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Peer-Review Reports

Deep-Brain Stimulation for Anorexia Nervosa


Hemmings Wu1, Pieter Jan Van Dyck-Lippens1, Remco Santegoeds1,2, Kris van Kuyck1, Loes Gabriëls 3,
Guozhen Lin 4, Guihua Pan 5, Yongchao Li 6, Dianyou Li7, Shikun Zhan7, Bomin Sun7, Bart Nuttin1,2

Key words 䡲 OBJECTIVE: Anorexia nervosa (AN) is a complex and severe, sometimes
䡲 Anorexia nervosa
life-threatening, psychiatric disorder with high relapse rates under standard
䡲 Bed nucleus of stria terminalis
䡲 Deep-brain stimulation treatment. After decades of brain-lesioning procedures offered as a last resort,
䡲 Nucleus accumbens deep-brain stimulation (DBS) has come under investigation in the last few years
Abbreviations and Acronyms
as a treatment option for severe and refractory AN.
5-HT: Serotonin 䡲 METHODS AND RESULTS: In this jointly written article, Sun et al. (the
AN: Anorexia nervosa
AVP: Arginine-vasopressin Shanghai group) report an average of 65% increase in body weight in four severe
BMI: Body mass index and refractory patients with AN after they underwent the DBS procedure
BNST: Bed nucleus of the stria terminalis (average follow-up: 38 months). All patients weighed greater than 85% of
CRH: Corticotropin-releasing hormone
expected body weight and thus no longer met the diagnostic criteria of AN at last
CT: Computed tomography
DBS: Deep-brain stimulation follow-up. Nuttin et al. (the Leuven group) describe other clinical studies that
HAM-A: Hamilton Anxiety Rating Scale provide evidence for the use of DBS for AN and further discuss patient selection
MRI: Magnetic resonance imaging criteria, target selection, and adverse event of this evolving therapy.
NuAcc: Nucleus accumbens
OCD: Obsessive-compulsive disorder 䡲 CONCLUSION: Preliminary results from the Shanghai group and other clinical
PET: Positron emission topography centers showed that the use of DBS to treat AN may be a valuable option for
Y-BOCS: Yale-Brown Obsessive-Compulsive Scale
weight restoration in otherwise-refractory and life-threatening cases. The nature
From the 1Laboratory of of this procedure, however, remains investigational and should not be viewed as
Experimental Neurosurgery and
Neuroanatomy, Katholieke Universiteit Leuven, Leuven, a standard clinical treatment option. Further scientific investigation is essential
Belgium; 2Department of Neurosurgery, University Hospitals to warrant the long-term efficacy and safety of DBS for AN.
Leuven, Leuven, Belgium; 3Department of Psychiatry,
University Hospitals Leuven, Leuven, Belgium; 4Department
of Psychology, Shanghai Jiaotong University Ruijin
Hospital, Shanghai, People’s Republic of China; 5Shanghai been proposed. Drury (24) reported a case tactic form of modern deep-brain stimula-
Mental Health Center, Shanghai, People’s Republic of study of transorbital leucotomy for the tion (DBS).
China; 6Shanghai Yangpu District Mental Health Center,
treatment of AN in 1950; leucotomy had
Shanghai, People’s Republic of China; and 7Department of
Functional Neurosurgery, Shanghai Jiaotong University been viewed as the last resort for treatment-
Ruijin Hospital, Shanghai, People’s Republic of China resistant AN between 1944 and 1973 (62).
To whom correspondence should be addressed: Bomin Sun, M.D. Its rationale included the observed release ETIOLOGY, CLINICAL FEATURES, AND
[E-mail: bominsun@sh163.net] of appetitive behaviors by brain damage, al- TREATMENT OF AN
Citation: World Neurosurg. (2013) 80, 3/4:S29.e1-S29.e10. leviation of chronic anxiety and tension as- AN, first described in the 17th century and
http://dx.doi.org/10.1016/j.wneu.2012.06.039 sociated with the perceived threat of weight later coined in the 19th century, is a psychi-
Journal homepage: www.WORLDNEUROSURGERY.org gain, and a construction of AN as a form of atric disorder characterized by behaviors
Available online: www.sciencedirect.com obsessive-compulsive disorder (OCD) (62). that result in the status of being harmfully
1878-8750/$ - see front matter © 2013 Elsevier Inc. Lesioning procedures in which different underweight (67). In the fourth edition of
All rights reserved. brain regions were targeted, including lim- the Diagnostic and Statistical Manual of Mental
bic leucotomy and thalamotomy, were per- Disorders (DSM-IV; American Psychiatric As-
INTRODUCTION
formed from the 1950s to 1990s in hopes of sociation, 1994), AN is classified under eat-
Anorexia nervosa (AN), a serious mental ill- treating AN, but the clinical outcome was ing disorders, and is characterized by the
ness notorious for its high level of physical inconclusive as the result of various diag- following essential features:
complications and comorbid psychiatric nostic standards, surgical procedures, and
disorders, has one of the greatest mortality outcome evaluation methods (10, 16, 17, 24, (1) Refusal to maintain body weight at or
rates among all psychiatric disorders (88). 31, 41, 58, 62, 73, 75, 78, 100). More than above a minimally normal weight for
Considering the lethality, level of social de- half a century since the first nonstereotactic age and height (e.g., weight loss lead-
bilitation, and high relapse rates for the ablative brain procedure was attempted, the ing to maintenance of body weight less
standard treatment of AN, experimental effect of neurosurgery for AN comes under than 85% of that expected; or failure to
neurosurgical treatment approaches have investigation once again, but in the stereo- make expected weight gain during pe-

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riod of growth, leading to body weight verse both physical and psychological ef- ops during adolescence, and its symptoms in-
less than 85% of that expected). fects of starvation. Weight restoration or clude distorted body image; restricted eating
stabilization is the primary treatment goal or binging-purging behavior; extreme fear or
(2) Intense fear of gaining weight or be- for patients with AN (7). tension for even the slightest weight gain;
coming fat, even though one is under- Nevertheless, evidence for the effective- preoccupation with food, exercise, and diet-
weight. ness of existing treatments of patients with ing; emaciation; and for postmenarchal fe-
eating disorders is weak (9). Studies about males also amenorrhea. Individuals who
(3) Disturbances in the way in which one’s
the effectiveness of treatment have limited suffer from AN often are prone to perfec-
body weight or shape is experienced,
scientific methodology and often lack a tionist and obsessive-compulsive behavior
undue influence of body shape on self-
nontreatment control group because it is and are likely to suffer from dysphoric
evaluation, or denial of the seriousness
ethically difficult not to treat anorectic pa- mood. Common traits for patients with AN,
of the current low body weight.
tients. Medication trials for AN show that often already present in childhood, include
(4) In postmenarcheal females, amenor- pharmacologic intervention does not have a anhedonia, asceticism, high constraint,
rhea, i.e., the absence of at least three significant impact on weight gain or the and constriction of affect and emotional ex-
consecutive menstrual cycles. psychological features of AN (9). Antipsy- pressiveness, which suggests that there is
chotic medications, including chlorproma- an early-onset vulnerability for these pa-
The etiology of AN is complex, and many zine, pimozide, and sulpiride, were among tients (48). Another important aspect in the
factors contribute to the development and the first studied in the treatment of AN, and pathogenesis is the role of serotonin (5-HT)
maintenance of the disorder. There are pre- all of which have been shown to have no pathways. Altered 5-HT brain functioning
disposing genetic and personality factors that advantage over placebo (70). No significant is involved in the dysregulation of appetite,
appear to render an individual susceptible. In difference is found between effects of fluox- mood, and impulse control in patients with
addition, environmental factors, such as so- etine and placebo on weight gain or psycho- AN, as studies indicate that 5-HT distur-
ciocultural pressure to be thin, are likely to act logical features of eating disorders (9, 86). bances occur in ill AN patients as well as in
as triggers during the vulnerable period of pu- Although a patient’s mood may improve recovered patients (55, 80, 82).
bertal development (98). with tricyclic antidepressants, this outcome This trait-related 5-HT disturbance might
This disorder is most common in is not associated with improved weight gain
women, with a female/male ratio of more lead to the onset of AN because it contrib-
(9, 70). In a systematic review by Bulik et al. utes to the anxiety, obsessionality, and
than 10:1 (45) and has a peak of onset at 15 (9), in which all forms of psychotherapy
to 19 years of age, which comprises approx- inhibition that is often inherent to pa-
(cognitive, supportive, dynamic, family, in- tients with AN (48). This disturbance
imately 40% of cases (8, 85). The prevalence dividual, and group therapy) were studied,
in adolescents and young women is esti- might involve an increase of 5-HT levels or
it concluded that for adult patients with AN, an imbalance in the postsynaptic 5-HT re-
mated to be 0.3%–1% (45, 56). However, there is tentative evidence that cognitive be-
this prevalence may be underestimated be- ceptor activity (5-HT1a and 5-HT2a, which
havioral therapy reduces the risk of relapse
cause patients with AN have a tendency to are highly colocalized in the rodent [pre-
after weight restoration has been accom-
conceal their problems and avoid profes- ]frontal cortex and other cortical regions)
plished; family therapy focusing on parental
sional help (45). (3, 52, 96). More specifically, the binding
control of renutrition is effective in treating
Long-lasting malnutrition may lead to potential of 5-HT1a and 5-HT2a receptors
younger, nonchronic, anorectic patients.
many severe physical complications, includ- has respectively elevated and diminished,
Long-term outcome studies indicate re-
ing osteoporosis, gastrointestinal and cardiac which mediates an altered serotonergic
covery rates of 25% to 70%, and it is a two-
complications, liver damage, electrolytes dis- response, as 5-HT1a activation depolar-
stage process consisting of weight restora-
turbances, and eventually multiple organ fail- izes and 5-HT2a activation hyperpolarizes
tion followed by relapse prevention (37). It
ure (63). Major psychiatric comorbidities in- through interneurons the activity of pre-
is a long and fluctuating course, and despite
clude major depression, anxiety disorder frontal neurons that project to cortical
advances in psychiatric treatment plans and
(often OCD), and personality disorders (65). and subcortical areas (2, 4, 28, 30, 50, 91).
psychopharmacology, 30% to 50% of those
Patients with AN also present a lifetime risk of 5-HT pathways are known to have a role
voluntarily admitted to specialty programs
alcohol, amphetamine, and other substance drop out prematurely and relapse rates are in the development of a dysphoric mood,
abuse problems. In a review of 10 cohort stud- as high as 30% to 50% within a year of dis- which may involve a dysregulation of the
ies, Steinhausen (84) reports that standard- charge among successfully weight-restored emotional and reward pathways and medi-
ized mortality rate of AN falls between 1.36 patients (37). ate the hedonic properties of food. A 1998
and 17.80%. Long-term mortality in patients study proved that the administration of se-
with AN is reported to be 4.27%, mostly as lective serotonin re-uptake inhibitors was
the result of suicide, alcohol abuse, or med- PATHOGENESIS AND NEUROCIRCUITRY not effective in underweight AN patients,
ical complications of marasmic malnutri- OF AN although for weight-restored patients with
tion (79). AN, fluoxetine did result in a significant re-
Medical complications in AN are almost Serotonin and Corticotropin-Releasing duction in relapse rate (51). Patients with
always reversible with food intake (63). Hormone AN “learn” that restricting food is a way to
Sodersten et al. (81) showed that eating nor- The pathogenesis of AN has not yet been en- alleviate the dysphoric mood because food
mal amount of food is the best way to re- tirely uncovered. The disorder usually devel- restriction includes a lower tryptophan in-

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take, whereas tryptophan is obligatory for synthesis of cortisol, which mobilizes en- research findings include decreased pari-
the correct synthesis of 5-HT (49). In doing ergy from adipose and liver tissue, which etal cortical theta activity during blinded
so, patients with AN enter a vicious circle is adaptive in acute stress situations but palpation activities of different objects even
because the food restriction and inherent maladaptive in chronic stress, eventually after refeeding (36); abnormal performance
lower 5-HT levels give only a brief respite leading to emaciation (21). In normal stress on the symbol digit test (66); cognitive def-
from dysphoric mood, whereas starvation situations, a switch from CRH-induced to icits (40); impairment on tests for atten-
induces several changes in the function of arginine-vasopressin (AVP)-induced hy- tional, perceptual, and motor functioning
neuropeptides and monoamines, which pothalamic⫺pituitary⫺adrenal axis acti- and tests for visuospatial construction (59);
contribute to the dysphoric mood. vation occurs when the stress situation and problem-solving (89).
During puberty, the time when most pa- becomes chronic, thus diminishing the These deficits in the parietal cortex can be
tients with AN develop the disease, some inhibiting effect of CRH on appetite. In related to the pathology of AN, as the pari-
changes might be the cause for the exacer- patients with AN, the levels of AVP are etal cortex is hypothesized to be the brain
bation of previously existing factors. Pu- significantly lower than in healthy con- region in which proprioceptive and visual
berty, as a transition phase between child- trols, whereas cortisol levels are consid- information are integrated to construct a
hood to adulthood, is imperative in the erably greater, which might demonstrate body image, which is disturbed in AN pa-
development of the human persona. When a failure to correctly switch from the tients, in terms of body weight, shape, and
this transition fails to be correctly accom- CRH-induced to AVP-induced hypotha- dimensions perceptions (77, 93). The pari-
plished, a window of vulnerability for AN lamic⫺pituitary⫺adrenal axis activation etal cortex also might play a role in the inap-
might open because this individual is likely and cortisol synthesis (15). propriate insight of self-body image and
to be exposed to profound intrapersonal state in AN patient. Anosognosia, the de-
and interpersonal conflict and stress con- nial, unawareness, or ignoring the sick-
Neurocircuitry and Neuroimaging
sidering the initial risk factors, such as im- ness, has been proven to be correlated with
Reports of computed tomography (CT)
paired emotional expressiveness, cognitive lesions in the parietal cortex (68). The pari-
showed an enlargement of cerebral-spinal
handling, poor self-reflective functioning, etal cortex has been associated with hunger,
fluid spaces, mainly of cortical sulci, which
and overprotective and controlling parents is reversible after weight gain (43). Func- satiety, and mood, and the presence of dis-
(14). Some metabolic changes in the sys- tional neuroimaging studies from different turbances in parietal cortex functioning can
tems regulating appetite, weight, and body groups have opposite results of cerebral be correlated with symptoms of AN involv-
composition are necessary for the peripu- metabolic levels. Herholz (43) reported a ing satiety and mood as well (74, 90).
bertal weight gain in female subjects. Some normal gross functional positron emission Other important brain structures in-
neural systems such as the hypothalamus topography with abnormally high resting volved in AN may include the bed nucleus of
reach a new set-point for leptin levels dur- metabolic rate in the caudate nuclei on both the stria terminalis (BNST) and the nucleus
ing this period, and during that time the sides in detailed regional analysis in female accumbens (NuAcc). In BNST, the anorexi-
set-point might be vulnerable to influences. anorectic patients, whereas Delvenne et al. genic effect of CRH, delivered intracere-
During puberty, female gonadal steroids (20) reported a global hypometabolism and broventricularly and delivered in the BNST
might aggravate the 5-HT dysregulation. an absolute as well as relative hypometabo- itself, is inhibited by in situ injection of no-
Estrogen modulates serotonergic function lism of glucose in cortical regions, with the ciceptin/orphanin FQ, which possesses
via a variety of mechanisms, including al- most significant differences found in the functional anti-stress and anti-CRH actions
tered 5HT receptor number and 5HT syn- frontal and the parietal cortices. A more re- (12, 35). This finding demonstrates that
thesis and metabolism (72), which may ac- cent neuroimaging clinical review sug- BNST is involved in modulation of stress
count for the gender differences in the gested alterations in cerebral activity in the and CRH-induced anorexia and that BNST
prevalence of anorexia. dorsolateral prefrontal cortex, the inferior might provide a site of interest for specific
Research suggests that patients with AN parietal lobule, the anterior cingulate cor- neurosurgical treatments (13). Positron
who are currently ill have elevated cortico- tex, and the caudate nucleus, which can be emission tomography also reveals hyper-
tropin-releasing hormone (CRH) levels, accounted for many core symptoms in the metabolism in BNST in a rat model of gen-
whereas patients who have recovered have disease itself (69). eralized anxiety disorder, a common psy-
significantly lower levels of CRH (53). The exact neural circuitry of anorexia has chiatric comorbidity in AN (57).
Furthermore, the anorexigenic effects of not yet been unveiled, although there are BNST receives input from NuAcc, which
CRH have been proven in animal models certain zones of interest known from which belongs to the antero-ventral-striatum and
when administered intracerebroventricu- pathologic properties derive. Research has is part of the cortico-striato-thalamo-corti-
larly (32). Excessive CRH activity induces shown that parietal activity was reduced be- cal circuitry involved in reward system (94).
symptoms that are largely the same as the fore and increased after treatment. Symp- NuAcc receives strong inputs from differ-
symptoms of AN, including loss of appe- tom provocation decreased the parietal ac- ent nuclei of the amygdala, whereas the
tite and weight, in part by inhibiting the tivity in patients with active AN in most interconnections between the amygdala
synthesis of neuropeptide Y, which is a studies, although the activity increased in and BNST also are essential in learned
powerful hypothalamic anabolic activa- some cases. Binding to 5-HT1a receptors in- food aversion (19, 23). The main outputs
tor, increasing food intake and fat storage creased and the binding to 5-HT2a de- of NuAcc include the pallidum, striatum,
(6, 83). In addition, CRH stimulates the creased in the parietal cortex (95). Other mediodorsal thalamus, prefrontal and

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cingulate cortex, and mesolimbic dopa- OCD started. She recovered from AN at the This clinical study was approved by the
minergic areas (87). Injections of am- age of 18 but developed OCD in her early ethics committee at Ruijin Hospital. After
phetamine into either NuAcc or amygdala twenties and underwent bilateral DBS im- complete explanation of the study and risk
caused both anorexia and adipsia (11), plantation in the anterior limb of the inter- of adverse effects to the patients, written
and calcitonin injection in NuAcc-in- nal capsule and BNST for OCD. To our informed consent was obtained from each
duced inhibition of eating (18). knowledge, they are the only groups who patient and her guardian. With thorough
Towell et al. (92) demonstrated that the have published reports of DBS for AN in understanding of DBS procedures and un-
direct administration of apomorphine into humans. DBS for AN is at the very early biased analysis and advice from the medical
NuAcc/ventral striatum reduced food con- stages of proof, and the nature of this pro- team, each patient and her guardian made
sumption, eating rate, and eating time and cedure remains investigational. The follow- the decision independently.
the authors further suggested that “apo- ing data and results are based on DBS for
morphine reduces eating rate by an action AN cases provided by Wu et al. (the Shang-
on dopamine axon terminal autorecep- hai group). Patient Demographics of the
tors.” Other studies showed that stimula- Shanghai Group
tion of 5-HT receptors in NuAcc reduces Four patients (all females) underwent bilat-
one’s physiological drive to eat, and lesions eral NuAcc DBS procedures between 2007
Patient Selection Criteria of the
in the NuAcc increase food intake in food- and 2011. Average age of onset was 15 years
Shanghai Group
deprived rodents (47, 54). Functional neu- (range, 14 –16 years), and average duration
Inclusion criteria of patients with AN for
roimaging showed significantly greater do- of illness was 18.5 months (range, 13–28
DBS neurosurgery included clear diagnosis
pamine D2/D3 receptor binding potentials months). Average age at baseline, before
of AN, confirmed by three independent psy-
in the anteroventral striatum (including surgery, was 16.5 years (range, 16 –17
NuAcc) in recovered AN patients than in chiatrists; failure to respond to standard
psychiatric treatment program of at least 12 years). Average baseline BMI was 11.9
healthy controls (27). All of the aforemen- kg/m2 (range, 10.0 –13.3 kg/m2), and aver-
tioned studies indicate the important roles months; desire to receive further medical
care cooperatively; substantial suffering age duration of amenorrhea was 11 months
BNST and NuAcc play in regulating appeti- (range, 9 –15 months). All four patients suf-
tive behavior, whereas clinical data already from the disease and significant reduction
in psychosocial function as the result of fail- fered psychiatric comorbidities: three had
suggest involvement of these structures in OCD (average Y-BOCS: 20) and one had
OCD and other anxiety disorders, which are ure to maintain normal body weight with
multiple unsuccessful attempts at treat- generalized anxiety disorder (HAM-A: 19).
common psychiatric comorbidities in AN Sufficient dose and duration of selective se-
(34, 87). ment with antiobsessional or antidepres-
sive medication at adequate dosing and du- rotonin reuptake inhibitors or atypical anti-
ration; and hormonal disturbances caused psychotics (olanzapine) had little or no ef-
by malnutrition. fects on AN symptoms of these patients,
DBS FOR AN Wu et al. (99) evaluated the efficacy of sur- and all of them were forced to take medical
Sun et al.’s group in Shanghai (listed as Wu gical treatment in the following aspects: leave from school as the result of severe ma-
et al. [99]) reported a severe case of intrac- weight restoration (body mass index [BMI]), rasmic conditions and psychiatric symp-
table AN in which NuAcc DBS was applied perception of self image and perception of toms. Patients’ demographic characteris-
in 2007. In 2010, a Canadian research group obesity, binge-eating or vomiting (spontane- tics are presented in Table 1.
reported subgenual cingulate cortex DBS ous or self-induced), and restoration of men-
for depression with concomitant intracta- struation. Yale-Brown Obsession-Compul-
ble AN (46). In 2011, Barbier et al. (5) re- sion Scale (Y-BOCS) (33) and Hamilton Surgical Procedures of the Shanghai
ported a case of a 39-year-old woman with Anxiety Rating Scale (HAM-A) (39) were Group
treatment-refractory OCD who had AN scored to document obsessive-compulsive DBS electrodes were implanted with mag-
from the age of 16 to 18 years before her and general anxiety symptoms. netic resonance imaging (MRI)-guided ste-

Table 1. Patient Demographics

Duration of Suspend from


Age of Onset, Disease, Duration of Schooling,
Patient Sex Years BMI Months Amenorrhea, Months Comorbidities Treatment Months

1 F 14 12.2 28 11 OCD SSRI, olanzapine 5


2 F 15 13.3 18 15 OCD SSRI, olanzapine 3
3 F 16 12 15 9 Generalized Anxiety Disorder SSRI, olanzapine 10
4 F 15 10 13 9 OCD SSRI 6
BMI, body mass index; F, female; OCD, obsessive-compulsive disorder; SSRI, selective serotonin reuptake inhibitors.

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nation questionnaire and interview were


comparable with the normal population at
3-year follow-up.
Barbier et al. (5) reported a 39-year-old
female patient with treatment-refractory
OCD who had AN from the age of 16 to 18
years before her OCD started. She recovered
from AN at the age of 18 but developed OCD
in her early twenties and underwent bilat-
eral DBS in the anterior limb of the internal
capsule and BNST for OCD in 2003. Her
OCD symptoms improved substantially
postoperatively, whereas her AN symptoms
Figure 1. Changes in body mass index (BMI) over time. This figure shows never reappeared. In the same report, Bar-
BMI measurements (n ⫽ 4) at 0 (baseline), 3, 6, 9, 12, 18, 24, 36, and 48 bier et al. described two other cases of treat-
months during follow-up (up to 9 months in case 4, who as of this writing ment-refractory AN with comorbid OCD, in
underwent the procedure less than a year ago).
which bilateral anterior capsulotomy was
performed, and the clinical results were sat-
isfactory: both OCD and AN symptoms im-
reotactic surgery. The stereotactic frame generators (Soletra; Medtronic) placed sub-
proved in these two patients (5).
(Elekta Inc., Stockholm, Sweden) was cutaneously in the subclavicular area under
mounted on patient’s head while they were general anesthesia. The day after surgery, a
under local anesthesia or mild sedation on postoperative MRI was obtained to docu- DISCUSSION
the morning of surgery. Preoperative MRI ment the placement of electrodes.
scans (1.5T; General Electric, Madison, Is There a Neurosurgical Indication
Wisconsin, USA) were taken for obtaining for AN?
high-resolution anatomical images of the Clinical Outcomes of the Shanghai Group As the history and technology of functional
brain. NuAcc could be recognized directly Average follow-up period was 38 months neurosurgery evolves, the application of its
in both axial and coronal section T2 and (range, 9 –50 months). Average BMI at last procedures has gradually expanded in the
inversion recovery images with high-reso- follow-up was 19.6 kg/m2 (range, 18.4 –22.1 last decades. DBS, a technique that is
lution MRI. The medial and most ventral kg/m2), an average increase of 65% in body mostly used to treat essential tremor, Par-
part of the nucleus was targeted for implan- weight (Figure 1). Average Y-BOCS and kinson disease, and other movement disor-
tation of electrode (Model 3387; Medtronic HAM-A were reduced to 1.7 and 2, respec- ders, accumulates evidence of its efficacy in
Inc, Minneapolis, Minnesota, USA), corre- tively, at last follow-up. All patients weighed treatment of psychiatric disorders after pos-
sponding to approximately 3 mm anterior greater than 85% of expected body weight and itive early-stage reports of DBS treatment
to anterior commissure, 4 mm from the thus no longer met the diagnostic criteria of for OCD, anxiety disorder, depression, and
midline, and 6 mm below the anterior com- AN. The menstruation cycle was restored in Tourette syndrome were published world-
missure-posterior commissure level. The all four patients in an average of 6.8 months wide (26, 60, 64, 87). The U.S. Food and
trajectory was 10 –15 degrees lateral in cor- after surgery (range, 3–12 months). All four Drug Administration has passed the hu-
onary plane and 45 degrees anterior in sag- patients were suspended from school because manitarian device exemption for the use of
ittal plane. of their severe physical and mental state of DBS for severe and refractory OCD in 2009.
With the subject under local anesthesia, health before the implantation, and at last fol- The expansion of clinical applications of
bilateral C-shaped scalp incisions were low-up, three of the four were able to continue DBS, nevertheless, should have sufficient
made, and burr holes were placed bilater- school education. scientific research foundation that sup-
ally anterior to the coronal suture and ap- ports its potential benefits before clinical
proximately 3 to 4 cm from midline, and the application.
dura was opened. The electrodes were im- Case Reports from Israel et al. and As previously mentioned, AN is a com-
planted at target coordinates. Macrostimu- Barbier et al. plex and multifactorial eating disorder of-
lation (180 Hz, 90 microseconds, 1– 8 V) Israel et al. (46) reported a 52-year-old fe- ten accompanied by psychiatric comor-
was used to confirm the electrode location male patient suffering from severe refrac- bidities. Studies in animals have already
and evaluate potential side effects. All pa- tory depression with concomitant recurrent demonstrated involvement of BNST and
tients were subjected to stimulation of at AN (AN age of onset: 17 years of age) who NuAcc in eating behavior, whereas DBS for
least 6 V. Intense feeling of heat in facial and underwent bilateral DBS at subgenual cin- depression and OCD (common psychiatric
upper trunk areas was reported by all pa- gulate cortex in 2005. She was able to main- comorbidities in AN) has proven its efficacy
tients, with significant increases in heart tain her BMI at an average of 19.1 kg/m2 for in early-stage clinical trials. On the basis of
rate and blood pressure simultaneously. more than two years postoperatively, and these animal and clinical studies, we specu-
Then, the electrodes were connected via her scores on the Eating Attitude Test-26 late that DBS offers potential clinical bene-
subcutaneous wires to implantable pulse and the results of Eating Disorders Exami- fits in the treatment of severe and refractory

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should not wait until patients are in critical


Table 2. Patient Selection Criteria of Deep-Brain Stimulation for Anorexia Nervosa condition and instead intervene more ag-
Used by the Shanghai Group gressively at earlier stages of disease. This is
Clear diagnosis of anorexia nervosa (AN), confirmed by three independent psychiatrists. especially worth noting in the case of DBS
for AN, because DBS is a neurosurgical in-
Failure to respond to standard psychiatric treatment program of at least 12 months.
tervention and the surgical risk increases if
Desire to receive further medical care cooperatively. the physical condition of patient continues
Substantial suffering from the disease and significant reduction in psychosocial function because of the to worsen. However, at this early stage of
failure to maintain normal body weight, with multiple unsuccessful attempts at treatment with investigating the effects of DBS for AN, it
antiobsessional or antidepressive medication at adequate dosing and duration. seems logical to only restrict it to extreme,
Hormonal disturbances caused by malnutrition (amenorrhea in female patient). desperate cases, in whom improvement is
not expected.
y Patient (and guardian(s), if minor) is able to give written informed consent.
There are other evaluation tools designed
specifically to measure the severity of an-
AN, anorexia nervosa. orexia other than BMI. Clinician-adminis-
tered measures including Eating Disorder
Examination and Yale-Brown-Cornell Eat-
AN. However, the use DBS in patients with than 10 years is low. Herzog et al. (44) re-
ing Disorder Scale, and self-report mea-
AN is still in very early stages of investiga- ported a similar finding in AN patients in
sures such as Diagnostic Survey for Eating
tion, it is not a routine surgery, and it should their long-term follow-up report. On the
Disorders, Bulimia Test-Revised, Eating At-
only be performed in clinical trials. basis of these data, DBS for AN patients titude Test, Eating Disorder Examination-
who have suffered from this disease for Questionnaire, Eating Disorders Invento-
more than 10 years seems justifiable be- ry-2, Eating Disorders Questionnaire, and
Discussion of Possible Patient Selection cause the chance of recovery from other Questionnaire on Eating and Weight Pat-
Criteria treatments is low. Again, this absolute value terns are representative instruments for the
Age and Duration of Illness. At present, Ra- is somewhat arbitrary and is not universal, assessment of eating disorders suggested
bins et al. (71) recommend DBS for disor- and a severely ill AN patient should not be by the American Psychiatric Association (1).
ders of mood, behavior, and thought to be excluded from DBS treatment simply be- Unlike Y-BOCS in DBS for OCD, there is no
limited to adult patients, and current clini- cause she (or he) does not meet the 10-year standard evaluating scale in DBS for AN nor
cal trials of DBS for psychiatric disorders duration of illness criterion. An indepen- an inclusion criterion (e.g., Y-BOCS ⱖ28 or
include only adult patients (e.g., 29, 60, 97) dent institutional review board or hospital 30) (34) in any of the aforementioned scales
to avoid unforeseeable side effects of DBS ethics committee should review the study at present; however, this should not stop
on the developing nervous system and men- protocol and the committee for neurosur- clinicians and researchers from using these
tal state and to rule out self-healing false gery for psychiatric disorders should review standardized evaluating tools as consensus
positive outcomes. However, this “18 years each case individually and decide whether a will gradually develop in time.
of age” limit is rather arbitrary and a patient patient is suitable for such novel and inva- Instruments evaluating the quality of life
should not be rejected to receive such a ther- sive treatment. should also be included. The Eating Disorder
apy simply because of being underage. The Quality of Life Instrument (EDQOL), the Eat-
multidisciplinary team needs to bear in BMI and Other Methods of Evaluation. Hebe-
ing Disorder Quality of Life Scale (EDQOLS),
mind that nearly 76% of adolescent-onset brand et al. (42) concluded that a BMI value
the Health-Related Quality of Life in Eating
AN patients achieved full recovery under less than 13–15 kg/m2 range indicates a sub-
Disorders Questionnaire (HeRQoLEDv2),
standard treatment whereas time to recov- stantial risk for chronic AN and death re-
and the Quality of Life for Eating Disorders
ery ranges from 57 to 79 months (86), but in lated to emaciation in their long-term fol-
(QOL ED) are the common disease-specific
extreme cases under critical conditions, low-up study. This information alone,
quality of life instruments for eating disorders
with approval from independent institu- however, is hardly robust enough to draw a
(25). Other evaluation tools, for instance, Y-
tional review board or hospital ethics com- line on the BMI and claim it the inclusion
BOCS, HAM-A, and Hamilton Depression
mittee, DBS for adolescent anorectic pa- criterion of DBS for AN. The prevention of
Rating Scale or Montgommery Åssberg Rat-
tients may be justified. According to the drastic body weight decrease is one of the
ing Scale, can be applied when corresponding
clinical outcome reported by the Shanghai most important clinical goals of physicians
psychiatric comorbidity is present.
group, adolescent anorectic patients can and psychiatrists when treating AN, and
substantially benefit from DBS interven- BMI is often used as an evaluation parame- Exclusion Criteria. Any patient whose phys-
tion. ter to determine degree of recovery of pa- ical condition is not suitable to undergo
In a long-term follow-up study of AN re- tients. If the BMI of a chronic and refractory anesthesia or neurosurgical operation is a
ported by Strober et al. (86), the cumulative anorectic patient falls below certain critical contraindication of DBS for AN. Patients
partial and full recovery probabilities no threshold, for instance, 14 kg/m2, it is rea- with AN have a greater risk of hypother-
longer increase after approximately 10 sonable to propose a more aggressive regi- mia, delayed gastric emptying, cardiac ar-
years, meaning that the chance of recovery men to improve prognosis. However, it is rhythmias caused by hypokalaemia, and
for patients suffering from AN for more also pertinent to argue that physicians delayed drug breakdown and excretion (hy-

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Table 3. Patient Inclusion/Exclusion Criteria of Deep-Brain Stimulation for Anorexia Nervosa Suggested by the Leuven Group on the
Basis of Previously Published Papers

Inclusion criteria
To be eligible for inclusion into this study, subjects must fulfill all of the following criteria before study enrollment:
y Patient has a primary psychiatric diagnosis of AN according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision
(DSM-IV-TR) diagnostic criteria for AN (307.1). Both restrictive as well as binging/purging type will be considered.
y Age 18-65 years.
y Subject has medical record documentation of AN diagnosis of a disabling nature ⱖ10 years (SEED-AN: severe and enduring eating disorder-anorexia nervosa).
y Subject has a BMI ⱕ14.
y Global Assessment of Function score of 45 or less.
y Subject’s AN is chronic and treatment-resistant, defined as:
y Subject has not clinically responded to an adequate trial of outpatient treatment for AN, with emphasis on cognitive behavior therapy or has demonstrated
marked intolerance to cognitive behavior therapy (in therapist’s judgment).
AND
y Minimum of two appropriate residential treatment programs, in centers specialized in the treatment of eating disorders, with a minimum duration of 3 months
each.
AND
y Patient has not been able to maintain an adequate weight restoration after adequate treatment program for longer than 3 months.
y If comorbidities with depression, anxiety, obsessive-compulsive disorder and personality disorder are present, AN is judged to be the primary diagnosis.
y Patient is able to comply with the operational and administrative requirements of participation in the study and able to comply with the questionnaires and the
protocol.
y Patient is able to give written informed consent.
y Patient is either drug-free or on a stable drug regimen for at least 6 weeks at the time of entry into the study.
y If female subject and of childbearing potential: use of medically acceptable contraceptive method(s).

Exclusion criteria
To be eligible for inclusion into this study, patients must not meet any of the following criteria:
y Patient has a current Axis I disorder that is primary to the AN as demonstrated by the SCID-I: Structured Clinical Interview for DSM-IV-TR Axis I Disorders
y DSM-IV-TR diagnosis on axis 2 of severe personality disorder in the case of heightened risk for acting-out behavior (in the opinion of the investigator).
y DSM-IV-TR diagnosis on axis 3 of organic brain pathology or significant abnormalities on MRI (except AN-related atrophy).
y Mental retardation. A minimum threshold of cognitive skills is needed for adequate reporting on questionnaires and evaluation, and for technical handling of the
instruments in a later phase.
y Patient has a somatic (e.g., neurologic) condition that may jeopardize the subject’s ability to give informed consent, follow study requirements, or that may
confound his/her diagnosis or assessments.
y Patient has any medical contraindications to undergoing implantation of a bilateral DBS system.
y Patient meets DSM-IV-TR criteria for substance abuse (other than laxative or diuretics) or substance dependence ⱕ6 months before surgery.
y Patient is determined during the clinical interview to have a comorbid personality disorder that in the opinion of the investigator may jeopardize his/her safety
or study compliance.
y Patient made a suicide attempt requiring medical treatment ⱕ3 months prior to the screening tests or has a history of 2 or more suicide attempts ⱕ12 months
prior to the screening tests.
y Patient poses a serious suicide risk as indicated by any of the following:
y Serious plans for suicide as identified by a MADRS item 10 response of ⱖ“5.”
y In the opinion of the investigator.
y In the opinion of the investigator, patient is expected to be noncompliant with follow-ups or attendance of study visits.
y Pregnancy.

AN, anorexia nervosa; BMI, body mass index; DBS, deep-brain stimulation.

poalbuminemia) during anesthetic proce- tion, psychosis, current or unstably remit- outlines the DBS for AN inclusion/exclu-
dure (76). Surgical team needs to take into ted substance abuse, and who are pregnant sion criteria suggested by the Leuven
account that anemia, leucopenia, and throm- also should be excluded. group.
bocytopenia are prevalent in AN patients, and Approximately 95% of patients with AN
the risk of infection and other surgical com- are female (38), and no clinical DBS for
plications is significantly higher (22). AN in male patients has been performed Optimal Stimulating Target
At this stage, patients with abnormal CT to our knowledge, but we do not consider Lobotomy, limbic leucotomy, and thalamot-
or MRI findings (e.g., visible brain damage) male gender as a contraindication. Table omy were applied in the past in an attempt to
should be excluded from DBS for AN. Pa- 2 summarizes patient selection criteria cure anorectic patients, and these ablative
tients with mild-to-severe mental retarda- used by the Shanghai group, and Table 3 procedures all, to some extent, target the neu-

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HEMMINGS WU ET AL. DBS FOR ANOREXIA NERVOSA

ral circuitry of emotion. Barbier et al. (5) re- CONCLUSIONS 7. Brewerton TD, Costin C: Long-term outcome of
residential treatment for anorexia nervosa and bu-
ported a case of anterior capsulotomy in a pa- AN is a complex and severe, sometimes life- limia nervosa. Eat Disord 19:132-144, 2011.
tient with OCD and concurrent AN and threatening, psychiatric disorder with high
suggested a therapeutic effect of anterior cap- relapse rates under standard treatment. 8. Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lich-
sulotomy in eating patterns and recovery of tenstein P, Pedersen NL: Prevalence, heritability,
There is preliminary evidence that DBS for and prospective risk factors for anorexia nervosa.
body weight. This same group (Nuttin et al.) AN may be a valuable option for weight res- Arch Gen Psychiatry 63:305-312, 2006.
uses BNST as their primary target in DBS for toration in otherwise-refractory and life-
OCD, whereas the Shanghai group (Wu et 9. Bulik CM, Berkman ND, Brownley KA, Sedway JA,
threatening cases. The nature of this proce-
Lohr KN: Anorexia nervosa treatment: a systematic
al.) uses NuAcc as the target in DBS for AN. dure, however, remains investigational and review of randomized controlled trials. Int J Eat
DBS at the subgenual cingulate cortex is should not be viewed as a standard clinical Disord 40:310-320, 2007.
another possible anatomical structure that treatment option. Clinicians and research-
10. Carmody JT, Vibber FL: Anorexia nervosa treated
may yield therapeutic result in AN (46). ers should use currently available guide- by prefrontal lobotomy. Ann Intern Med 36:647-
lines of neurosurgery for psychiatric disor- 652, 1952.
ders as references to establish a technically
11. Carr GD, White NM: Contributions of dopamine
and ethically sound study protocol (e.g., pa-
Adverse Events terminal areas to amphetamine-induced anorexia
tient inclusion/exclusion criteria), with and adipsia. Pharmacol Biochem Behav 25:17-22,
No report of adverse events was made by
oversight from institutional review board or 1986.
Wu et al. nor Israel et al. in their DBS for AN
ethics committee. A brain region needs to
case reports. One of the main advantages of 12. Ciccocioppo R, Biondini M, Antonelli L, Wich-
have enough scientific rationale for being mann J, Jenck F, Massi M: Reversal of stress- and
DBS over ablative procedure is that the
selected as target for DBS. Further scientific CRF-induced anorexia in rats by the synthetic noci-
stimulation is adjustable and reversible. investigation is essential to warrant the ceptin/orphanin FQ receptor agonist, Ro 64-6198.
However, this does not rule out the possibil- long-term efficacy and safety of DBS for AN. Psychopharmacology (Berl) 161:113-119, 2002.
ity of therapy-related adverse events in this
13. Ciccocioppo R, Fedeli A, Economidou D, Policani
invasive procedure. Worsening of psychiat- F, Weiss F, Massi M: The bed nucleus is a neuro-
ric symptoms, overcorrection of symptoms anatomical substrate for the anorectic effect of cor-
(i.e. obesity), worsening of comorbid psy- ticotropin-releasing factor and for its reversal by
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