0%
and scarce data is
available
Higher response ratios for changes
and greater on quality in
Y-BOCS-decrease ofOCD patients with a
later age of onset life in these severally ill patients
No statistical difference in improvement amongst the different areas of
stimulation
(Alonso et al., 2015)
DBS studies in OCD
Use in Depression
 Network Model of Depression

Integrates: Biochemical, Electrophysiological, Imaging and animal studies

Depression as a result of dysregulation of limbic-cortical connections:
Cognitive symptoms (e.g., apathy, anhedonia, hopelessness, decits in
attention and executive function) - Changes in dorsal brain regions
(dorsolateral prefrontal cortex, inferior parietal cortex and striatum)
Vegetative and somatic aspects of depression (sleep disturbance,
appetite, endocrine dysregulation): Changes in ventral areas
(hypothalamic-pituitary-adrenal axis, Insula, subgenual cingulate and
brainstem)
(Mayberg HS., 1991)
 Road to DBS in Depression

Studies in OCD noted that DBS of striatal targets (NAc, VC/VS, and ALIC)
had a prominent antidepressant effect, often unrelated to the decrease in
obsessive-compulsive symptoms
(Denys et al., 2010; Greenberg et al.,2010)
 Target Areas in Depression
Target Hypothesis Hypothesis based on
Subgenual cingulate Reduction of hypermetabolic activity Functional neuroimaging
cortex (SCC) following successful treatment with ndings
(Mayberg et al., 2005) antidepressants
Anterior limb of Inactivation of dysfunctional connections Clinically effective
Capsula interna neurosurgical interventions
for OCD and depression
Nucleus Accumbens Central structure in the reward system, Clinical experience
(Sesack & Grace, 2010) modulation leads to improvement of neurobiology of reward
anhedonia system
Habenula Inhibition leads to upregulation of Functional neuroimaging
(Sartorius et al., 2010) serotonergic, ndings animal studies
noradrenergic,dopaminergic system
and downregulation of HPA axis
Thalamus Dysfunctional connection between Functional neuroimaging
(Jiminez et al., 2005) thalamic system and orbitofrontal in ndings animal studies
depression.
RCT regarding use of DBS In Depression
Randomized Sham-Controlled Trial of Deep Brain Stimulation of the
Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant
Depression
Author Methodology Procedure Result

Dougherty Patients randomized to N=30 No significant difference in response

et al.,2014 active versus sham DBS rates between the active (3 of 15
(Biological treatment in a blinded Target Site- subjects; 20%) and control (2 of 14
Study failed to demonstrate a
Psychiatry) fashion for 16 weeks, Ventral subjects; 14.3%)
significant
followed by an open-
difference between
Capsule/Ventr No significant difference between
the
label continuation active
phase al and sham-control
Striatum change in MADRS scores as a
groups during the blindedcontinuous
phase measure upon completion of
of the study the 16-week controlled phase of the trial
The response rates at 12, 18, and 24
months during the open-label
continuation phase were 20%, 26.7%,
and 23.3%, respectively
DBS of Ventral Anterior Limb of Internal Capsule for TRD- Randomised
Control Trial
Author Methodology Procedure Result

Bergfeld et 52-week open-label N=25 In optimization phase:

al., 2016) trial during which (16 entered Mean HAM-D-17 scores decreased from
(JAMA patients received Randomised 22.2 at baseline to 15.9 (P = .001)
Remission
Deep brain stimulation
HAMDof<7the vALIC resulted in
Psychiatry) DBS phase) Montgomery-sberg Depression Rating
Responders
decrease of depressive
>50% symptoms
decrease ininHAMD
16 of 25
A randomized, Target Site- Scale scores from 34.0 to 23.8 (P < .001)
Partial
patients
double-blind, 12-andresponder
was tolerated
Ventral 25-50%
welldecrease in
(6 patients(25%)
week crossoverHAMD were partial
Anterior Limb responders
HDRS scores andwere significantly lower
phase,10 patients
with 16 entered
(40%) randomised
of were responders,
Internal phase (9out
during theofactive phase (mean = 13.6)
patientswhich responders
5 achieved
receiving and
remission
Capsule7 non responders)
than during the sham phase (mean =
active treatment 23.1)
followed by sham MADRS score of 21.3 following the
or vice versa active and of 34.1 following the sham
phase
DBS Studies in Depressive Disorder
 Ongoing Study For DBS in Depression

Interim analysis of an ongoing pilot study

With results of four patients treated with DBS of the Medial Forebrain
Bundle with a 26 week follow-up
During the sham phase no significant changes in mood were observed
Seven days post active stimulation, three patients had >50% symptom
decrease
Two out of three patients continued to have a > 80% symptom decrease at
26 weeks follow
(Fenoy et al., 2016)
 Review on effectiveness of DBS in Depression and
Anxiety in Parkinson's disease
Couto MI et al., 2014 Gkbayrak NS et al., 2014

Meta-analysis Review of RCT

Improvement of depression and Findings are mixed for the
anxiety isapparent
Both theafter DBS, more
analysis commented effectiveness
upon shortofterm
DBS as a treatment for
pronouncedbeneficial
in the short-term,
effects of DBS on depression
Depression,in which
PD
however thewaned
effect wanes
in due in later of time
course
assessment
Superiority of Medical treatment of Effectiveness varies with the Target
Anxiety over DBS and vice versa in sites
case of Depression
 Tourettes Syndrome

Caused by dysfunction of the Cortico-Strial-Thalamo-Cortical circuit

Hypothesis based on neuroimaging studies showing enhanced connectivity
between the basal ganglia and cortex in patients of Tourettes Syndrome
(Cheng et al., 2014; Worbe et al., 2015)
 Meta-analysis on role of DBS In TS
57 studies; N=150
Thalamus- 78
Anteromedial part of the Globus Pallidus
internum (GPi-am)- 44
Posteroventrolateral part of the GPi (GPi- 81% the TS patients showed at least a 25%
pl)- 20
Anterior limb of Internal Capsule 9
Both GPi-am and GPi-pl- 2
GPi with no further description-2
Sub Thalamic Nucleus- 1
Average 52.68% (p <0.001) reduction on
the Yale Global Tic Severity Scale (YGTSS)
Median score declining from 83.0 to 35.0 at
last follow-up
reduction of the YGTSS
54.0% of patients improved by more than
50%
Significantly greater mean reduction in
Vocal tics than Motor tics (50.72% vs
44.96% reduction)
(Baldermann et al., 2015)
Other DBS Studies in Tourettes Syndrome
 Role of DBS in Addiction

Deep Brain Stimulation of Nucleus accumbens

Nicotine addiction (Kuhn et al., 2009; Mantione et al., 2010)
Alcohol dependence
Alcohol Dependence- Nac DBS on Five patients
(Voges et al., 2013)
Cocaine dependence
(average follow-up 38 months) (Ferreire et al., 2015)
Mode of action
All unclear
experienced significant improvement in craving
Two
Reducing patients remained
the rewarding completely
quality of the abstinentperhaps
abused substance, for by replacing
the desiremore
for the substance
than 4 yearswith stimulation, i.e, intracranial self stimulation
(Jacques S 1979; Olds & Fobes 1981)
Decreasing cue-associated reinstatement of addictive behaviour
(Muller et al., 2009; Vassoler et al., 2008)
 Anorexia Nervosa (AN)

Marked by compulsivity and impaired emotional processing

Strong Involvement of cotico-limbic system
Pilot Trial of DBS on Subgenual Cingulate Cortex
Mean BMI increase of 12% along with a 40% reduction of depression scores
(HDRS) in six treatment-refractory AN patients at 6 months follow-up
At 9 months post-DBS, three of the six patients had substantially improved
core symptoms of AN accompanied by weight gain and an increase in QoL
PET scans showed that DBS of the SCC led to increased activity in parietal
regions, which are hypometabolic in AN patients
(Lipsman & Lozano, 2014)
 Other DBS studies in Anorexia Nervosa

Stimulation of the Nac (N=4)

At final follow up (mean 3 years), in all of the four, weight exceeded 85% of
the expected body weight thus no longer met the diagnostic criteria
(Wu et al.,2013)
Reduction of AN symptoms following DBS of the VC/VS for refractory OCD
BMI normalized from 17.4 kg/m2 to 19.6 kg/m2 and less distressed with
regard to caloric intake and weight
(McLaughlin et al.,2013)
 Autism Spectrum Disorder
Three case-reports of DBS in treatment refractory autism spectrum disorder
(ASD)
Author Target Effect
site
Sturm et al., Basolateral After 24 months, Self Injurious behaviour, core symptoms in
2012 (N=1) nucleus of emotional, social, and cognitive domains improved
the
amygdale
Stocco and Globus 1st Patient - 13 months post-DBS, score on the Hopkins motor
Baizabal- Pallidus stereotypy rating scale (JHMRS) decreased by 91.3% (from 46
Carvallo, 2014 internum to 4)
(N=2) 2nd Patient- At 3 months, an initial decrease of his JHMRS score
from 67 to 19 however, at 6 months post-surgery, his
stereotypies gradually returned to baseline
 Role of DBS in Schizophrenia

The first medical application of DBS in an experimental setting was in a

patient with schizophrenia (Heath et al.,1955)
For around 60 years no further research
Case report, wherein treatment-refractory schizophrenia treated with DBS
of the NAc
At 44 weeks follow-up
61.54% reduction on the Positive and Negative Syndrome Scale [PANSS],
positive factor (13 to 5)
33.4% reduction in PANSS negative factor (18 to 12)
(Corripio et al., 2016)
 On going RCT -Deep Brain Stimulation in Treatment-
resistant Schizophrenia

Prospective, randomized, double-blind, Sham controlled clinical trial

6 out of 8 were responders (PANSS reduction >25%)
N=8 After Stimulation, mean PANSS total scores were
Target area- 58.7%,
Nucleuswith
Accumbens
scores ofand
15.0(23)
Subgenual
on theCingualate
positive Cortex
Preliminary results
subscale, 14.7(25)
support theon the negative
hypothesis
29.0(40) on the general subscale
thatsubscale,
DBS can and
be an effective
therapy to treat refractory schizophrenia
The sham phase is still in process
(Roldan A et al., 2017)
 Issues with the Methodology of Studies

Small patient numbers

Different areas of brain targets
Variable follow up times
Impossibility of double blind placebo controlled methods

(Barrett K, 2017)
 Tiding over the Deficiencies..

Though the issues might be various with the studies, still the importance of
DBS cannot be negated as:
The patients, though the improvement rate may vary, had severe conditions
that failed to respond to various other modalities of treatment
Some of the targets were proved to be effective in lesion based surgery
DBS allows to be a natural double blind method as the stimulating device can
be switched on or off without the knowledge of the patient or the assessor
(Barrett K, 2017)
 Side Effects

Surgical Procedure Device and Equipment Stimulation

Seizure(1-2%) 5% to 15% Most common
Hemorrhage(1-5%) Fracture of leads Paresthesias
Infection (2% to 25%) Disconnection Muscle contraction
Lead movement Dysarthria
Malfunction Diplopia
Mood changes
Memory defects
Defects of cognition
(Nuttin et al., 2014)
(Alonso et al., 2015)
 Conclusion
DBS a legacy of Psychosurgery
Has credit of being reversible, modifiable
and with minimal trauma as compared to
psychosurgery
The results of DBS for psychiatric
disorders that have been published to
date are encouraging
They open up a new perspective in the
treatment of otherwise intractable
disorders
Much robust evidence is needed for the
efficacy and mechanism of action of DBS
for psychiatric disorders
Thank You