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Journal of NeurosurgeryOctober 2008 / Vol. 109 / No. 4 / Pages 625634

A REVIEWDeep brain stimulation in the treatment of obesityA reviewCasey H. Halpern, M.D.1, John A. Wolf, Ph.D.3, Tracy L. Bale, Ph.D.2, Albert J. Stunkard, M.D.3,5, Shabbar F.Danish, M.D.1, Murray Grossman, M.D., Ph.D.4, Jurg L. Jaggi, Ph.D.1, M. Sean Grady, M.D.1, and Gordon H.Baltuch, M.D., Ph.D.1

1Departments of Neurosurgery, 2Neuroscience, 3Psychiatry, and 4Neurology; and 5Center forWeight and Eating Disorders, University of Pennsylvania School of Medicine, Philadelphia,Pennsylvania

Abbreviations used in this paper: BMI = body mass index; DBS = deep brain stimulation; GABA = γaminobutyric acid; LH = lateral hypothalamus; MCH = melaninconcentrating hormone; NAc =nucleus accumbens; OCD = obsessivecompulsive disorder; PD = Parkinson disease; 6OHDA = 6hydroxydopamine; STN = subthalamic nucleus; VMH = ventromedial hypothalamus; VP = ventralpallidum.

Address correspondence to: Casey H. Halpern, M.D., Department of Neurosurgery, 3 Silverstein,Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.email: casey.halpern@uphs.upenn.edu.

AbstractObesity is a growing global health problem frequentlyintractable to current treatment options. Recent evidencesuggests that deep brain stimulation (DBS) may be effectiveand safe in the management of various, refractoryneuropsychiatric disorders, including obesity. The authorsreview the literature implicating various neural regions in the

pathophysiology of obesity, as well as the evidence supporting these regions as targets for DBS, inorder to explore the therapeutic promise of DBS in obesity.

The lateral hypothalamus and ventromedial hypothalamus are the appetite and satiety centers inthe brain, respectively. Substantial data support targeting these regions with DBS for the purpose ofappetite suppression and weight loss. However, reward sensation associated with highly caloricfood has been implicated in overconsumption as well as obesity, and may in part explain the failurerates of conservative management and bariatric surgery. Thus, regions of the brain's rewardcircuitry, such as the nucleus accumbens, are promising alternatives for DBS in obesity control.

The authors conclude that deep brain stimulation should be strongly considered as a promisingtherapeutic option for patients suffering from refractory obesity.

HIGHFREQUENCY deep brain stimulation is the treatment of choice for wellselected patients withmedically refractory PD. Deep brain stimulation provides significant symptomatic improvement in

parkinsonism in both animal and human studies,31,56 and at high frequencies (130–160 Hz)

mimics the clinical effects of tissue lesioning.6,9,11 In contrast to stereotactic lesions, however, DBS

provides the added benefit of reversibility and titratability,28 as well as a very low risk of

complications.27,118 Excessive or aberrant output from the STN, currently the most favored target

for DBS in PD, is postulated to play a crucial role in the pathophysiology of this disease.1 Given theremarkable improvement in parkinsonism, highfrequency STN DBS appears to induce functional

inhibition of this region.9 Indeed, some have shown that highfrequency STN DBS has an inhibitory

effect on STN single unit activity.111 There is evidence that the primary effect of DBS is related to the

frequency of stimulation,58 but the precise mechanism of action remains unclear, whether it be

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excitatory59 or inhibitory in nature.60,73,111

The success of DBS in relieving parkinsonism has led to its application in multiple neurological

diseases and more recently to treatmentresistant psychiatric conditions.39 The purpose of thispaper is to motivate the neurosurgical community to consider DBS for obesity control. Obesity is achronic disease with wellsubstantiated neuropsychiatric underpinnings. Appetite and satiety

centers in the brain have been welldocumented93 and thus represent primary areas for

investigation.21,97,98 Many studies have indicated that the reward sensation associated with food

intake is also largely implicated in the pathophysiology of obesity.7,44,123 In support of this concept,it was recently proposed that obesity be included as a mental disorder in the next (fifth) edition of

the Diagnostic and Statistical Manual of Mental Disorders (DSMV).119 Below, we review 3 potentialneural targets for DBS believed to be involved in the excessive consumption of food in obesity.

Background

Obesity, defined as a BMI > 30 kg/m2, affects more than 30% of adult Americans83 and over 300

million people worldwide.25 Annual health care costs are estimated at nearly 100 billion dollars in

the US alone.2 Obesity is associated with diminished quality of life,92 high risk of

comorbidities,32,81 and the reduction of life expectancy by up to 20 years.34 Pharmacological

therapies and behavioral techniques are rarely effective due to high relapse rates,51,63 explaining

the more than 10fold increase in bariatric surgeries performed over the past 8 years.107 Althoughmean weight loss after bariatric surgery ranges from ~ 20 to ~ 60%, with concomitant improvement

in morbidity,65,70,121 complications occur in 15–55% of patients, and the perisurgical mortality rate

is ~ 1.5% even in experienced centers.82,86 Furthermore, significant weight gain occurs after the

nadir weight is reached, approximately 2 years postoperatively.20 The failure rate due tononcompliant eating patterns in patients followed up for 10 years is as high as 20% for obese and

40% for superobese (BMI > 50 kg/m2) patients.15,20 One followup study reported recurrent binge

eating in 46% of patients who had undergone bariatric surgery.52 Thus, consideration of theneuropsychiatric basis of obesity may help explain these refractory eating habits and the significantsurgical failure rate.

Deep Brain Stimulation of the Hypothalamus: RationaleOverconsumption of calorically dense foods is a likely contributor to the rapidly progressing

epidemic of obesity.16 Body weight results at least in part from a balance between food intake andenergy expenditure, and obesity is due to an imbalance between energy input and output. Thehypothalamus has been shown to be integral in maintaining this energy homeostasis. Specifically,food intake is at least in part controlled by a feeding center in the lateral hypothalamus and a satiety

center in the ventromedial hypothalamus.93 We will discuss these regions below as potentialtargets of DBS.

The Lateral Hypothalamus

The LH has long been implicated in feeding behavior and energy expenditure.12 Its role in appetite

regulation was well described in early studies of LH lesioning, which induced leanness.3 Thisimpact on appetite can be partially explained by peptides expressed in the LH, such as MCH and

orexins (also known as hypocretins), as well as orexin receptors.23,85,96 Indeed, MCH−/− micehave been shown to be lean and hypophagic, and mice with overexpression of MCH, obese and

insulinresistant.64 Chronic administration of an orally active MCH receptor antagonist decreased

food intake, body weight, and adiposity in rodent obesity models.71 Injections of orexins into the LHincreased feeding behavior and enhanced arousal. Indeed, upregulated expression of the orexin

gene has been demonstrated in fasting rats.55 Other peptides shown to be critical regulators of

feeding behavior and body weight include neuropeptide Y68 and agoutirelated protein,14 which

densely project to the LH.30,105

Anatomy of the LHThe LH is a fairly large region of the hypothalamus, measuring approximately 6 × 5 × 3.5 mm in the

largest dimensions laterally, anteroposteriorly, and dorsoventrally, respectively.99 (See Fig. 1 forfurther definition of this target structure.) Targeting the LH with DBS has been associated with risk ofthe spread of stimulation to nearby hypothalamic nuclei. The hypothalamus comprises a largenumber of distinct nuclei, and thus has many physiological functions not limited to appetite control,including body temperature regulation, sexual activity, reproductive endocrinology, and the fightor

flight response.89 The effect of stimulating any adjacent hypothalamic region is thus associated withaltering these physiological responses. Other neural structures located adjacent to the LH includethe fornix and the optic nerve. Portions of the LH are just inferior to the fornix and directly superiorand posterior to the optic nerve and chiasm, further complicating the targeting of this nucleus with

DBS.99

FIG. 1.A sagittal section depicting the lateral hypothalamus adjacent to the optic nerve. Thefornix is not well visualized in this section. *lateral hypothalamus (L); #optic nerve (II); ^nucleus accumbens (Fu.st). From Schaltenbrand G, Warren W: Atlas for Stereotaxy

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of the Human Brain. Stuttgart: Thieme, 1977. Reprinted,with the addition of *, #, and ^, by permission.

Stereotaxy and Stimulation of the LHNevertheless, targeting the hypothalamus with DBS has already been shown to be safe and

potentially effective in managing patients with intractable chronic cluster headache.61 Furthermore,stereotactic electrocoagulation of the LH in obese humans was performed safely more than 30years ago, resulting in significant, although transient, appetite suppression and slight weight

reduction in 3 patients.90 Given this evidence, it was recently proposed that chronic bilateral DBS ofthe LH at high frequencies would mimic the results of lesion studies, just as STN DBS for PD mirrors

the effect of subthalamotomy.98

To test this hypothesis, Sani et al.97 stereotactically implanted electrodes bilaterally into the rat LH.Half of the implanted animals underwent highfrequency stimulation (stimulation parameters: 2.0 V,pulse width 100 msec, frequency 180–200 Hz), while the other half were left unstimulated. Onpostoperative Day 24, stimulation was associated with a mean loss of 2.3% of body weight, whilethe unstimulated group had a mean weight gain of 13.8% (p < 0.001). Interestingly, no difference infood intake was found between groups. Thus, the authors concluded that the stimulationinducedweight loss seen in the stimulated group was secondary to metabolic change, although nomeasurements of individual animals' metabolic profiles were made. In contrast to high frequency LHstimulation, LH stimulation at lower frequencies (50–100 Hz) elicited feeding in earlier

studies.13,75,87,113 Hypothalamic stimulation at 50 Hz resulted in immediate and sustained

hoarding of food in satiated rats.42 Similarly, unilateral LH stimulation resulted in increased feeding

in cats26,33 and induced rhythmic oral activity in rabbits.101 Other effects of LH stimulation includedexploration, as well as escape and attack behaviors associated with autonomic changes withincreases in stimulation strength. These findings are consistent with those observed in canine LHstimulation at 100 Hz, which induced increases in coronary flow, blood pressure, heart rate, and

other sympathetic responses.35 Importantly, such changes were also associated with cardiacarrhythmias.

Ventromedial HypothalamusLike the LH, the VMH has also been implicated in appetite regulation and the maintenance of

energy homeostasis.43,54 Lesions of the VMH have been shown to induce weight gain in obese

animals,18 and lesions resulted in substantially more carcass lipid and hyperinsulinemia in rats

even if pairfed with shamlesioned controls, suggesting a metabolic bias toward obesity.22

Anatomy of the VMHThere are various challenges to surgically targeting the VMH that need to be considered. The VMHis a small bilobed target in the vertical axis measuring approximately 2 × 3 × 5 mm in the largest

dimensions (Fig. 2).99 Although found slightly inferior to the anterior commissure in theanteroposterior plane, which may facilitate accurate localization, an intraventricular trajectory maybe required given such a medial location of the VMH. Furthermore, the VMH is bounded by the opticnerve anteriorly and the mammillary body posteriorly. Deep brain stimulation of the mammillary

bodies is currently under investigation as a potential target for seizure control.116 Due to theirconnections to the circuit of Papez, and given substantial evidence pointing to an important role ofthis circuitry in seizure propagation and expression, it is possible that the spread of stimulation from

this area may induce seizures.76 The VMH is located just inferior and medial to the LH. The

hypothalmic nuclei are wellknown to be largely interconnected,89 and thus it is conceivable thatstimulation spread to the LH may directly antagonize the effect of lowfrequency DBS of the VMH.

FIG. 2.A sagittal section depicting the ventromedial hypothalamusbounded anteriorly by the optic nerve and posteriorly bythe ipsilateral mammillary body. *ventromedialhypothalamus (Vm); #mammillary body (M.m); +opticchiasm (Ch. II); ^anterior commissure (Cm.a). FromSchaltenbrand G, Warren W: Atlas for Stereotaxy of the

Human Brain. Stuttgart: Thieme, 1977. Reprinted, with the addition of *, #, +, and ^, bypermission.

Stereotaxy and Stimulation of the VMHElectrical stimulation of the VMH has been reported, and stimulation at low frequencies (60–100

Hz) inhibited feeding in hungry rats, and eating resumed once the current was terminated.46,57 In

goats, VMH stimulation at low frequencies (for example, 50 Hz) inhibited feeding as well.5,127 Othereffects of stimulation included fear, aversion, restlessness, and attempts at escape, which may have

partially accounted for the decreased feeding behavior in these animals.46,57 These effects may berelated to autonomic changes due to VMH stimulation, which has been shown to increase

metabolic rate.94 This increase in energy expenditure was associated with increased fat oxidation

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given a concomitant drop in the respiratory quotient. Thus, heightened metabolism induced by VMHstimulation was sustained by utilization of fat stores, most likely due to noradrenergic

turnover.95,106 Recently, VMH DBS at 4 different frequencies (25, 50, 75, and 100 Hz) in a rat was

shown by means of indirect calorimetry to result in an increase in metabolism.21 There was a trendtoward an indirect relationship between energy expenditure and increasing frequencies,suggesting that lower frequencies of stimulation drive VMH activity, while higher frequencies mayhave lesioning effects (A. L. Benabid, 2006, personal communication). These findings are

consistent with a frequencydependent effect of stimulation.58

Deep Brain Stimulation of the Nucleus Accumbens: RationalePhysiological states associated with energy balance, such as hunger and satiety, are strongdeterminants of feeding behavior. The above data support the idea that DBS of the LH or VMH atvarious frequencies may be able to modulate the neural regions associated with energyhomeostasis. However, the assumption that feeding behavior in obesity can be effectivelymodulated by inhibiting appetite sensation or driving satiety may not be correct. In fact, there is asignificant amount of evidence that feeding behavior is strongly influenced by palatability, or thereinforcing value of food, irrespective of appetite. For example, there is a 90% increase in food

intake in mice fed a highfat diet compared with their consumption when fed normal house chow.110

Such a palatable diet (45 kcal % fat) is preferred to standard house chow because of reinforcing

properties believed to be mediated largely in the NAc.44,104,123

Anatomy of the NAcThe NAc is a ventral striatal region located immediately inferior to the anterior limb of the internalcapsule. As a DBS target, the NAc is very similar to the STN. It measures approximately 8 × 6 × 6mm in the largest dimensions, thus making it only slightly larger than the STN, which is

approximately 8 × 4 × 4 mm.99 (See Figs. 1 and 3 for further delineation of the NAc.) The NAc has awellcircumscribed, ellipsoid shape with relatively clearcut boundaries on myelinstained sections,

with the most superior edge directed medially.99 The center of the NAc is located just about 3 mmanterior to the anterior commissure and approximately 6 mm lateral from the midline. To target theNAc, a trajectory can be taken just lateral to the ventricle and through the caudate nucleus; this

approach has been well tolerated in reports of DBS for OCD and depression37,100 as well as DBS

of the globus pallidus in PD.4 Certainly some cognitive deficits such as memory impairment arepossible due to microtrauma to the caudate, but patients without preoperative dementia are less at

risk.19 Some of the other nearby structures that may compromise safe targeting of the NAc include

the anterior cerebral artery located just inferiorly, as well as the optic nerve found inferomedially.99

FIG. 3.A coronal section depicting the nucleus accumbenslocated in the ventral striatum just inferior to the caudatenucleus and inferolateral to the lateral ventricle. *nucleusaccumbens (Fu.st); #caudate nucleus (Cd); + putamen(Put). From Schaltenbrand G, Warren W: Atlas forStereotaxy of the Human Brain. Stuttgart: Thieme, 1977.Reprinted, with the addition of *, #, and ^, by permission.

The NAc is divided into 2 subregions, core and shell, based on cytoarchitectonic and

neurotransmitter characteristics, as well as differences in the afferent and efferent connections.128

Anatomical tracing studies have shown that the core region connects extensively to extrapyramidal

motor structures, such as the VP, the STN, and the substantia nigra.29 The shell region is believed

to be confined to the ventromedial margins of the NAc41 and is embedded in a complexmesocorticolimbic circuit providing control of reward sensitivity. The NAc shell receivesdopaminergic input from the ventral tegmental area, as well as afferents from the amygdala,

hippocampus, prefrontal cortex, and thalamus.29,38,130 Efferent output projects mainly to the VP, as

well as the thalamus and cingulate cortex.24,129 Recent work has implicated simultaneousinvolvement of the NAc shell and the VP in favorable reactions to taste in rodents (“liking”), such astongue protrusions, whereas the NAc shell exerted independent control of food intake

(“wanting”).104 Thus, output from the NAc shell may in part bypass the VP and project directly to the

LH,129 suggesting that communication exists between the reward processing and feeding centersin the brain. Significant debate exists as to whether electrical stimulation of the LH alone induces

rewarding sensations.13,45

The NAc and Food RewardThe NAc is integral to the modulation of reward sensation shown to be associated with palatabilityof foods. Results from singleunit recordings from the NAc demonstrated that in a subset of neurons,

firing rates varied significantly as a function of sucrose concentration.109 Furthermore, palatablefood such as chow with high fat content (45 kcal % fat) was preferred to standard house chowbecause of reinforcing properties believed to be mediated in part by dopamine neurotransmission

in the NAc.44,123 Indeed, NAc injections of dopamine antagonists suppressed feeding.10

Furthermore, the levels of dopamine release were proportional to the amount ingested,69 and thereis a significantly greater amount of dopamine released in the NAc of obese rats relative to lean rats

in response to food stimuli.74,123

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Sensitivity to reward can vary from one person to another, but those individuals with more frequent

and intense food cravings are more likely to be obese.8 Mice withdrawn from a highly palatable dietwill endure an aversive environment to obtain preferred foods, and show a significant increase in

expression of corticotropinreleasing factor associated with a stress state.110 Thus, we support therecent suggestion that at least some forms of obesity may be driven by an excessive motivationaldrive for food intake that overrides the hypothalamic circuitry normally involved in regulating food

consumption.77 In fact, in addition to projections from the NAc to the LH,129 there are projections

from the LH to the NAc,85 suggesting that signals of internal homeostasis may be relevant in

modulating food reward.67 Studies in animal models of obesity, however, have demonstratedaltered expression of many of the peptides involved in feeding behavior at the level of the LH,

resulting in increased hunger for highly palatable food.47,48,125 Thus, hypothalamic control of

intake may be impaired in obesity.47,125 It is conceivable that significant relapse and failure ratesmay be at least in part a result of a dysregulated reward system, leading to our experience to datewith conservative measures and bariatric surgery.

The idea that dopamine plays a dominant role in modulating palatability has been recently calledinto question. Multiple neurotransmitters have been implicated in accumbal reward processes,some with potent effects on intake of highfat diets. Injections of opioid receptor agonists into theNAc induced hyperphagia and a preference for fat consumption that was independent of dopamine

neurotransmission and was blocked by cotreatment with naltrexone.79,122,131 The majority ofcorticolimbic inputs to the NAc use an excitatory amino acid as their neurotransmitter. Indeed,blockade of αaminohydroxy5methylisoxazole4propionic acid (AMPA) receptors in the shell

subregion of the NAc resulted in pronounced feeding.67 However, the majority of the cells in theNAc are GABAergic and therefore inhibitory, both locally and at their projection targets. In addition,there is also significant cholinergic neuromodulation of these cells. Thus, within the NAc is anextensive network of multiple neurotransmitter systems, some or all of which may be intimatelyinvolved in food reward sensation. Further study, including detailed computational modeling of themodulation of this network, will be necessary to determine the effect of DBS on specific components

of this network.78,124

Evidence From Lesion StudiesDestruction of the dopaminergic neuron terminals projecting to the NAc with a stereotactic injectionof the neurotoxin 6OHDA results in dopamine depletion in this region. The 6OHDA lesions of NAc

resulted in significant attenuation of food hoarding and weight loss in rats,53 and administration oflevodopa restored normal hoarding behavior. While lesioning effects of DBS at high frequenciesare well documented, it is difficult to predict whether DBS could mimic the effects of 6OHDA lesionsgiven the variety of neurotransmitter systems involved in the NAc and the differentiated anatomicalprojections of the accumbal subregions. NmethylDaspartate lesions of the NAc core induced

weight loss in rats, whereas the shelllesion group gained weight.66 The authors of the studyargued that the loss of weight in the core group was due to changes in motor function given the

core's connections to the extrapyramidal system.29 It is conceivable that the core and shell haveopposing effects on ingestive behavior, explaining the lack of any change in weight with large,nonspecific excitotoxic lesions encompassing both regions of the NAc. Given the functionaldissociation within the NAc, further investigation is necessary to determine if modulation of rewardsensation is possible with DBS, what region of the NAc is most appropriate to target, and whatfrequencies are necessary to obtain the desired effects. Furthermore, given the proximity of the NActo various structures, including the globus pallidus, anterior limb of the internal capsule, VP, andcaudate, rigorous stereotactic methods are necessary to ensure precise placement of thepermanent electrode.

Evidence From Neurofunctional ImagingFunctional MR imaging studies have demonstrated activation of striatal reward areas during

exposure to a highfat stimulus, particularly in those patients with enhanced reward sensitivity.8 Ahyperfunctioning region is known to be susceptible to the effects of DBS given the lesioning effect ofhigh frequency stimulation of the overactive STN in PD. Positron emission tomography andautoradiographic studies have shown reductions in striatal D2 receptors, as well as elevated levels

of the dopamine transporter.49,120 It follows that lower extracellular levels of dopamine have beenfound in the NAc of obese mice relative to the levels found in obesityresistant mice, a differnce that

may be due to enhanced clearance.49,102 While heightened reward is evident in obesityassociated with increased levels of accumbal dopamine release following exposure to a foodstimulus, this sensation may be shortlived due to a decreased sensitivity of dopaminergic rewardcircuits. Thus, a need to compensate with food reinforcers in conjunction with an increased stressresponse to palatable food restriction may be the underlying causes for the reported high rates ofrecurrent binge eating and surgical failures in bariatric patients.

Evidence From NAc Stimulation Studies

Electrical stimulation of the NAc has been performed in rats.53,72,88 Multiple effects of NAcstimulation have been reported in rats, including increased sniffing, excitement, and even

aggression, which were all observed at a stimulation frequency of 60 Hz.40 These findings have

been replicated in cats,36 although no such effects were noted in rhesus monkeys.126 Noconsistent documentation of the response of feeding behavior to NAc DBS has been

reported,80,117 but none of these studies included overweight or obese animals. Some evidence forthe potential of NAc DBS in obesity control can be derived from its success in relieving symptoms of

OCD.37

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1. Albin RL, Young AB, Penney JB: The functional anatomy of basal ganglia disorders. TrendsNeurosci 12:366–375, 1989 CrossRef, Medline

2. Allison DB, Zannolli R, Narayan KM: The direct health care costs of obesity in the UnitedStates. Am J Public Health 89:1194–1199, 1999

3. Anand BK, Brobeck JR: Localization of a “feeding center” in the hypothalamus of the rat. ProcSoc Exp Biol Med 77:323–324, 1951 Medline

4. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP: Pallidal vs subthalamicnucleus deep brain stimulation in Parkinson disease. Arch Neurol 62:554–560, 2005CrossRef, Medline

5. Andersson B: The effect and localization of electrical stimulation of certain parts of the brainstem in sheep and goats. Acta Physiol Scand 23:8–23, 1951

6. Andy OJ, Jurko MF, Sias FR Jr: Subthalamotomy in treatment of parkinsonian tremor. JNeurosurg 20:860–870, 1963 Abstract, Medline

7. Aou S, Oomura Y, Nishino H, Inokuchi A, Mizuno Y: Influence of catecholamines on rewardrelated neuronal activity in monkey orbitofrontal cortex. Brain Res 267:165–170, 1983

8. Beaver JD, Lawrence AD, van Ditzhuijzen J, Davis MH, Woods A, Calder AJ: Individualdifferences in reward drive predict neural responses to images of food. J Neurosci26:5160–5166, 2006

9. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J: Combined (thalamotomy andstimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease.Appl Neurophysiol 50:344–346, 1987 Abstract, Medline

10. Bendotti C, Berettera C, Invernizzi R, Samanin R: Selective involvement of dopamine in the

Reward Circuitry DBS in Other TreatmentResistant ConditionsBilateral NAc stimulation in a rat model of OCD has shown promise for the use of this modality inhumans. Electrodes were implanted bilaterally using stereotactic coordinates similar to those

previously documented.53 Although further investigation is required, highfrequency stimulation

appeared to diminish OCD symptoms in various rat models of OCD.50,114,115 One explanation forthese findings, as well as for the success of NAc DBS in patients with OCD, comes from a recentstudy in which highfrequency NAc stimulation at 130 Hz reduced the firing rate of orbitofrontal

cortex neurons in rats.72 Indeed, metabolic hyperactivity in this region has been consistently

associated with OCD symptoms.17

A trial of DBS of the ventral capsule/ventral striatum site, a region that encompasses the NAc, in 10OCD patients with longterm followup demonstrated a 36% decrease in disease severity and

nearly a 50% improvement in global functioning.37 This region has been consistently implicated inOCD given its central position between the amygdala, basal ganglia, thalamus, and prefrontal

cortex, all regions known to be involved in this disorder.91,103 Furthermore, the ventral striatum, andparticularly the NAc, has been shown to respond abnormally to pleasurable stimuli in patients

suffering from severe depression.112 Deep brain stimulation of the NAc provided a 42%

improvement in depression severity in one study.100 These reports not only provide encouragingevidence for the therapeutic effect and safety of DBS, but also for its promise in modulating neuralregions implicated in reward sensation associated with the pathophysiology of obesity.

ConclusionsAppetite modulation in conjunction with enhancement of the metabolic rate by means ofhypothalamic lesions has been widely documented in animal models and even in humans. Itappears that these effects can be reproduced by DBS, and the titratability and reversibility of thisprocedure, in addition to its wellestablished safety profile, make hypothalamic DBS an appealingoption for obesity treatment. Given that palatability significantly increases food intake, however,suppressing appetite and increasing energy expenditure may prove to be inadequate, especiallyover the long term. Indeed, electrocoagulation of the LH in humans only transiently suppressed

appetite and provided minimal weight loss.90 Chronic NAc DBS may allow us to modulate rewardsensation and dietary preferences by interacting with the systems known to be implicated in thereinforcing properties of food. Inhibition of food reward may provide significant weight reductionover time and effectively lessen relapse rates associated with conservative and surgical treatments.Moreover, stimulation frequency may be titratable to adequate inhibition of food preference andoverconsumption. Deep brain stimulation of the NAc region has already been established as safe in

the treatment of patients with refractory OCD and depression.84,108 Thus, we need to consider thepotential role of DBS in attenuating the reinforcing properties of highly palatable foods that haveclearly contributed to the worldwide epidemic of obesity. Furthermore, established animal models of

obesity exist62 and should be used in studies measuring the effects of DBS on weight loss.

DisclaimerThe authors do not report any conflict of interest concerning the materials or methods used in thisstudy or the findings specified in this paper.

References

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nucleus accumbens in the feeding response elicited by muscimol injection in the nucleusraphe dorsalis of sated rats. Pharmacol Biochem Behav 24:1189–1193, 1986

11. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions ofthe subthalamic nucleus. Science 249:1436–1438, 1990 CrossRef, Medline

12. Bernardis LL, Bellinger LL: The lateral hypothalamic area revisited: ingestive behavior.Neurosci Biobehav Rev 20:189–287, 1996

13. Berridge KC, Valenstein ES: What psychological process mediates feeding evoked byelectrical stimulation of the lateral hypothalamus?. Behav Neurosci 105:3–14, 1991

14. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z, et al.: Postembryonicablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J 19:1680–1682, 2005

15. Biron S, Hould FS, Lebel S, Marceau S, Lescelleur O, Simard S, et al.: Twenty years ofbiliopancreatic diversion: what is the goal of the surgery?. Obes Surg 14:160–164, 2004

16. Blundell JE, Lawton CL, Cotton JR, Macdiarmid JI: Control of human appetite: implications forthe intake of dietary fat. Annu Rev Nutr 16:285–319, 1996

17. Breiter HC, Rauch SL: Functional MRI and the study of OCD: from symptom provocation tocognitivebehavioral probes of corticostriatal systems and the amygdala. Neuroimage4:S127–S138, 1996

18. Brobeck JR: Mechanism of the development of obesity in animals with hypothalamic lesions.Physiol Rev 26:541–559, 1946 Medline

19. Broggi G, Franzini A, Marras C, Romito L, Albanese A: Surgery of Parkinson's disease:inclusion criteria and followup. Neurol Sci 24:1 SupplS38–S40, 2003

20. Christou NV, Look D, Maclean LD: Weight gain after shortand longlimb gastric bypass inpatients followed for longer than 10 years. Ann Surg 244:734–740, 2006

21. Covalin A, Feshali A, Judy J: Deep brain stimulation for obesity control: analyzing stimulationparameters to modulate energy expenditure. Proceedings of the 2nd International IEEEEMBS, Conference on Neural Engineering Arlington, VA, IEEE EMBS, 2005. v–viii

22. Cox JE, Powley TL: Intragastric pair feeding fails to prevent VMH obesity or hyperinsulinemia.Am J Physiol 240:E566– E572, 1981

23. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al.: The hypocretins:hypothalamusspecific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA95:322–327, 1998

24. de Olmos JS, Heimer L: The concepts of the ventral striatopallidal system and extendedamygdala. Ann N Y Acad Sci 877:1–32, 1999

25. Deitel M: The International Obesity Task Force and “globesity”. Obes Surg 12:613–614, 2002CrossRef, Medline

26. Delgado JMR, Anand BK: Increase of food intake induced by electrical stimulation of thelateral hypothalamus. Am J Physiol 172:162–168, 1953

27. Deogaonkar M, Boulis N, Machado A, Azmi H, Senatus P, Rezai A: Surgical complications in800 consecutive DBS implants. American Association of Neurological Surgeons 2007 AnnualMeeting Proceedings Park Ridge, Ill, American Association of Neurosurgeons, 2007. AbstractNo. 40777

28. Deuschl G, Herzog J, KleinerFisman G, Kubu C, Lozano AM, Lyons KE, et al.: Deep brainstimulation: postoperative issues. Mov Disord 21:14 SupplS219–S237, 2006

29. Deutch AY, Cameron DS: Pharmacological characterization of dopamine systems in thenucleus accumbens core and shell. Neuroscience 46:49–56, 1992

30. Elmquist JK, Elias CF, Saper CB: From lesions to leptin: hypothalamic control of food intakeand body weight. Neuron 22:221–232, 1999

31. Fang X, Sugiyama K, Akamine S, Namba H: Improvements in motor behavioral tests duringdeep brain stimulation of the subthalamic nucleus in rats with different degrees of unilateralparkinsonism. Brain Res 1120:202–210, 2006 CrossRef

32. Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, et al.: Impact of overweight onthe risk of developing common chronic diseases during a 10year period. Arch Intern Med161:1581–1586, 2001

33. Folkow B, Rubinstein EH: Behavioral and autonomic patterns evoked by stimulation of thelateral hypothalamic area in the cat. Acta Physiol Scand 65:292–299, 1965

34. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB: Years of life lost due to obesity.JAMA 289:187–193, 2003

35. Garvey HL, Melville KI: Cardiovascular effects of lateral hypothalamic stimulation in normaland coronaryligated dogs. J Cardiovasc Surg (Torino) 10:377–385, 1969

36. Goldstein JM, Siegel J: Suppression of attack behavior in cats by stimulation of ventraltegmental area and nucleus accumbens. Brain Res 183:181–192, 1980

37. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, et al.: Threeyearoutcomes in deep brain stimulation for highly resistant obsessivecompulsive disorder.

6/11/2015 JNS Journal of Neurosurgery

http://thejns.org/doi/full/10.3171/JNS/2008/109/10/0625 8/14

Neuropsychopharmacology 31:2384–2393, 2006 CrossRef, Medline

38. Groenewegen HJ, Russchen FT: Organization of the efferent projections of the nucleusaccumbens to pallidal, hypothalamic, and mesencephalic structures: a tracing andimmunohistochemical study in the cat. J Comp Neurol 223:347–367, 1984

39. Halpern C, Hurtig H, Jaggi J, Grossman M, Won M, Baltuch G: Deep brain stimulation inneurologic disorders. Parkinsonism Relat Disord 13:1–16, 2007 CrossRef, Medline

40. Hano J, Przewlocki R, Smialowska M, Chlapowska M, RokoszPelc A: The effect of electricstimulation of caudate nucleus and nucleus accumbens septi on serotonergic neurons in therat brain. Pol J Pharmacol Pharm 30:475–481, 1978

41. Heimer L: Basal forebrain in the context of schizophrenia. Brain Res Brain Res Rev31:205–235, 2000 CrossRef, Medline

42. Herberg LJ, Blundell JE: Lateral hypothalamus: hoarding behavior elicited by electricalstimulation. Science 155:349– 350, 1967

43. Hetherington AW, Ranson SW: The spontaneous activity and food intake in rats withhypothalamic lesions. Am J Physiol 36:609–616, 1942

44. Hoebel BG: Brain neurotransmitters in food and drug reward. Am J Clin Nutr 42:1133–1150,1985

45. Hoebel BG, Neuroscience and motivation: pathways and peptides that define motivationalsystems. Atkinson RC, Herrnstein RJ, Lindzey G, et al.: Stevens' Handbook of ExperimentalPsychology New York, Wiley, 1988. 547–625

46. Hoebel BG, Teitelbaum P: Hypothalamic control of feeding and selfstimulation. Science135:375–377, 1962

47. Huang XF, Han M, South T, Storlien L: Altered levels of POMC, AgRP and MC4R mRNAexpression in the hypothalamus and other parts of the limbic system of mice prone orresistant to chronic highenergy dietinduced obesity. Brain Res 992:9– 19, 2003

48. Huang XF, Xin X, McLennan P, Storlien L: Role of fat amount and type in ameliorating dietinduced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor,neuropeptide Y and proopiomelanocortin mRNA expression. Diabetes Obes Metab 6:35–44,2004

49. Huang XF, Zavitsanou K, Huang X, Yu Y, Wang H, Chen F, et al.: Dopamine transporter andD2 receptor binding densities in mice prone or resistant to chronic high fat dietinducedobesity. Behav Brain Res 175:415–419, 2006

50. Jalali R, Bergmann O, Hosmann K, Kupsch A, Juckel D, Morgenstern R, et al.: High frequencystimulation of the subthalamic nucleus reduces quinpirole induced compulsive checkingbehavior in rats. Program No. 115.8. 2004 Abstract Viewer/Itinerary Planner Washington DC,Society for Neuroscience, 2004. 118

51. Jeffery RW, Kelly KM, Rothman AJ, Sherwood NE, Boutelle KN: The weight loss experience:a descriptive analysis. Ann Behav Med 27:100–106, 2004

52. Kalarchian MA, Marcus MD, Wilson GT, Labouvie EW, Brolin RE, LaMarca LB: Binge eatingamong gastric bypass patients at longterm followup. Obes Surg 12:270–275, 2002

53. Kelley AE, Stinus L: Disappearance of hoarding behavior after 6hydroxydopamine lesions ofthe mesolimbic dopamine neurons and its reinstatement with Ldopa. Behav Neurosci99:531–545, 1985 CrossRef, Medline

54. Kennedy GC: The hypothalamic control of food intake in rats. Proc R Soc Lond B Biol Sci137:535–549, 1950

55. Kotz CM, Teske JA, Levine JA, Wang C: Feeding and activity induced by orexin A in thelateral hypothalamus in rats. Regul Pept 104:27–32, 2002

56. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al.: Fiveyear followupof bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl JMed 349:1925–1934, 2003 CrossRef, Medline

57. Krasne FB: General disruption resulting from electrical stimulus of ventromedialhypothalamus. Science 138:822–823, 1962

58. Lado FA, Velisek L, Moshe SL: The effect of electrical stimulation of the subthalamic nucleuson seizures is frequency dependent. Epilepsia 44:157–164, 2003

59. Lee KH, Chang SY, Roberts DW, Kim U: Neurotransmitter release from highfrequencystimulation of the subthalamic nucleus. J Neurosurg 101:511–517, 2004 Abstract, Medline

60. Lee KH, Roberts DW, Kim U: Effect of highfrequency stimulation of the subthalamic nucleuson subthalamic neurons: an intracellular study. Stereotact Funct Neurosurg 80:32–36, 2003CrossRef, Medline

61. Leone M, Franzini A, Felisati G, Mea E, Curone M, Tullo V, et al.: Deep brain stimulation andcluster headache. Neurol Sci 26:2 SupplS138–S139, 2005

62. Levin BE, Hogan S, Sullivan AC: Initiation and perpetuation of obesity and obesity resistancein rats. Am J Physiol 256:R766– R771, 1989

63. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, et al.: Metaanalysis:pharmacologic treatment of obesity. Ann Intern Med 142:532–546, 2005

6/11/2015 JNS Journal of Neurosurgery

http://thejns.org/doi/full/10.3171/JNS/2008/109/10/0625 9/14

64. Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J, et al.: Melaninconcentrating hormone overexpression in transgenic mice leads to obesity and insulinresistance. J Clin Invest 107:379–386, 2001

65. Maggard MA, Shugarman LR, Suttorp M, Maglione M, Sugerman HJ, Livingston EH, et al.:Metaanalysis: surgical treatment of obesity. Ann Intern Med 142:547–559, 2005 CrossRef,Medline

66. MaldonadoIrizarry CS, Kelley AE: Excitotoxic lesions of the core and shell subregions of thenucleus accumbens differentially disrupt body weight regulation and motor activity in rat.Brain Res Bull 38:551–559, 1995

67. MaldonadoIrizarry CS, Swanson CJ, Kelley AE: Glutamate receptors in the nucleusaccumbens shell control feeding behavior via the lateral hypothalamus. J Neurosci15:6779–6788, 1995

68. Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD: Role of the Y5 neuropeptide Y receptor infeeding and obesity. Nat Med 4:718–721, 1998

69. Martel P, Fantino M: Influence of the amount of food ingested on mesolimbic dopaminergicsystem activity: a microdialysis study. Pharmacol Biochem Behav 55:297–302, 1996

70. MathusVliegen EM: Longterm weight loss after bariatric surgery in patients visited at homeoutside the study environment. Obes Surg 16:1508–1519, 2006

71. McBriar MD, Guzik H, Xu R, Paruchova J, Li S, Palani A, et al.: Discovery of bicycloalkyl ureamelanin concentrating hormone receptor antagonists: orally efficacious antiobesitytherapeutics. J Med Chem 48:2274–2277, 2005

72. McCracken CB, Grace AA: Highfrequency deep brain stimulation of the nucleus accumbensregion suppresses neuronal activity and selectively modulates afferent drive in ratorbitofrontal cortex in vivo. J Neurosci 27:12601–12610, 2007

73. McIntyre CC, Savasta M, KerkerianLe Goff L, Vitek JL: Uncovering the mechanism(s) ofaction of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol 115:1239–1248, 2004 CrossRef, Medline

74. Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, et al.: Hypothalamicdopamine and serotonin in the regulation of food intake. Nutrition 16:843–857, 2000

75. Mendelson J, Chorover SL: Lateral hypothalamic stimulation in satiated rats: Tmaze learningfor food. Science 149:559– 561, 1965

76. Mirski MA, Ferrendelli JA: Interruption of the mammillothalamic tract prevents seizures inguinea pigs. Science 226:72– 74, 1984 CrossRef, Medline

77. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW: Central nervous systemcontrol of food intake and body weight. Nature 443:289–295, 2006

78. Moyer JT, Wolf JA, Finkel LH: Effects of dopaminergic modulation on the integrativeproperties of the ventral striatal medium spiny neuron. J Neurophysiol 98:3731–3748, 2007

79. Mucha RF, Iversen SD: Increased food intake after opioid microinjections into nucleusaccumbens and ventral tegmental area of rat. Brain Res 397:214–224, 1986

80. Murer MG, Pazo JH: Behavioral responses induced by electrical stimulation of the caudatenucleus in freely moving cats. Behav Brain Res 57:9–19, 1993

81. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH: The disease burdenassociated with overweight and obesity. JAMA 282:1523–1529, 1999 CrossRef, Medline

82. Ocón Bretón J, Pérez Naranjo S, Gimeno Laborda S, Benito Ruesca P, García Hernández R:[Effectiveness and complications of bariatric surgery in the treatment of morbid obesity.]. NutrHosp 20:409–414, 2005. (Span)

83. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM: Prevalence ofoverweight and obesity in the United States, 1999–2004. JAMA 295:1549–1555, 2006CrossRef, Medline

84. Okun MS, Mann G, Foote KD, Shapira NA, Bowers D, Springer U, et al.: Deep brainstimulation in the internal capsule and nucleus accumbens region: responses observedduring active and sham programming. J Neurol Neurosurg Psychiatry 78:310–314, 2007CrossRef, Medline

85. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al.: Neuronscontaining hypocretin (orexin) project to multiple neuronal systems. J Neurosci18:9996–10015, 1998

86. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al.: Who wouldhave thought it? An operation proves to be the most effective therapy for adultonset diabetesmellitus. Ann Surg 222:339–352, 1995

87. Poschel BPH: Comparison of reinforcing effects yielded by lateral versus medialhypothalamic stimulation. J Comp Physiol Psychol 61:346–352, 1966

88. Predy PA, Kokkindis L: Sensitization to the effects of repeated amphetamine administrationon intracranial selfstimulation: evidence for changes in reward processes. Behav Brain Res13:251–259, 1984

89. Purves D, Augustine GJ, Fitzpatrick D, Katz L, LaMantia A, McNamara JO, et al.:

6/11/2015 JNS Journal of Neurosurgery

http://thejns.org/doi/full/10.3171/JNS/2008/109/10/0625 10/14

Neuroscience ed 2Sunderland, MA, Sinauer Associated, Inc., 2001

90. Quaade F, Vaernet K, Larsson S: Stereotaxic stimulation and electrocoagulation of the lateralhypothalamus in obese humans. Acta Neurochir (Wien) 30:111–117, 1974 CrossRef,Medline

91. Rauch SL: Neuroimaging and neurocircuitry models pertaining to the neurosurgical treatmentof psychiatric disorders. Neurosurg Clin N Am 14:213–223, vii–viii, 2003 CrossRef, Medline

92. Roe DA, Eickwort KR: Relationships between obesity and associated health factors withunemployment among low income women. J Am Med Womens Assoc 31:193–194, 198–199,203–194, 1976

93. Rolls ET: The neurophysiology of feeding. Int J Obes 8:1 Suppl139–150, 1984

94. Ruffin M, Nicolaidis S: Electrical stimulation of the ventromedial hypothalamus enhances bothfat utilization and metabolic rate that precede and parallel the inhibition of feeding behavior.Brain Res 846:23–29, 1999

95. Saito M, Minokoshi Y, Shimazu T: Accelerated norepinephrine turnover in peripheral tissuesafter ventromedial hypothalamic stimulation in rats. Brain Res 481:298–303, 1989

96. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al.: Orexins and orexinreceptors: a family of hypothalamic neuropeptides and G proteincoupled receptors thatregulate feeding behavior. Cell 92:573–585, 1998

97. Sani S, Jobe K, Smith A, Kordower JH, Bakay RA: Deep brain stimulation for treatment ofobesity in rats. J Neurosurg 107:809–813, 2007 Abstract, Medline

98. Sani SB, Jobe KW, Kordower J, Bakay RA: Deep brain stimulation for the treatment of obesityin the rat. 73rd Annual Meeting, American Association of Neurological Surgeons RollingMeadows, IL, AANS, 2005. (Abstract #24653)

99. Schaltenbrand G, Warren W: Atlas for Stereotaxy of the Human Brain Stuttgart, Thieme, 1977

100. Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, et al.: Deep brainstimulation to reward circuitry alleviates anhedonia in refractory major depression.Neuropsychopharmacology 33:368–377, 2007 CrossRef, Medline

101. Schwartzbaum JS: Electrophysiology of taste, feeding and reward in lateral hypothalamus ofrabbit. Physiol Behav 44:507–526, 1988

102. Shimizu H, Shimomura Y, Takahashi M, Uehara Y, Fukatsu A, Sato N: Altered ambulatoryactivity and related brain monoamine metabolism in genetically obese Zucker rats. Exp ClinEndocrinol 97:39–44, 1991

103. Shumyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, et al.:Identification of a signaling network in lateral nucleus of amygdala important for inhibitingmemory specifically related to learned fear. Cell 111:905–918, 2002

104. Smith KS, Berridge KC: Opioid limbic circuit for reward: interaction between hedonic hotspotsof nucleus accumbens and ventral pallidum. J Neurosci 27:1594–1605, 2007

105. Stanley BG, Magdalin W, Seirafi A, Thomas WJ, Leibowitz SF: The perifornical area: the majorfocus of (a) patchily distributed hypothalamic neuropeptide Ysensitive feeding system(s).Brain Res 604:304–317, 1993

106. Stenger J, Fournier T, Bielajew C: The effects of chronic ventromedial hypothalamicstimulation on weight gain in rats. Physiol Behav 50:1209–1213, 1991

107. Sturm R: Increases in morbid obesity in the USA: 2000–2005. Public Health 121:492–496,2007 CrossRef, Medline

108. Sturm V, Lenartz D, Koulousakis A, Treuer H, Herholz K, Klein JC, et al.: The nucleusaccumbens: a target for deep brain stimulation in obsessivecompulsive and anxietydisorders. J Chem Neuroanat 26:293–299, 2003 CrossRef, Medline

109. Taha SA, Fields HL: Encoding of palatability and appetitive behaviors by distinct neuronalpopulations in the nucleus accumbens. J Neurosci 25:1193–1202, 2005

110. Teegarden SL, Bale TL: Decreases in dietary preference produce increased emotionality andrisk for dietary relapse. Biol Psychiatry 61:1021–1029, 2007 CrossRef, Medline

111. Toleikis JR, Toleikis SC, Barborica A, Verhagen L, Sturaitis MK, Bakay R: Analysis of humansingle unit activity acquired during deep brain stimulation. Proceedings of the AmericanAssociation of Neurological Surgeons, Annual Meeting 2007 Park Ridge, IL, AANS, 2007

112. Tremblay LK, Naranjo CA, Graham SJ, Herrmann N, Mayberg HS, Hevenor S, et al.:Functional neuroanatomical substrates of altered reward processing in major depressivedisorder revealed by a dopaminergic probe. Arch Gen Psychiatry 62:1228–1236, 2005CrossRef, Medline

113. Valenstein ES, Cox VC, Kakolewski JW: Modification of motivated behavior elicited byelectrical stimulation of the hypothalamus. Science 159:1119–1121, 1968

114. van Kuyck K, Demeulemeester H, Feys H, De Weerdt W, Dewil M, Tousseyn T, et al.: Effectsof electrical stimulation or lesion in nucleus accumbens on the behaviour of rats in a Tmazeafter administration of 8OHDPAT or vehicle. Behav Brain Res 140:165–173, 2003

115. van Kuyck K, Gabriëls L, Cosyns P, Arckens L, Sturm V, Rasmussen S, et al.: Behavioural andphysiological effects of electrical stimulation in the nucleus accumbens: a review. Acta

6/11/2015 JNS Journal of Neurosurgery

http://thejns.org/doi/full/10.3171/JNS/2008/109/10/0625 11/14

Neurochir Suppl 97375–391, 2007

116. Van Rijckevorsel K, Basel A, de Tourtchaninoff M, Gwenaelle M, Ivanoiu A, Grandin C, et al.:Safety and tolerability of deep brain stimulation of mammillary bodies and mammillothalamicarea in patients with chronic refractory epilepsy. Epilepsia 45:164, 2004

117. Velley L, Cardo B: Longterm improvement of learning after early electrical stimulation ofsome central nervous structures: is the effect structure and agedependent?. Brain Res Bull4:459–466, 1979

118. Voges J, Waerzeggers Y, Maarouf M, Lehrke R, Koulousakis A, Lenartz D, et al.: Deepbrainstimulation: longterm analysis of complications caused by hardware and surgery–experiences from a single centre. J Neurol Neurosurg Psychiatry 77:868– 872, 2006CrossRef, Medline

119. Volkow ND, O'Brien CP: Issues for DSMV: should obesity be included as a brain disorder?.Am J Psychiatry 164:708– 710, 2007

120. Wang GJ, Volkow ND, Thanos PK, Fowler JS: Similarity between obesity and drug addictionas assessed by neurofunctional imaging: a concept review. J Addict Dis 23:39–53, 2004

121. Weber M, Muller MK, Bucher T, Wildi S, Dindo D, Horber F, et al.: Laparoscopic gastricbypass is superior to laparoscopic gastric banding for treatment of morbid obesity. Ann Surg240:975–983, 2004

122. Will MJ, Pratt WE, Kelley AE: Pharmacological characterization of highfat feeding induced byopioid stimulation of the ventral striatum. Physiol Behav 89:226–234, 2006

123. Wise RA, Rompre PP: Brain dopamine and reward. Annu Rev Psychol 40:191–225, 1989

124. Wolf JA, Moyer JT, Lazarewicz MT, Contreras D, BenoitMarand M, O'Donnell P, et al.:NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computationalmodel of the nucleus accumbens medium spiny projection neuron. J Neurosci25:9080–9095, 2005

125. Wortley KE, Chang GQ, Davydova Z, Leibowitz SF: Peptides that regulate food intake: orexingene expression is increased during states of hypertriglyceridemia. Am J Physiol Regul IntegrComp Physiol 284:R1454–R1465, 2003

126. Wright J, Kelly DF, MitchellHeggs N, Frankel R, Respiratory changes induced by intracranialstimulation: anatomical localizing value and related functional effects in rhesus monkeys.Sweet WH, Obrador S, MartinRodriguez JG: Neurosurgical Treatment in Psychiatry, Pain,and Epilepsy Baltimore, University Park Press, 1977. 751–756

127. Wyrwicka W, Dobrzecka C: Relationship between feeding and satiation centers of thehypothalamus. Science 132:805–806, 1960

128. Zaborszky L, Alheid GF, Beinfeld MC, Eiden LE, Heimer L, Palkovits M: Cholecystokinininnervation of the ventral striatum: a morphological and radioimmunological study.Neuroscience 14:427–453, 1985

129. Zahm DS: An integrative neuroanatomical perspective on some subcortical substrates ofadaptive responding with emphasis on the nucleus accumbens. Neurosci Biobehav Rev24:85– 105, 2000

130. Zahm DS, Brog JS: On the significance of subterritories in the “accumbens” part of the ratventral striatum. Neuroscience 50:751–767, 1992 CrossRef, Medline

131. Zhang M, Gosnell BA, Kelley AE: Intake of highfat food is selectively enhanced by mu opioidreceptor stimulation within the nucleus accumbens. J Pharmacol Exp Ther 285:908–914,1998

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http://thejns.org/doi/full/10.3171/JNS/2008/109/10/0625 13/14

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28. J Luigjes, W van den Brink, M Feenstra, P van den Munckhof, P R Schuurman, R Schippers,A Mazaheri, T J De Vries, D Denys. (2012) Deep brain stimulation in addiction: a review ofpotential brain targets. Molecular Psychiatry 17, 572583. . Online publication date: 1Jun2012. [CrossRef]

29. JoséAlberto Palma, Jorge Iriarte. (2012) Regulación del apetito: bases neuroendocrinas eimplicaciones clínicas. Medicina Clínica 139, 7075. . Online publication date: 1Jun2012.[CrossRef]

30. Casey H. Halpern, Grant W. Mitchell, Aaron Paul, Daniel R. Kramer, Kathryn R. McGill, DanaBuonacuore, Marie Kerr, Jurg L. Jaggi, John J. Stern, Gordon H. Baltuch. (2012) Selfadministered preoperative antiseptic wash to prevent postoperative infection after deepbrain stimulation. American Journal of Infection Control 40, 431433. . Online publicationdate: 1Jun2012. [CrossRef]

31. R. Aaron Robison, Alexander Taghva, Charles Y. Liu, Michael L.J. Apuzzo. (2012) Surgeryof the Mind, Mood, and Conscious State: An Idea in Evolution. World Neurosurgery 77, 662686. . Online publication date: 1May2012. [CrossRef]

32. Judy Luigjes, Bart P. de Kwaasteniet, Pelle P. de Koning, Marloes S. Oudijn, Pepijn van denMunckhof, P. Richard Schuurman, Damiaan Denys. (2012) Surgery for PsychiatricDisorders. World Neurosurgery. . Online publication date: 1Mar2012. [CrossRef]

33. Daniel R. Kramer, Casey H. Halpern, Shabbar F. Danish, Jurg L. Jaggi, Gordon H. Baltuch.(2012) The Effect of Intraventricular Trajectory on Brain Shift in Deep Brain Stimulation.Stereotactic and Functional Neurosurgery 90, 2024. . Online publication date: 1Jan2012.[CrossRef]

34. Daniel R. Kramer, Casey H. Halpern, Patrick J. Connolly, Jurg L. Jaggi, Gordon H. Baltuch.(2012) Error Reduction with Routine Checklist Use during Deep Brain Stimulation Surgery.Stereotactic and Functional Neurosurgery 90, 255259. . Online publication date: 1Jan2012. [CrossRef]

35. Alexander S. Taghva, Chima O. Oluigbo, Ali R. Rezai. 2012. Basic Principles of Deep BrainStimulation for Movement Disorders, Neuropsychiatric Disorders, and New Frontiers.Principles of Neurological Surgery, 783795. [CrossRef]

36. K.S. Ettrup, J.C. Sørensen, A. Rodell, A.K.O. Alstrup, C.R. Bjarkam. (2012) HypothalamicDeep Brain Stimulation Influences Autonomic and Limbic Circuitry Involved in theRegulation of Aggression and Cardiocerebrovascular Control in the Göttingen Minipig.Stereotactic and Functional Neurosurgery 90, 281291. . Online publication date: 1Jan2012. [CrossRef]

37. Zoë MeleoErwin. 2012. “I Just Couldn’t Keep it in Control Anymore:” Weight Loss Surgery,Food Addiction, and AntiFat Stigma. Critical Perspectives on Addiction, 201224. [CrossRef]

38. Marc Baroncini, Patrice Jissendi, Eglantine Balland, Pierre Besson, JeanPierre Pruvo,JeanPaul Francke, Didier Dewailly, Serge Blond, Vincent Prevot. (2012) MRI atlas of thehuman hypothalamus. NeuroImage 59, 168180. . Online publication date: 1Jan2012.[CrossRef]

39. C. O. Oluigbo, A. Salma, A. R. Rezai. (2012) Deep Brain Stimulation for NeurologicalDisorders. IEEE Reviews in Biomedical Engineering 5, 8899. . Online publication date: 1Jan2012. [CrossRef]

40. Nestor D. Tomycz, Donald M. Whiting, Michael Y. Oh. (2011) Deep brain stimulation forobesity—from theoretical foundations to designing the first human pilot study. NeurosurgicalReview. . Online publication date: 15Oct2011. [CrossRef]

41. James H Stephen, Casey H Halpern, Cristian J Barrios, Usha Balmuri, Jared M Pisapia,John A Wolf, Kyle M Kampman, Gordon H Baltuch, Arthur L Caplan, Sherman C Stein.(2011) DEEP BRAIN STIMULATION COMPARED WITH METHADONE MAINTENANCEFOR THE TREATMENT OF HEROIN DEPENDENCE: A THRESHOLD AND COSTEFFECTIVENESS ANALYSIS. Addiction, nono. . Online publication date: 1Sep2011.[CrossRef]

42. W. Nager, J.K. Krauss, M. Heldmann, J. MarcoPallares, H.H. Capelle, G. Lütjens, S. Bolat,R. Dengler, T.F. Münte. (2011) Human hypothalamus shows differential responses to basicmotivational stimuli—an invasive electrophysiology study. Neuroscience 189, 330336. .Online publication date: 1Aug2011. [CrossRef]

43. Mark K. Lyons. (2011) Deep Brain Stimulation: Current and Future Clinical Applications.Mayo Clinic Proceedings 86, 662672. . Online publication date: 1Jul2011. [CrossRef]

44. C O Oluigbo, A R Rezai. (2011) Addressing Neurological Disorders With Neuromodulation.IEEE Transactions on Biomedical Engineering 58, 19071917. . Online publication date: 1Jul2011. [CrossRef]

45. Ioannis Mavridis, Efstathios Boviatsis, Sophia Anagnostopoulou. (2011) Stereotacticanatomy of the human nucleus accumbens: from applied mathematics to microsurgicalaccuracy. Surgical and Radiologic Anatomy. . Online publication date: 25Mar2011.[CrossRef]

46. Ioannis Mavridis, Efstathios Boviatsis, Sophia Anagnostopoulou. (2011) Anatomy of the

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http://thejns.org/doi/full/10.3171/JNS/2008/109/10/0625 14/14

human nucleus accumbens: a combined morphometric study. Surgical and RadiologicAnatomy. . Online publication date: 4Jan2011. [CrossRef]

47. Jay L. Shils. 2011. Programming – DBS Programming. Essential Neuromodulation, 349373. [CrossRef]

48. Yakov Gologorsky, Ron Alterman. 2011. Cerebral – Deep. Essential Neuromodulation, 4772. [CrossRef]

49. Jens Clausen. (2010) Ethical brain stimulation neuroethics of deep brain stimulation inresearch and clinical practice. European Journal of Neuroscience32:10.1111/ejn.2010.32.issue7, 11521162. . Online publication date: 1Oct2010.[CrossRef]

50. Daniel R. Kramer, B.A., Casey H. Halpern, M.D., Dana L. Buonacore, M.S.N., Kathryn R.McGill, M.S.N., Howard I. Hurtig, M.D., Jurg L. Jaggi, Ph.D., and Gordon H. Baltuch, M.D.,Ph.D.. (2010) Best surgical practices: a stepwise approach to the University of Pennsylvaniadeep brain stimulation protocol. Neurosurgical Focus 29:2, E3. . Online publication date: 1Aug2010. Abstract | Full Text | PDF (492 KB) | PDF Plus

51. Jared M. Pisapia, B.A., Casey H. Halpern, M.D., Noel N. Williams, M.D., Thomas A. Wadden,Ph.D., Gordon H. Baltuch, M.D., Ph.D., and Sherman C. Stein, M.D.. (2010) Deep brainstimulation compared with bariatric surgery for the treatment of morbid obesity: a decisionanalysis study. Neurosurgical Focus 29:2, E15. . Online publication date: 1Aug2010.Abstract | Full Text | PDF (538 KB) | PDF Plus

52. Adrien Quintana, Christophe Melon, Lydia KerkerianLe Goff, Pascal Salin, Marc Savasta,Véronique SgambatoFaure. (2010) Forelimb dyskinesia mediated by highfrequencystimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of Nmethyldaspartate receptors. European Journal of Neuroscience32:10.1111/ejn.2010.32.issue3, 423434. . Online publication date: 1Aug2010. [CrossRef]

53. Federico Bilotta, Antonio Santoro, Giovanni Rosa. (2010) A Wake “Anesthesia” forIntraoperative Language Testing During Temporary Clip Application in a Patient With GiantIntracranial Aneurysm. Journal of Neurosurgical Anesthesiology 22, 272273. . Onlinepublication date: 1Jul2010. [CrossRef]

54. M J Lehmkuhle, S M Mayes, D R Kipke. (2010) Unilateral neuromodulation of theventromedial hypothalamus of the rat through deep brain stimulation. Journal of NeuralEngineering 7, 036006. . Online publication date: 1Jun2010. [CrossRef]

55. Kaare S. Ettrup, Jens Christian Sørensen, Carsten R. Bjarkam. (2010) The anatomy of theGöttingen minipig hypothalamus. Journal of Chemical Neuroanatomy 39, 151165. . Onlinepublication date: 1May2010. [CrossRef]

56. Federico Bilotta, Giovanni Rosa. (2009) ‘Anesthesia’ for awake neurosurgery. CurrentOpinion in Anaesthesiology 22, 560565. . Online publication date: 1Oct2009. [CrossRef]

57. Shigeki Kameyama, Hiroatsu Murakami, Hiroshi Masuda, Ichiro Sugiyama. (2009)MINIMALLY INVASIVE MAGNETIC RESONANCE IMAGINGGUIDED STEREOTACTICRADIOFREQUENCY THERMOCOAGULATION FOR EPILEPTOGENIC HYPOTHALAMICHAMARTOMAS. Neurosurgery 65, 438449. . Online publication date: 1Sep2009.[CrossRef]

58. Nasir Raza Awan, M.B.B.S., F.C.P.S., Andres Lozano, M.D., Ph.D., and Clement Hamani,M.D., Ph.D.. (2009) Deep brain stimulation: current and future perspectives. NeurosurgicalFocus 27:1, E2. . Online publication date: 1Jul2009. Abstract | Full Text | PDF (818 KB) |PDF Plus

59. Michael Y. Oh, David B. Cohen, Donald M. Whiting. 2009. Deep Brain Stimulation forObesity. Neuromodulation, 959966. [CrossRef]

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