Literature Review

Effectiveness of Deep Brain Stimulation in Treatment of Anorexia Nervosa and Obesity: A

Systematic Review
Timothy I. Hsu1, Andrew Nguyen2, Nithin Gupta3, Nikhil Godbole4, Naveen Perisetla5, Matthew J. Hatter1,
Ryan S. Beyer1, Nicholas E. Bui6, Janya Jagan4, Chenyi Yang6, Julian Gendreau7, Nolan J. Brown6, Michael Oh6

Key words - OBJECTIVE: Anorexia nervosa and obesity are common appetite disorders,
- Anorexia nervosa which may be life threatening if not treated and often coincide with psychiatric
- Appetite disorder
- BMI
disorders. We sought to investigate whether deep brain stimulation (DBS) of
- Deep brain stimulation specific regions within the brain could aid in the treatment of these disorders.
- Obesity This review aims to organize the literature regarding the feasibility of DBS via
- Systematic review
clinical outcomes and synthesize the data on patient demographics and elec-
Abbreviations and Acronyms trode parameters for future optimization.
AN: Anorexia nervosa
- METHODS: PubMed, Scopus, and Web of Science databases were all queried
BMI: Body mass index
BNST: Bed nucleus of the stria terminalis on 7 June 2022 to identify studies reporting the effect of DBS in treatment of
DBS: Deep brain stimulation either anorexia nervosa or obesity. We included studies involving 1) DBS, 2)
MDD: Major depressive disorder treatment of anorexia nervosa or obesity, and 3) body mass index (BMI) as the
NAcc: Nucleus accumbens
NOS: Newcastle-Ottawa Scale primary outcome variable. Case reports, retrospective cohort studies, and ran-
OCD: Obsessive-compulsive disorder domized controlled trials were all eligible for inclusion. Exclusion of articles
SCC: Subcallosal cingulate was based on the following criteria: 1) meta-analyses or systematic reviews or
From the 1University of California, Irvine, School of Medicine,
2) describes diseases other than only anorexia or obesity. Screening of the 999
Orange, California; 2University of Florida, College of articles returned by an initial search yielded 23 studies for inclusion and further
Medicine, Gainesville, Florida; 3Campbell University, School data extraction. Qualitative assessment of included studies was subsequently
of Osteopathic Medicine, Lillington, North Carolina; 4Tulane
University, School of Medicine, New Orleans, Louisiana;
conducted in accordance with Newcastle-Ottawa Scale criteria.
5
University of South Florida, College of Medicine, Tampa,
- RESULTS: We included 23 articles (17 anorexia, 5 obesity) that met our in-
Florida; 6University of California, Irvine, Department of
Neurological Surgery, Irvine, California; and 7Johns Hopkins clusion and exclusion criteria, which included 8 case reports, 13 case series,
University, Department of Biomedical Engineering, Baltimore, and 1 case-control study. Our primary variables of interest were location of DBS,
Maryland, USA
change in BMI after intervention, electrode parameters, and psychiatric
To whom correspondence should be addressed:
Timothy I. Hsu, B.S.
comorbidities. A total of 131 patients were included and analyzed, 118 of those
[E-mail: [email protected]] belonging in the anorexia cohort.
Timothy I. Hsu and Andrew Nguyen contributed equally to
For patients with anorexia, we found that the most common place for DBS was
this study. the subcallosal cingulate followed by the nucleus accumbens, resulting in an
Citation: World Neurosurg. (2022) 168:179-189. overall increase in BMI by 24.82% over the span of a mean 17.1 months. Psy-
https://doi.org/10.1016/j.wneu.2022.09.114 chiatric comorbidities (major depressive disorder, obsessive-compulsive disor-
Journal homepage: www.journals.elsevier.com/world- der, and anxiety) were common in the anorexia cohort. For patients with obesity,
neurosurgery
DBS was most common in the lateral hypothalamus followed by the nucleus
Available online: www.sciencedirect.com
accumbens, resulting in a small decrease in BMI by 3.97% over a mean 17.2
1878-8750/ª 2022 The Author(s). Published by Elsevier Inc.
This is an open access article under the CC BY license
months. Data were insufficient for this cohort to report on additional psychiatric
(http://creativecommons.org/licenses/by/4.0/). comorbidities or calculate the duration from diagnosis to treatment.
- CONCLUSIONS: DBS seems to be a promising solution in addressing
INTRODUCTION
treatment-refractory anorexia, but additional prospective studies are still
Anorexia nervosa (AN) and obesity are needed to confirm this same usefulness for the treatment of obesity. Primary
both severe appetite disorders with high
limitations included the apparent lack of data on DBS for obesity as well as the
mortality.1,2 AN is a debilitating disorder
characterized by extreme caloric dearth of cohort studies assessing efficacy of DBS compared with control
restriction and has the highest mortality treatments. Although these limitations could not be addressed in the current
of any psychiatric disorder, at 5.9%.3,4 review, this study may incentivize future trials to assess DBS in patients with
Similarly, morbid obesity is responsible appetite disorders in a more controlled fashion.
for 300,000 annual deaths in the United
States alone,2 and its incidence has more

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 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

than doubled since the 1980s.5 The beneficial for 79% of patients, there instrumental in establishing DBS as a
pathophysiology of eating disorders is remains a subset in whom AN follows a safe and efficacious treatment for AN,
highly complex, with multiple factors chronic and deadly course.14 Obesity is marking the transition from in vitro
including psychological, social, and similarly curable in many after the evaluations to human trials. After this
environmental factors contributing to the implementation of dietary and lifestyle research, Whiting et al.23 expanded on
pathogenesis.6 An important tool in changes. However, in more serious cases, their preliminary data, showing that DBS
elucidating the altered neurocircuitry obesity is managed with pharmacologic could be safely and effectively used for
involved in AN and obesity is functional therapies, many of which have treatment of refractory obesity. An
magnetic resonance imaging. Although undesirable side effects.15 Still, there increase in research efforts focused on
the mechanisms for these disorders are remains a population in whom more the use of DBS in eating disorders has
not well understood, it is widely accepted invasive surgical management is required. been seen in the past few years;
that the mesolimbic system is altered. It The standard of care in these patients is however, as a relatively new field, the
has been shown that there are structural to decrease the volume of the stomach or results of several ongoing large scale
abnormalities in individuals with AN in decrease the absorption of nutrients. This clinical trials are still pending.
the mesolimbic system; however, there goal is accomplished through bariatric Several studies have investigated DBS
are varying reports regarding increased surgeries, such as gastric bypass, sleeve targets such as the NAcc for its role in
or decreased volume in these areas.7 gastrectomy, and laparoscopic gastric reward homeostasis,24 and the subcallosal
Mechanistically, dopaminergic and banding, procedures that have high cingulate (SCC) for its role in affective
serotonergic pathways are both key complication rates and even higher rates regulation using a range of electrode
players in the pathogenesis of AN. Using of nutritional deficiency.15 Furthermore, parameters to produce successful patient
positron emission tomography, it has each of these therapeutic approaches has outcomes.25 Although the use of DBS has
been shown that individuals with AN a nonnegligible risk of complete relapse.15 shown improved clinical outcome in
have increased dopamine binding in the To address these shortcomings, a novel clinical series and case reports, its
anterior ventral striatum.8,9 A possible therapeutic approach has recently been effectiveness to achieve that aim (as
explanation for this situation could be introduced to directly treat the underlying measured by adverse outcomes and
that in individuals with AN, food intake pathogenesis of these 2 conditions, rather changes in body mass index [BMI],
acts as an anxiolytic and, thus, reduced than mere symptom management. calculated as weight in kilograms divided
food intake may reduce anxious Deep brain stimulation (DBS) has been by the square of height in meters) has
emotions (through lack of postulated to improve clinical outcomes in not been systematically assessed via
neurotransmitter release).10 Similarly to patients with intractable AN and obesity quantitative pooled analysis. Our
AN, obesity functional magnetic by rewiring the dysfunctional reward cir- objective is to evaluate the safety and
resonance imaging of individuals with cuitry that has been linked to these dis- efficacy of DBS in the treatment of adults
obesity has shown increased activity of orders.16 DBS acts to both stimulate and with intractable AN and obesity through
reward-associated areas such as the nu- dampen brain connectivity to mitigate a systematic description of electrode
cleus accumbens (NAcc) and insula.11 disease-maintaining behaviors.17 In 2008, parameters and changes in BMI.
Furthermore, dopamine and serotonin researchers at University of California at
are also implicated as major players in Los Angeles School of Medicine were the
obesity. It is hypothesized that in obesity first to assess the feasibility of DBS for METHODS
there is a reward deficiency syndrome in the treatment of eating disorders,
which an initial increase in dopamine as showing that stimulation of the Eligibility Criteria
a result of eating causes reduced activity ventromedial hypothalamus could alter This systematic review was reported
of receptors leading to overeating, food consumption in nonhuman following the PRISMA (Preferred Report-
similar to what is seen in drug primates.18 In 2013, Dr. Andres Loranzo ing Items for Systematic Reviews and
tolerance.12 Taken together, the cortical of the University of Toronto reported the Meta-Analyses) guidelines.26 We included
areas affected by AN and obesity are results of a phase 1 pilot trial19 showing all studies involving 1) DBS, 2) treatment
similar; however, the mechanistic the safety of DBS in patients with AN. of AN or obesity, and 3) BMI as the
dysfunctions in each respective disorder That same year, Whiting et al.20 also primary outcome variable. Case reports,
are not well understood, making reported preliminary data regarding the retrospective cohort studies, and
treatment difficult. efficacy and safety of DBS in treatment of randomized controlled trials were all
Further complicating management of refractory obesity. After these reports, a eligible for inclusion. The exclusion of
these disorders, both include a subset of 2013 jointly published article was among articles was based on the following
highly intractable cases. In this population, the first reports of the efficacy of DBS in criteria: 1) meta-analyses or systematic
available treatments yield modest results. humans, with Wu et al.21 reporting a reviews or 2) describes diseases other than
Standard conservative treatment of AN 65% increase in body weight in 4 only anorexia or obesity.
consists of pharmacologic therapies and patients with refractory AN; however, it
psychological counseling, including family was not until 2017 that Dr. Loranzo Screening of Studies
therapy and cognitive behavioral therapy.13 reported the 1 year follow-up results of A literature search of the PubMed, Scopus,
Although this treatment regimen is the first clinical trial.22 This research was and Web of Science databases was

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 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

conducted on 7 June 2022 to identify arti- pooled for separate anorexia and obesity reports/series scored 6 within the anorexia
cles reporting the use of DBS for the analysis to provide a comprehensive pa- study set. In the obesity study set, 1 case
treatment of AN or obesity. The same tient volume enabling more robust con- report/series scored 4, 1 case report/series
search strategy “(DBS or deep brain stim- clusions. Microsoft Excel (Microsoft, scored 5, and 4 case reports/series
ulation) AND (obesity OR anorexia OR Redmond, Washington, USA) was collab- scored 6.
anorexia nervosa OR eating disorder OR oratively used by extractors to organize
appetite disorder OR BMI)” was used in all data. If any relevant clinical features were Demographics
3 databases and was developed by 2 re- not reported in an article, it was assumed Data were analyzed in 2 sets: DBS for
viewers (A.N. and T.I.H.). Study selection that these data were not present in that either the treatment of AN or obesity. The
was performed independently by 3 re- patient set. Weighted means were derived sample size across all AN studies was 118
viewers (A.N., T.I.H., and N.P.) using the for data when applicable. patients. The mean age was 30 years.
Rayyan Intelligent Systematic Reviews Gender was reported for 86 patients, of
program.27 Articles with potentially whom 83% were female. The mean dura-
RESULTS
relevant titles and abstracts based on the tion from diagnosis to surgical treatment
inclusion criteria were included. We show the study selection process used via DBS was 16 years. The primary psy-
Simultaneously, these articles were in Figure 1. The initial literature search chiatric comorbidities were major depres-
screened for correct interventions, study identified 999 articles for inclusion. sive disorder (MDD) and obsessive-
types, and outcomes to determine Further screening yielded 381 duplicates compulsive disorder (OCD), with both
eligibility for full-text review. Data extrac- across the 3 databases used (PubMed, being present in 24% of patients, followed
tion was conducted on included full-text Scopus, and Web of Science), which by anxiety disorder at a rate of 12%. Other
articles. When disagreements arose were subsequently removed. Of the comorbidities presented at rates <8%
regarding study selection, a fourth remaining 618 original studies, 584 were (Table 2).
reviewer (N.J.B.) acted as a mediator. excluded because they did not satisfy The sample size across all obesity
Rayyan was used as a collaborative inter- inclusion criteria. The remaining 34 treated studies was 13 patients. The mean
face to record reasons for study exclusion studies were included based on simple age was 40 years. Gender was reported for
after the independent screening. title and abstract screening using Rayyan. 10 patients, of whom 60% were female.
Full-text review then identified another 11 Data were insufficient for the obesity
Qualitative Analysis articles to be excluded because they were cohort to calculate duration from diag-
Assessment of article quality was reported pretrial protocols, animal studies, or other nosis to DBS treatment or psychiatric
on a scale of 1 (highest) to 5 (lowest) using undesired publication types. The final 23 comorbidities.
the Levels Of Evidence categorization articles to be included for data extraction
system developed by the Oxford Center for included 6 describing DBS for obesity and Electrode Parameters
Evidence-Based Medicine.28 The 17 describing DBS for AN. Those In the AN cohort, 15 studies provided the
Newcastle-Ottawa Scale (NOS) was used regarding AN were conducted in Canada number of electrodes applied; all these
for risk of bias assessment. The NOS in 6 studies, China in 3, Spain in 2, Italy in studies reported implantation of 2 bilateral
criteria allowed for a maximum of 4 stars 2, the United Kingdom in 1, Netherlands electrodes. The number of active target
in selection, 2 stars in comparability, and 3 in 1, Sweden in 1, and Germany in 1. For contacts ranged from 2 to 6, with a me-
stars in outcome; the total range was 0e9. obesity, 2 studies were conducted in the dian of 4, among included studies (i.e.,
Case reports and series were analyzed with United States, 1 in Germany, 1 in Brazil, 1 structural targets, e.g., NAcc, may have
NOS cohort guidelines without the appli- in Poland, 1 in Canada. Study design is been in contact with an electrode at more
cation of comparability questions, making shown in Table 1. than 1 point/contact) The mean maxima
their effective range 0e7. Case-control for current, voltage, electric application
studies were analyzed in full with a Qualitative Assessment time, and frequency stimulation settings
maximum score of 9. Two reviewers All 23 included studies were assessed with were 3.64 mA (range, 1.5e5.5 mA), 4.21 V
(T.I.H. and A.N.) conducted this appropriate guidelines to characterize (range, 2.5e8.0 V), 115.87 milliseconds
assessment. their quality based on several criteria (range, 60e350 milliseconds), and 114.6
(Table 1). NOS scores of 7e9 were deemed Hz (range, 130e204 Hz) (Table 3). The
Data Charting Process and Data Items sufficient for the study because they were primary area of stimulation was the SCC
Data were collected independently by 2 in the region of “high-quality” study gyrus in 52% of patients, followed by the
reviewers (A.N. and T.I.H.). Data items according to the NOS guidelines, NAcc in 33%. Electrode parameters were
collected included author, publication including case-control studies. For case also analyzed in the context of each
year, institution of study, study type, reports/series that had a maximum of 7, target brain structure (Table 3).
number of patients, patient characteris- sufficient studies included those that did In the obesity cohort, 4 studies provided
tics, reason for DBS, stimulated area in the not satisfy only 1 item per domain at the number of electrodes applied: 3 of
brain, specific electrode settings, psychi- maximum, with a total score of 5/7. A these studies reported 2 electrodes for
atric comorbidities, initial BMI, final BMI, single case-control anorexia study scored bilateral DBS, with the fourth reporting
percent change in BMI, and postoperative 9. Two case reports/series scored 4, 3 case use of 4 electrodes. The number of active
surgical complications. These data were reports/series scored 5, and 11 case target contacts was 4 for all 4 studies. The

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 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

Figure 1. PRISMA study selection flow diagram.

mean maximum current, voltage, elec- disturbances, and infections were 9%, 5%, to deliver programmed electric stimula-
trode application time, and frequency and 1%, respectively. Homogenous data tion.44,45 Although DBS is a well-
settings were 2.95 mA (range, 2.75e3.75 were not present for other complications established tool for treating various
mA), 5.70 V (range, 3.5e7.0 V), 138.0 including psychiatric postoperative symp- neurologic and kinetic conditions such as
milliseconds (range, 90e208 millisec- toms, device functioning, or incision site Parkinson disease, epilepsy, and depres-
onds), and 120.0 Hz (range, 62.5e185 Hz), healing complications. The obesity cohort sion, with relatively high clinical success,
respectively (Table 3). There were only 2 showed an average decrease in BMI of its use in other disorders is experi-
stimulated areas in this obesity data set, 3.37%, with an average follow-up time of mental.28,46 However, as DBS research
the lateral hypothalamus (60%) and the 17.2 months (Table 4). Data regarding expands into treatment of more
NAcc (40%). Electrode parameters were postoperative complications were refractory conditions such as OCD,
also analyzed in the context of each reported for only 2 studies, although they posttraumatic stress disorder, and
target brain structure for obesity studies included 2 occurrences of infection and Tourette syndrome, our study sought to
(Table 3). insomnia onset. The same outcome investigate the use of DBS in treatment
measures were also analyzed according of AN and obesity, quantifying results in
to target structure (Table 4). terms of increase or decrease in BMI,
Treatment Outcomes and Complications respectively.47,48
The AN cohort showed an average percent
increase in BMI of 24.82%, with an DISCUSSION
average follow-up time of 17.1 months. DBS is a neurosurgical procedure that in- DBS for AN
Presence of postoperative and post- volves the use of electrodes that are AN is a potentially deadly psychiatric dis-
stimulative seizures, electrolyte implanted into specific targets in the brain ease that has no single known

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WORLD NEUROSURGERY 168: 179-189, DECEMBER 2022

TIMOTHY I. HSU ET AL.

Table 1. Newcastle-Ottawa Scale Qualitative Analysis Revised
Selection Comparability Outcome

Selection of
Representativeness the Demonstration that Outcome Comparability of Cohorts Was Follow-Up Adequacy of
Study of the Exposed Nonexposed Ascertainment of Interest Was Not Present on the Basis of the Assessment Long Enough for Follow-Up of
Reference Type Cohort Cohort of Exposure at Start of Study Design or Analysis of Outcome Outcomes to Occur Cohorts Total

Anorexia (cohort)
Israel et al., 201029 CR 1 N/A 1 1 N/A 1 1 1 6
Lipsman et al., CS 1 N/A 1 1 N/A 1 1 1 6
201319
Wang et al., 201330 CS 1 N/A 1 1 N/A 1 1 1 6
17
Zhang et al., 2013 Cohort 1 N/A 1 1 N/A 1 0 0 4
Blomstedt et al., CR 1 N/A 1 1 N/A 1 1 1 6
201731
Lipsman et al., CS 1 N/A 1 1 N/A 1 1 1 6
201722
Fernandes Arroteia CR 1 N/A 1 1 N/A 1 1 1 6
et al., 202032
Liu et al., 202033 CS 1 N/A 1 1 N/A 1 1 1 6
Manuelli et al., CR 1 N/A 0 1 N/A 1 1 1 5
www.journals.elsevier.com/world-neurosurgery

202034
Villalba Martinez et CS 1 N/A 1 1 N/A 1 1 1 6
al., 202035
Vismara et al., CR 1 N/A 1 1 N/A 1 1 1 6
202036
De Vloo et al., CS 1 N/A 1 1 N/A 1 1 0 5
202137
Oudijn et al., 202138 CS 1 N/A 1 1 N/A 1 1 0 5

DBS IN ANOREXIA AND OBESITY

Perez et al., 202239 CS 1 N/A 1 1 N/A 1 1 1 6
40
Scaife et al., 2022 CS 1 N/A 1 1 N/A 1 1 1 6
Obesity (cohort)
Whiting et al., CS 1 N/A 1 0 N/A 1 1 1 6

LITERATURE REVIEW
201320
Harat et al., 201615 CR 1 N/A 1 1 N/A 1 1 1 6

CR, case report; N/A, not available; CS, case series.

183

Continues
 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

pathogenesis. Factors including genetic

Cohorts Total

Total
predisposition, coping mechanisms, sex-

9
ual abuse, and environment may all play a

Assessment Long Enough for Follow-Up of

Was Follow-Up Adequacy of

Ascertainment Same Method of Ascertainment Nonresponse

role in creating a distorted body image,

Rate
leading to large decreases in dietary

1
intake.49 The associated drastic decreases
in BMI are further linked with high
of Outcome Outcomes to Occur

morbidity and mortality. AN is most

Outcome

prevalent in females according to the

for Cases and Controls

current understanding,50 which is
1

1
confirmed in our own study cohort
consisting of 83% females.

1
Because of the complexity and hetero-
geneity of factors contributing to AN
pathogenesis, as well as a tendency to
1

1
present with comorbidities such as MDD
or OCD, AN remains a difficult disease to
Demonstration that Outcome Comparability of Cohorts

of Exposure treat. The mainstay treatment of AN in-

on the Basis of the
Design or Analysis

cludes cognitive behavioral therapy, phar-

Comparability

macologic medications, and simple

1 dietary/nutritional support.51,52 A variety of
N/A

N/A

N/A

N/A

different pharmacologic modalities have

been tested, including antidepressants,
Comparability of Cases and
Controls via Basis/Design

antipsychotics, zinc, and opiates.53 Each

option has been met with variable levels
Nonexposed Ascertainment of Interest Was Not Present

of success, without any consistent

improvement in long-term health or sig-
at Start of Study

nificant decreases in remission rates. This

situation has led to the proposal of DBS as
0

a possible intervention in AN treatment.

Our study found that the SCC gyrus (52%)
was the primary area of DBS for treatment
Study Adequacy of Representativeness Selection of Definition of

of AN, followed by the NAcc (33%). Both

Controls

the SCC (ventral to the corpus callosum)

1
of Exposure

and the NAcc (rostral to the hypothala-

mus) are brain regions commonly involved
Selection

in MDD, and both play a role in the nat-

Controls

ural reward pathway of the body. We

1

found that DBS of these regions resulted

Selection of

in an average postintervention BMI in-

Cohort

N/A

N/A

N/A

N/A
the

crease of 24.82% in patients with re-

of the Cases

fractory AN, with an average follow-up

time of 17.1 months, showing this poten-
1
Representativeness

tial benefit. As parallels are drawn be-

of the Exposed

tween AN and other compulsive/addictive

CR, case report; N/A, not available; CS, case series.
Cohort

psychiatric disorders, a common recurring

1

factor is the activity of the reward pathway

Type Case Definition

of the brain. Targeting locations such as

the SCC and NAcc, which have been
1

shown to be effective in other abnormal

Study
Type

CR

CS

CR

CS

reward-driven disorders, may explain the

Table 1. Continued

Anorexia (case-control)

potential efficacy of DBS for AN as shown

al., 201525 control
Hayes et Case-

by the increase in BMI.

Talakoub et al.,

Tronnier et al.,

Whiting et al.,
Franco et al.,

There is a well-established relationship

between AN and concomitant psychiatric
Reference

Reference
201741

201842

201824

201923

disorders.54,55 In conjunction, our current

study found that psychiatric
comorbidities were common in the AN

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 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

Table 2. Characteristics of Included Studies and Patient Demographics

Mean Sex
Study Level of Total Number Age (Male/
Reference Type Evidence Country of Patients (years) Female) Stimulation Target Clinical Outcomes

Patients with anorexia

BMJ, 201343 Case 3 Canada 6 N/A 0/6 CC DBS resulted in moderate BMI increase; no
series reported relapses
Israel et al., 201029 Case 4 Canada 1 56.00 0/1 SCC DBS resulted in moderate BMI increase; no
report reported relapses
Lipsman et al., Case 3 Canada 6 20.00 0/6 SCC DBS resulted in moderate BMI increase; no
201319 series reported relapses
Wang et al., 201330 Case 2 China 2 23.00 0/2 NAcc DBS resulted in moderate BMI increase; no
series reported relapses
Zhang et al., 201317 Case 3 China 4 16.50 0/4 NAcc DBS resulted in moderate BMI increase; no
series reported relapses
Hayes et al., 201525 Case- 2 Canada 8 35.00 0/8 SCC DBS resulted in moderate BMI increase;
control remission not achieved
Blomstedt et al., Case 4 Sweden 1 60.00 0/1 N/A No consistent weight changes; persistent
201731 report psychiatric symptoms; second surgery performed
Lipsman et al., Case 3 Canada 16 34.00 N/A SCC DBS resulted in moderate BMI increase; no
201722 series reported relapses
Fernandes Arroteia Case 4 Germany 1 42.00 0/1 N/A DBS resulted in a large BMI increase; no reported
et al., 202032 report relapses
Liu et al., 202033 Case 3 China 29 22.80 0/29 NAcc DBS resulted in moderate BMI increase; no
series reported relapses
Manuelli et al., Case 4 Italy 1 37.00 0/1 BNST DBS resulted in moderate BMI increase; no
202034 report reported relapses
Villalba Martinez Case 2 Spain 8 40.75 1/7 4 SCC, 4 NAcc DBS resulted in moderate BMI increase; no
et al., 202035 series reported relapses, mild cutaneous complications
Vismara et al., Case 4 Italy 1 37.00 0/1 BNST DBS resulted in mild BMI increase; no reported
202036 report relapses
De Vloo et al., Case 3 Canada 15 N/A N/A SCC DBS resulted in moderate BMI increase; no
202137 series reported relapses
Oudijn et al., 202138 Case 3 Netherlands 4 39.00 0/4 Ventral anterior limb of DBS resulted in a large BMI increase; no reported
series the internal capsule relapses
Perez et al., 202239 Case 2 Spain 8 40.80 1/7 5 SCC, 1 NAcc DBS resulted in moderate BMI increase; no
series reported relapses
Scaife et al., 202240 Case 3 United 7 37.00 1/6 NAcc DBS resulted in moderate BMI increase; no
series Kingdom reported relapses
Total (mean) mean 118 30.42 3/83
Patients with obesity
Franco et al., Case 2 Brazil 4 N/A 2/2 LH DBS was largely ineffective; BMI increased
201842 series slightly after treatment
Harat et al., 201615 Case 4 Poland 1 19.00 0/1 NAcc DBS resulted in moderate BMI decrease; no
report reported relapses
Talakoub et al., Case 4 Canada 1 19.00 1/0 LH DBS was largely ineffective; no change in BMI
201741 report after treatment

N/A, not available; CC, corpus callosum; DBS, deep brain stimulation; BMI, body mass index; SCC, subcallosal cingulate; NAcc, nucleus accumbens; BNST, bed nucleus of the stria terminali; LH,
lateral hypothalamus.
Continues

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 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

Table 2. Continued
Mean Sex
Study Level of Total Number Age (Male/
Reference Type Evidence Country of Patients (years) Female) Stimulation Target Clinical Outcomes
Tronnier et al., Case 4 Germany 1 47.00 0/1 NAcc DBS resulted in moderate BMI decrease; no
201824 report reported relapses
Whiting et al., Case 3 United 3 51.67 1/2 LH DBS resulted in mild BMI decrease; no reported
201923 series States relapses

N/A, not available; CC, corpus callosum; DBS, deep brain stimulation; BMI, body mass index; SCC, subcallosal cingulate; NAcc, nucleus accumbens; BNST, bed nucleus of the stria terminali; LH,
lateral hypothalamus.

cohort, with MDD and OCD being the DBS for Obesity BMI, with an average follow-up time of
most frequent (24%), followed by anxiety Obesity is a major health concern in the 17.2 months. These early results are
disorder (12%), and other psychiatric United States, with the prevalence of adult promising, because a major issue with
disorders (8%). Although this interwoven morbid obesity at 21%.59 Although the rate non-CNS surgical or pharmacologic treat-
dynamic could pose a complication for of morbid obesity has increased for both ment of obesity is the loss of long-term
conventional pharmacologic or behavioral males and females, there remains a effectiveness.59 If the proven decrease in
treatment, these accompanying higher prevalence in women and older BMI were to continue beyond the year
psychiatric comorbidities have been persons; this parallels the composition of and a half follow-up period, DBS might
treated using DBS as well.56-58 With the the cohort of this study, consisting of be a viable alternative to the aforemen-
low rate of minor side effects found in 60% females and a mean age of 40 tioned treatment methods. Further study
our study (seizures, 9%; electrolytic years.59 The multifaceted pathogenesis of of the efficacy of DBS as a long-term
disturbances, 5%; and infections, 1%), obesity makes treatment complex, and treatment for obesity is warranted. On
future studies should investigate the necessitates the need for newer examination of the brain areas stimulated
efficacy of DBS when jointly treating AN treatments such as DBS. Our analysis by DBS in the obesity cohort, the lateral
and other psychiatric comorbidities. found that there was a 3.97% decrease in hypothalamus (involved in hunger) was

Table 3. Electrode Parameters

Median Number of Median Number of Active Maximum Maximum Maximum Application Maximum
Electrodes Applied Target Contacts Current (mA) Voltage (V) Time (seconds) Frequency (Hz)

Patients with anorexia 2 4 (2e6) 3.64
1.80 4.21
1.90 115.87
97.78 (60e350) 147.57
27.63
(1.5e5.0) (2.5e8.0) (130e204)
Subcallosal cingulate 2 2 (2e4) 3.80
1.06 7.45
0.71 90.09
0.58 (90e91) 130
(3.5e5.0) (7.0e8.0)
Nucleus accumbens 2 2 (2e4) 3.50 2.68
3.89 115.52
21.21 (90e120) 156.36
21.21
(2.5e8.0) (130e160)
Bed nucleus of the stria 2 N/A N/A N/A 60 130
terminali
Ventral anterior limb of the 2 4 N/A 4.45 90 130
internal capsule
Corpus callosum 2 N/A N/A N/A N/A N/A
Patients with obesity 2 (2e4) 4 2.95
0.71 5.70
1.89 137.90
57.87 (90e208) 119.50
43.45
(2.75e3.75) (3.5e7.0) (62.5e185)
Nucleus accumbens 4 N/A 3.75 4 149
83.44 (90e208) 130
Lateral hypothalamus 2 4 2.75 6.13
2.47 135.13
52.11 (90e180) 116.88
61.36
(4e7) (63e185)

Median values are provided with the range in parentheses and means are provided with the standard deviation, and range in parentheses. If a reported statistic had only 1 data point, this
could not be reported with ranges, standard deviations.
N/A, not available.

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 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

Limitations
Table 4. Treatment Outcomes The limitations of this study include the
% Change in Body Mass Complications Follow-Up lack of randomized studies in the obesity
Index* (%) (months)* cohort, which did not allow for analysis of
psychiatric comorbidities or postoperative
Patients with anorexia 24.82
16.04 39.2 17.1
10.36 complications. It is also worthwhile to
Subcallosal cingulate 18.73
10.47 N/A 19.81
19.81 highlight the apparent lack of published
data on DBS for treatment of obesity,
Nucleus accumbens 31.65
20.30 N/A 18.85
8.84
considering that the global proportion of
Bed nucleus of the stria terminali 13.76
3.69 N/A 9.00
4.24 treatment-refractory morbid obesity cases
Ventral anterior limb of the internal 36.00 N/A 12.00
10.36 is 20%.65 Most of the included studies
capsule were case reports and case series, which
Corpus callosum 46.15 N/A 9.00
10.36 may skew the data toward more
significant treatment effects for DBS. As
Patients with obesity e3.37
11.74 23 17.2
12.63 the nature of the studies lends itself to
Nucleus accumbens e12.15
17.18 25 13.00
1.41 publication bias, favoring presentation of
Lateral hypothalamus e0.33
7.27 12.5 16.13
20.51 significant results, the potential for
overestimation should be acknowledged.
*Values reported as either means with standard deviations or sole proportions. Our study suggests support of use of
DBS for anorexia disorders, urging
further exploration for this disorder. The
granularity of provided data seldom
stimulated in 60% of patients, and the optimal stimulation parameters and tar- encompassed the subtype of appetite
NAcc (involved in the reward pathway) gets. By investigating the most effective disorder regarding AN, often categorized
was stimulated in 40% of patients. electrode implantation methods and as a restrictive or purging subtype. The
Although the lateral hypothalamus regu- stimulator programming settings for DBS behavioral variation within the two has
lates hunger, the ventromedial hypotha- in treatment of these 2 disorders, future been linked to a lower level of mental
lamic nucleus regulates satiety, and its studies might be able to better establish eating disorder psychopathologies in the
role in DBS treatment of obesity is being the efficacy of DBS for AN and obesity. latter (clinically).66 Those with purging
investigated in clinical trials.60-62 anorexia tend to show higher
There are several trials assessing the psychological aberrancies regarding
efficacy of DBS for the treatment of re- DBS Safety appetite, including abnormal eating
fractory obesity as measured by energy Although safety of DBS has not been restraints and morphic concerns. This
intake and expenditure. Of the stimulated explicitly studied in the literature exten- situation implies a potential discrepancy
regions indicated, only the lateral hypo- sively, complication rates in studies using in the clinical progression of the two,
thalamus was specified. In consideration DBS to treat specific diseases have shown making it worthwhile to specify the exact
of the data volume for the obesity cohort, it to be a relatively safe process, with few subtypes in future studies. In future
it would be valuable to encourage the use adverse long-term side effects.63,64 This reviews, it would be valuable to conduct
of DBS for patients with refractory morbid finding was confirmed in our own review a systematic review and formal meta-
obesity as their treatment options become studies, in which various cutaneous analysis comparing DBS and non-DBS
exhausted. This strategy would supple- symptoms such as ulceration resulting treated groups via inclusion of random-
ment the current trials in providing more from infection of the surgical electrode ized controlled trials or pooled cohort
robust data in future analyses and reviews. site were the main complications. data.
As more research on the use of DBS Although a few articles have documented There remains a paucity of data directly
emerges in the treatment of appetite dis- certain instances of preoperative and comparing the efficacy of DBS for appetite
orders such as AN and obesity, the need intraoperative bouts of anxiety and panic disorders with other treatment modalities.
for standardization of baseline parame- attacks, none of the studies reported any As these data accumulate, it would be
ters, including number of electrodes, adverse long-term neurologic or muscu- valuable to explore a similar question in
maximum current, voltage, electrode loskeletal abnormalities postoperatively. the form of more robust statistical anal-
application time, and frequency settings Thus, DBS as a whole seems to be a well- ysis. We were also unable to control for
should be established. Although exact tolerated and useful procedure in dealing variation in surgical technique, experi-
values may be unattainable, a generaliz- with otherwise treatment-refractory dis- ence, and other intrinsic characteristics
able range may be determined. Although eases. More longitudinal studies are war- such as the mental fortitude of the patient
the number of electrode brain targets per ranted to explore the complications sample. An inherent limitation regarding
patient was consistent in the AN cohort of associated with DBS of specific brain re- the subject of psychiatric diseases is the
this study, it was not consistent for the gions to refine safety protocols and complex process of quantifying the effects
obesity cohort, further establishing the improve efficacy as procedural use of DBS of patient disposition in outcome mea-
need for improved understanding of continues to expand. sures, or rather lack thereof.

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 LITERATURE REVIEW
TIMOTHY I. HSU ET AL. DBS IN ANOREXIA AND OBESITY

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