Deep brain stimulation in the treatment of...

J. Neurosurg. / Volume 109 / October 2008

J Neurosurg 109:000–000, 2008

625

HigH-frequency deep brain stimulation is the treat-ment of choice for well-selected patients with medically refractory PD. Deep brain stimulation

provides significant symptomatic improvement in par-kinsonism in both animal and human studies,31,56 and at high frequencies (130–160 Hz) mimics the clinical ef-fects of tissue lesioning.6,9,11 In contrast to stereotactic lesions, however, DBS provides the added benefit of re-versibility 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 the remarkable improvement in par-kinsonism, high-frequency STN DBS appears to induce functional inhibition of this region.9 Indeed, some have

shown that high-frequency 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 re-mains unclear, whether it be 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 treatment-resistant psychiatric condi-tions.39 The purpose of this paper is to motivate the neuro-surgical community to consider DBS for obesity control. Obesity is a chronic disease with well-substantiated neu-ropsychiatric underpinnings. Appetite and satiety centers in the brain have been well-documented93 and thus rep-resent 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 pathophysiolo-gy of obesity.7,44,123 In support of this concept, it was recent-ly proposed that obesity be included as a mental disorder in the next (fifth) edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V).119 Below, we review 3 potential neural targets for DBS believed to be involved in the excessive consumption of food in obesity.


J Neurosurg 109:625–634, 2008

Deep brain stimulation in the treatment of obesity

A review

Casey 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

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

Obesity is a growing global health problem frequently intractable to current treatment options. Recent evidence suggests that deep brain stimulation (DBS) may be effective and safe in the management of various, refractory neu-ropsychiatric disorders, including obesity. The authors review the literature implicating various neural regions in the pathophysiology of obesity, as well as the evidence supporting these regions as targets for DBS, in order to explore the therapeutic promise of DBS in obesity.

The lateral hypothalamus and ventromedial hypothalamus are the appetite and satiety centers in the brain, respec-tively. Substantial data support targeting these regions with DBS for the purpose of appetite suppression and weight loss. However, reward sensation associated with highly caloric food has been implicated in overconsumption as well as obesity, and may in part explain the failure rates of conservative management and bariatric surgery. Thus, regions of the brain’s reward circuitry, 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 promising therapeutic op-tion for patients suffering from refractory obesity. (DOI: 10.3171/JNS/2008/109/10/0625)

key WorDs • deep brain stimulation • hypothalamus • obesity • nucleus accumbens • reward

625

Abbreviations used in this paper: BMI = body mass index; DBS = deep brain stimulation; GABA = γ-aminobutyric acid; LH = lateral hypothalamus; MCH = melanin-concentrating hormone; NAc = nucleus accumbens; OCD = obsessive-compulsive disorder; PD = Parkinson disease; 6-OHDA = 6-hydroxydopamine; STN = sub-thalamic nucleus; VMH = ventromedial hypothalamus; VP = ventral pallidum.

C. H. Halpern et al.

626 J. Neurosurg. / Volume 109 / October 2008

BackgroundObesity, defined as a BMI > 30 kg/m2, affects more

than 30% of adult Americans83 and over 300 million peo-ple 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 10-fold increase in bariatric sur-geries performed over the past 8 years.107 Although mean 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 peri-surgical mortality rate is ~ 1.5% even in experienced cen-ters.82,86 Furthermore, significant weight gain occurs after the nadir weight is reached, approximately 2 years post-operatively.20 The failure rate due to noncompliant eating patterns in patients followed up for 10 years is as high as 20% for obese and 40% for super-obese (BMI > 50 kg/m2) patients.15,20 One follow-up study reported recurrent binge eating in 46% of patients who had undergone bariatric sur-gery.52 Thus, consideration of the neuropsychiatric basis of obesity may help explain these refractory eating habits and the significant surgical failure rate.

Deep Brain Stimulation of the Hypothalamus: Rationale

Overconsumption of calorically dense foods is a like-ly contributor to the rapidly progressing epidemic of obe-sity.16 Body weight results at least in part from a balance between food intake and energy expenditure, and obesity is due to an imbalance between energy input and output. The hypothalamus has been shown to be integral in main-taining this energy homeostasis. Specifically, food intake is at least in part controlled by a feeding center in the lat-eral hypothalamus and a satiety center in the ventrome-dial hypothalamus.93 We will discuss these regions below as potential targets 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 in-duced leanness.3 This impact 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−/− mice have been shown to be lean and hypophagic, and mice with overexpression of MCH, obese and insulin-resistant.64 Chronic administra-tion of an orally active MCH receptor antagonist decreased food intake, body weight, and adiposity in rodent obesity models.71 Injections of orexins into the LH increased feed-ing 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 in clude neuropeptide Y68 and agouti-related protein,14 which densely project to the LH.30,105

Anatomy of the LH. The 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 for further definition of this target structure.) Targeting the LH with DBS has been associated with risk of the spread of stimulation to nearby hypothalamic nuclei. The hypothalamus comprises a large number of distinct nuclei, and thus has many physiological functions not limited to appetite control, including body temperature regulation, sexual ac-tivity, reproductive endocrinology, and the fight-or-flight response.89 The effect of stimulating any adjacent hypotha-lamic region is thus associated with altering these physio-logical responses. Other neural structures located adjacent to the LH include the fornix and the optic nerve. Portions of the LH are just inferior to the fornix and directly supe-rior and posterior to the optic nerve and chiasm, further complicating the targeting of this nucleus with DBS.99

Stereotaxy and Stimulation of the LH. Nevertheless, targeting the hypothalamus with DBS has already been shown to be safe and potentially effective in managing pa-tients with intractable chronic cluster headache.61 Further-more, stereotactic electrocoagulation of the LH in obese hu mans was performed safely more than 30 years ago, re-sulting in significant, although transient, appetite suppres-sion and slight weight reduction in 3 patients.90 Given this evidence, it was recently proposed that chronic bilateral DBS of the LH at high frequencies would mimic the re-sults 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 high-frequency stimula-tion (stimulation parameters: 2.0 V, pulse width 100 msec, frequency 180–200 Hz), while the other half were left un-stimulated. On postoperative Day 24, stimulation was as-sociated with a mean loss of 2.3% of body weight, while the unstimulated group had a mean weight gain of 13.8% (p < 0.001). Interestingly, no difference in food intake was found between groups. Thus, the authors concluded that the stimulation-induced weight loss seen in the stimulated group was secondary to metabolic change, although no mea surements of individual animals’ metabolic profiles were made. In contrast to high frequency LH stimulation, 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 rhyth-mic oral activity in rabbits.101 Other effects of LH stimula-tion included exploration, as well as escape and attack be-haviors associated with autonomic changes with increases in stimulation strength. These findings are consistent with those observed in canine LH stimulation 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 cardiac arrhythmias.

Ventromedial HypothalamusLike the LH, the VMH has also been implicated in



627

ap petite regulation and the maintenance of energy homeo-stasis.43,54 Le sions of the VMH have been shown to induce weight gain in obese animals,18 and lesions resulted in sub-stantially more carcass lipid and hyperinsulinemia in rats even if pair-fed with sham-lesioned controls, suggesting a metabolic bias toward obesity.22

Anatomy of the VMH. There are various challenges to surgically targeting the VMH that need to be considered. The VMH is a small bilobed target in the vertical axis measuring approximately 2 × 3 × 5 mm in the largest di-mensions (Fig. 2).99 Although found slightly inferior to the anterior commissure in the anteroposterior plane, which may facilitate accurate localization, an intraventricular trajectory may be required given such a medial location of the VMH. Furthermore, the VMH is bounded by the optic nerve anteriorly and the mammillary body posteri-orly. Deep brain stimulation of the mammillary bodies is currently under in vestigation as a potential target for sei-zure control.116 Due to their connections to the circuit of Papez, and given substantial evidence pointing to an im-

portant role of this circuitry in seizure propagation and ex-pression, 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 well-known to be largely interconnected,89 and thus it is conceivable that stimulation spread to the LH may directly antagonize the effect of low-frequency DBS of the VMH.

Stereotaxy and Stimulation of the VMH. Electrical stimulation of the VMH has been reported, and stimula-tion at low frequencies (60–100 Hz) inhibited feeding in hungry rats, and eating resumed once the current was ter-minated.46,57 In goats, VMH stimulation at low frequencies (for example, 50 Hz) inhibited feeding as well.5,127 Other effects of stimulation included fear, aversion, restlessness, and attempts at escape, which may have partially account-ed for the decreased feeding behavior in these animals.46,57 These effects may be related to autonomic changes due to VMH stimulation, which has been shown to increase meta-bolic rate.94 This increase in energy expenditure was as-sociated with increased fat oxidation given a concomitant

Fig. 1. A sagittal section depicting the lateral hypothalamus adjacent to the optic nerve. The fornix is not well visu-alized in this section. *lateral hypothalamus (L); #optic nerve (II); ^ nucleus accumbens (Fu.st). From Schaltenbrand G, Warren W: Atlas for Stereotaxy of the Human Brain. Stuttgart: Thieme, 1977. Reprinted, with the addition of *, #, and ^, by permission.



drop in the respiratory quotient. Thus, heightened metabo-lism induced by VMH stimulation was sustained by utili-zation of fat stores, most likely due to noradrenergic turn-over.95,106 Recently, VMH DBS at 4 different frequencies (25, 50, 75, and 100 Hz) in a rat was shown by means of in-direct calorimetry to result in an increase in metabolism.21 There was a trend toward an indirect relationship between energy expenditure and increasing frequencies, suggesting that lower frequencies of stimulation drive VMH activity, while higher frequencies may have lesioning effects (A. L. Benabid, 2006, personal communication). These findings are consistent with a frequency-dependent effect of stimu-lation.58

Deep Brain Stimulation of the Nucleus Accumbens: Rationale

Physiological states associated with energy balance, such as hunger and satiety, are strong determinants of feed-ing behavior. The above data support the idea that DBS of the LH or VMH at various frequencies may be able to modulate the neural regions associated with energy ho-meostasis. However, the assumption that feeding behavior in obesity can be effectively modulated by inhibiting ap-petite sensation or driving satiety may not be correct. In fact, there is a significant amount of evidence that feeding behavior is strongly influenced by palatability, or the rein-forcing value of food, irrespective of appetite. For example, there is a 90% increase in food intake in mice fed a high-fat diet compared with their consumption when fed normal house chow.110 Such a palatable diet (45 kcal % fat) is pre-

ferred to standard house chow because of reinforcing prop-erties believed to be mediated largely in the NAc.44,104,123

Anatomy of the NAcThe NAc is a ventral striatal region located immedi-

ately inferior to the anterior limb of the internal capsule. As a DBS target, the NAc is very similar to the STN. It measures approximately 8 × 6 × 6 mm 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 a well-circumscribed, ellipsoid shape with relatively clear-cut boundaries on myelin-stained sections, with the most superior edge directed medially.99 The center of the NAc is located just about 3 mm anterior to the anterior com-missure and approximately 6 mm lateral from the mid-line. To target the NAc, a trajectory can be taken just lat-eral 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 pal lidus in PD.4 Certainly some cognitive deficits such as mem ory impairment are possible 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 an terior cerebral artery located just inferiorly, as well as the optic nerve found inferomedially.99

The NAc is divided into 2 subregions, core and shell, based on cytoarchitectonic and neurotransmitter charac-teristics, as well as differences in the afferent and efferent

Fig. 2. A sagittal section depicting the ventromedial hypothalamus bounded anteriorly by the optic nerve and pos-teriorly by the ipsilateral mammillary body. *ventromedial hypothalamus (Vm); #mammillary body (M.m); +optic chiasm (Ch. II); ^anterior commissure (Cm.a). From Schaltenbrand G, Warren W: Atlas for Stereotaxy of the Human Brain. Stuttgart: Thieme, 1977. Reprinted, with the addition of *, #, +, and ^, by permission.



629

connections.128 Anatomical tracing studies have shown that the core region connects extensively to extrapyrami-dal motor structures, such as the VP, the STN, and the substantia nigra.29 The shell region is believed to be con-fined to the ventromedial margins of the NAc41 and is em-bedded in a complex mesocorticolimbic circuit providing control of reward sensitivity. The NAc shell receives dop-aminergic input from the ventral tegmental area, as well as afferents from the amygdala, hippocampus, prefron-tal 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 simultaneous in-volvement of the NAc shell and the VP in favorable reac-tions to taste in rodents (“liking”), such as tongue protru-sions, 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 centers in the brain. Sig-nifi cant 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 sen-

sation shown to be associated with palatability of foods. Results from single-unit recordings from the NAc demon-strated that in a subset of neurons, firing rates varied signif-icantly as a function of sucrose concentration.109 Further-more, palatable food such as chow with high fat content (45 kcal % fat) was preferred to standard house chow because 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

Fig. 3. A coronal section depicting the nucleus accumbens located in the ventral striatum just inferior to the cau-date nucleus and inferolateral to the lateral ventricle. *nucleus accumbens (Fu.st); #caudate nucleus (Cd); + putamen (Put). From Schaltenbrand G, Warren W: Atlas for Stereotaxy of the Human Brain. Stuttgart: Thieme, 1977. Re-printed, with the addition of *, #, and ^, by permission.



Furthermore, the levels of dopamine release were propor-tional to the amount ingested,69 and there is a significantly greater amount of dopamine released in the NAc of obese rats relative to lean rats in response to food stimuli.74,123

Sensitivity to reward can vary from one person to another, but those individuals with more frequent and in-tense food cravings are more likely to be obese.8 Mice withdrawn from a highly palatable diet will endure an aversive environment to obtain preferred foods, and show a significant increase in expression of corticotropin-re-leasing factor associated with a stress state.110 Thus, we support the recent suggestion that at least some forms of obesity may be driven by an excessive motivational drive 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 suggest-ing that signals of internal homeostasis may be relevant in modulating food reward.67 Studies in animal models of obesity, however, have demonstrated altered expres-sion 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 rates may be at least in part a result of a dysregulated reward system, leading to our experience to date with conservative measures and bariatric surgery.

The idea that dopamine plays a dominant role in mod-ulating palatability has been recently called into question. Multiple neurotransmitters have been implicated in ac-cumbal reward processes, some with potent effects on in-take of high-fat diets. Injections of opioid receptor agonists into the NAc induced hyperphagia and a preference for fat consumption that was independent of dopamine neu-rotransmission and was blocked by cotreatment with nal-trexone.79,122,131 The majority of corticolimbic inputs to the NAc use an excitatory amino acid as their neurotransmitter. Indeed, blockade of α-amino-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the shell subregion of the NAc resulted in pronounced feeding.67 However, the majority of the cells in the NAc are GABAergic and there-fore inhibitory, both locally and at their projection targets. In addition, there is also significant cholinergic neuromod-ulation of these cells. Thus, within the NAc is an extensive network of multiple neurotransmitter systems, some or all of which may be intimately involved in food reward sensa-tion. Further study, including detailed computational mod-eling of the modulation 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 injection of the neurotoxin 6-OHDA results in dopamine depletion in this region. The 6-OHDA lesions of NAc resulted in significant attenuation of food hoarding and weight loss in rats,53 and administration of levodopa restored normal hoarding behavior. While lesioning effects of DBS at high frequencies are well documented, it is difficult to predict

whether DBS could mimic the effects of 6-OHDA lesions given the variety of neurotransmitter systems involved in the NAc and the differentiated anatomical projections of the accumbal subregions. N-methyl-d-aspartate lesions of the NAc core induced weight loss in rats, whereas the shell-lesion group gained weight.66 The authors of the study argued that the loss of weight in the core group was due to changes in motor function given the core’s con-nections to the extrapyramidal system.29 It is conceivable that the core and shell have opposing effects on inges-tive behavior, explaining the lack of any change in weight with large, nonspecific excitotoxic lesions encompassing both regions of the NAc. Given the functional dissocia-tion within the NAc, further investigation is necessary to determine if modulation of reward sensation is possible with DBS, what region of the NAc is most appropriate to target, and what frequencies are necessary to obtain the desired effects. Furthermore, given the proximity of the NAc to various structures, including the globus pallidus, anterior limb of the internal capsule, VP, and caudate, rig-orous stereotactic methods are necessary to ensure pre-cise placement of the permanent electrode.

Evidence From Neurofunctional ImagingFunctional MR imaging studies have demonstrated

activation of striatal reward areas during exposure to a high-fat stimulus, particularly in those patients with en-hanced reward sensitivity.8 A hyperfunctioning region is known to be susceptible to the effects of DBS given the lesioning effect of high frequency stimulation of the over-active STN in PD. Positron emission tomography and au-toradiographic 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 been found in the NAc of obese mice relative to the levels found in obesity-resistant mice, a dif-fernce that may be due to enhanced clearance.49,102 While heightened reward is evident in obesity associated with increased levels of accumbal dopamine release follow-ing exposure to a food stimulus, this sensation may be short-lived due to a decreased sensitivity of dopaminergic reward circuits. Thus, a need to compensate with food re-inforcers in conjunction with an increased stress response to palatable food restriction may be the underlying causes for the reported high rates of recurrent binge eating and surgical failures in bariatric patients.

Evidence From NAc Stimulation StudiesElectrical stimulation of the NAc has been performed

in rats.53,72,88 Multiple effects of NAc stimulation have been reported in rats, including increased sniffing, excitement, and even aggression, which were all observed at a stim-ulation frequency of 60 Hz.40 These findings have been replicated in cats,36 although no such effects were noted in rhesus monkeys.126 No consistent documentation of the response of feeding behavior to NAc DBS has been report-ed,80,117 but none of these studies included overweight or obese animals. Some evidence for the potential of NAc DBS in obesity control can be derived from its success in re lieving symptoms of OCD.37



631

Reward Circuitry DBS in Other Treatment-Resistant Conditions

Bilateral NAc stimulation in a rat model of OCD has shown promise for the use of this modality in humans. Electrodes were implanted bilaterally using stereotactic coordinates similar to those previously documented.53 Al-though further investigation is required, high-frequency stimulation appeared to diminish OCD symptoms in vari-ous rat models of OCD.50,114,115 One explanation for these findings, as well as for the success of NAc DBS in patients with OCD, comes from a recent study in which high-fre-quency 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 associ-ated with OCD symptoms.17

A trial of DBS of the ventral capsule/ventral striatum site, a region that encompasses the NAc, in 10 OCD patients with long-term follow-up demonstrated a 36% decrease in disease severity and nearly a 50% improvement in global functioning.37 This region has been consistently implicated in OCD 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, and particularly the NAc, has been shown to respond abnormally to pleasurable stimuli in patients suffering from severe depression.112 Deep brain stimula-tion of the NAc provided a 42% improvement in depres-sion severity in one study.100 These reports not only provide encouraging evidence for the therapeutic effect and safety of DBS, but also for its promise in modulating neural re-gions implicated in reward sensation associated with the pathophysiology of obesity.

ConclusionsAppetite modulation in conjunction with enhancement

of the metabolic rate by means of hypothalamic lesions has been widely documented in animal models and even in humans. It appears that these effects can be reproduced by DBS, and the titratability and reversibility of this pro-cedure, in addition to its well-established safety profile, make hypothalamic DBS an appealing option for obesity treatment. Given that palatability significantly increases food intake, however, suppressing appetite and increasing energy expenditure may prove to be inadequate, especially over 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 reward sensation and dietary preferences by interacting with the systems known to be implicated in the reinforcing properties of food. Inhibition of food reward may provide significant weight reduction over time and ef-fectively lessen relapse rates associated with conservative and surgical treatments. Moreover, stimulation frequency may be titratable to adequate inhibition of food preference and overconsumption. 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 the potential role of DBS in attenu-ating the reinforcing properties of highly palatable foods

that have clearly 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.

Disclaimer

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

References

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

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

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

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

5. Andersson B: The effect and localization of electrical stimu-lation of certain parts of the brain stem 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. J Neurosurg 20:860–870, 1963

7. Aou S, Oomura Y, Nishino H, Inokuchi A, Mizuno Y: Influ-ence of catecholamines on reward-related 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: Individual differences in reward drive predict neural responses to images of food. J Neurosci 26:5160–5166, 2006

9. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J: Combined (thalamotomy and stimulation) stereotactic sur-gery of the VIM thalamic nucleus for bilateral Parkinson dis-ease. Appl Neurophysiol 50:344–346, 1987

10. Bendotti C, Berettera C, Invernizzi R, Samanin R: Selective involvement of dopamine in the nucleus accumbens in the feeding response elicited by muscimol injection in the nucleus raphe dorsalis of sated rats. Pharmacol Biochem Behav 24: 1189–1193, 1986

11. Bergman H, Wichmann T, DeLong MR: Reversal of experi-mental parkinsonism by lesions of the subthalamic nucleus. Science 249:1436–1438, 1990

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

13. Berridge KC, Valenstein ES: What psychological process me-diates feeding evoked by electrical stimulation of the lateral hypothalamus? Behav Neurosci 105:3–14, 1991

14. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Web-ster Z, et al: Post-embryonic ablation 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 of biliopancreatic 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 for the 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 to cognitive-behavioral probes of cortico-striatal systems and the amygdala. Neuroimage 4: S127–S138, 1996



18. Brobeck JR: Mechanism of the development of obesity in an-i mals with hypothalamic lesions. Physiol Rev 26:541–559, 1946

19. Broggi G, Franzini A, Marras C, Romito L, Albanese A: Sur-gery of Parkinson’s disease: inclusion criteria and follow-up. Neurol Sci 24 (1 Suppl):S38–S40, 2003

20. Christou NV, Look D, Maclean LD: Weight gain after short- and long-limb gastric bypass in patients followed for longer than 10 years. Ann Surg 244:734–740, 2006

21. Covalin A, Feshali A, Judy J: Deep brain stimulation for obe-sity control: analyzing stimulation parameters to modulate energy expenditure, in Proceedings of the 2nd International IEEE EMBS, Conference on Neural Engineering. Arlington, VA: IEEE EMBS, 2005, pp 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, Daniel-son PE, et al: The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95: 322–327, 1998

24. de Olmos JS, Heimer L: The concepts of the ventral striatopal-lidal system and extended amygdala. Ann N Y Acad Sci 877: 1–32, 1999

25. Deitel M: The International Obesity Task Force and “globe-sity”. Obes Surg 12:613–614, 2002

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

27. Deogaonkar M, Boulis N, Machado A, Azmi H, Senatus P, Rezai A: Surgical complications in 800 consecutive DBS implants, in American Association of Neurological Surgeons 2007 Annual Meeting Proceedings. Park Ridge, Ill: American Association of Neurosurgeons, 2007, Abstract No. 40777

28. Deuschl G, Herzog J, Kleiner-Fisman G, Kubu C, Lozano AM, Lyons KE, et al: Deep brain stimulation: postoperative issues. Mov Disord 21 (14 Suppl):S219–S237, 2006

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

30. Elmquist JK, Elias CF, Saper CB: From lesions to leptin: hypo-thalamic control of food intake and body weight. Neuron 22: 221–232, 1999

31. Fang X, Sugiyama K, Akamine S, Namba H: Improvements in motor behavioral tests during deep brain stimulation of the subthalamic nucleus in rats with different degrees of unilat-eral parkinsonism. Brain Res 1120:202–210, 2006

32. Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, et al: Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 161:1581–1586, 2001

33. Folkow B, Rubinstein EH: Behavioral and autonomic patterns evoked by stimulation of the lateral 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 hy-pothalamic stimulation in normal and coronary-ligated dogs. J Cardiovasc Surg (Torino) 10:377–385, 1969

36. Goldstein JM, Siegel J: Suppression of attack behavior in cats by stimulation of ventral tegmental area and nucleus accum-bens. Brain Res 183:181–192, 1980

37. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, et al: Three-year outcomes in deep brain stimula-tion for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 31:2384–2393, 2006

38. Groenewegen HJ, Russchen FT: Organization of the efferent projections of the nucleus accumbens to pallidal, hypothalamic,

and mesencephalic structures: a tracing and immunohistochem-ical 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 in neurologic disorders. Parkinsonism Relat Disord 13:1–16, 2007

40. Hano J, Przewlocki R, Smialowska M, Chlapowska M, Rokosz-Pelc A: The effect of electric stimulation of caudate nucleus and nucleus accumbens septi on serotonergic neurons in the rat brain. Pol J Pharmacol Pharm 30:475–481, 1978

41. Heimer L: Basal forebrain in the context of schizophrenia. Brain Res Brain Res Rev 31:205–235, 2000

42. Herberg LJ, Blundell JE: Lateral hypothalamus: hoarding be-havior elicited by electrical stimulation. Science 155:349– 350, 1967

43. Hetherington AW, Ranson SW: The spontaneous activity and food intake in rats with hypothalamic 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 pep-tides that define motivational systems, in Atkinson RC, Herrn-stein RJ, Lindzey G, et al (eds): Stevens’ Handbook of Experimental Psychology. New York: Wiley, 1988, pp 547–625

46. Hoebel BG, Teitelbaum P: Hypothalamic control of feeding and self-stimulation. Science 135:375–377, 1962

47. Huang XF, Han M, South T, Storlien L: Altered levels of POMC, AgRP and MC4-R mRNA expression in the hypothalamus and other parts of the limbic system of mice prone or resistant to chronic high-energy diet-induced obesity. Brain Res 992:9– 19, 2003

48. Huang XF, Xin X, McLennan P, Storlien L: Role of fat amount and type in ameliorating diet-induced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor, neu-ropeptide Y and pro-opiomelanocortin 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 and D2 receptor binding densities in mice prone or resistant to chronic high fat diet-induced obesity. Behav Brain Res 175:415–419, 2006

50. Jalali R, Bergmann O, Hosmann K, Kupsch A, Juckel D, Mor-genstern R, et al: High frequency stimulation of the subtha-lamic nucleus reduces quinpirole induced compulsive checking behavior in rats. Program No. 115.8. 2004 Abstract Viewer/Itinerary Planner. Washington DC: Society for Neuroscience, 2004, pp 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, Bro-lin RE, LaMarca LB: Binge eating among gastric bypass pa-tients at long-term follow-up. Obes Surg 12:270–275, 2002

53. Kelley AE, Stinus L: Disappearance of hoarding behavior after 6-hydroxydopamine lesions of the mesolimbic dopamine neu-rons and its reinstatement with L-dopa. Behav Neurosci 99: 531–545, 1985

54. Kennedy GC: The hypothalamic control of food intake in rats. Proc R Soc Lond B Biol Sci 137:535–549, 1950

55. Kotz CM, Teske JA, Levine JA, Wang C: Feeding and activ-ity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 104:27–32, 2002

56. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ar-douin C, et al: Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 349:1925–1934, 2003

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

58. Lado FA, Velisek L, Moshe SL: The effect of electrical stimu-lation of the subthalamic nucleus on seizures is frequency dependent. Epilepsia 44:157–164, 2003



633

59. Lee KH, Chang SY, Roberts DW, Kim U: Neurotransmitter release from high-frequency stimulation of the subthalamic nucleus. J Neurosurg 101:511–517, 2004

60. Lee KH, Roberts DW, Kim U: Effect of high-frequency stimu-lation of the subthalamic nucleus on subthalamic neurons: an intracellular study. Stereotact Funct Neurosurg 80:32–36, 2003

61. Leone M, Franzini A, Felisati G, Mea E, Curone M, Tullo V, et al: Deep brain stimulation and cluster headache. Neurol Sci 26 (2 Suppl):S138–S139, 2005

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

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

64. Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J, et al: Melanin-concentrating hormone overex-pression in transgenic mice leads to obesity and insulin resis-tance. J Clin Invest 107:379–386, 2001

65. Maggard MA, Shugarman LR, Suttorp M, Maglione M, Sug-erman HJ, Livingston EH, et al: Meta-analysis: surgical treat-ment of obesity. Ann Intern Med 142:547–559, 2005

66. Maldonado-Irizarry CS, Kelley AE: Excitotoxic lesions of the core and shell subregions of the nucleus accumbens differen-tially disrupt body weight regulation and motor activity in rat. Brain Res Bull 38:551–559, 1995

67. Maldonado-Irizarry CS, Swanson CJ, Kelley AE: Glutamate re-ceptors in the nucleus accumbens shell control feeding behav-ior via the lateral hypothalamus. J Neurosci 15:6779–6788, 1995

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

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

70. Mathus-Vliegen EM: Long-term weight loss after bariatric surgery in patients visited at home outside the study environ-ment. Obes Surg 16:1508–1519, 2006

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

72. McCracken CB, Grace AA: High-frequency deep brain stim-ulation of the nucleus accumbens region suppresses neuronal activity and selectively modulates afferent drive in rat orbito-frontal cortex in vivo. J Neurosci 27:12601–12610, 2007

73. McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL: Un-covering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol 115:1239– 1248, 2004

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

75. Mendelson J, Chorover SL: Lateral hypothalamic stimulation in satiated rats: T-maze learning for food. Science 149:559– 561, 1965

76. Mirski MA, Ferrendelli JA: Interruption of the mammillotha-lamic tract prevents seizures in guinea pigs. Science 226:72– 74, 1984

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

78. Moyer JT, Wolf JA, Finkel LH: Effects of dopaminergic mod-ulation on the integrative properties of the ventral striatal me-dium spiny neuron. J Neurophysiol 98:3731–3748, 2007

79. Mucha RF, Iversen SD: Increased food intake after opioid mi-

croinjections into nucleus accumbens and ventral tegmental area of rat. Brain Res 397:214–224, 1986

80. Murer MG, Pazo JH: Behavioral responses induced by electri-cal stimulation of the caudate nucleus 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 burden associated with overweight and obe-sity. JAMA 282:1523–1529, 1999

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

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

84. Okun MS, Mann G, Foote KD, Shapira NA, Bowers D, Spring-er U, et al: Deep brain stimulation in the internal capsule and nucleus accumbens region: responses observed during active and sham programming. J Neurol Neurosurg Psychiatry 78: 310–314, 2007

85. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al: Neurons containing hypocretin (orexin) pro-ject to multiple neuronal systems. J Neurosci 18:9996–10015, 1998

86. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al: Who would have thought it? An opera-tion proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 222:339–352, 1995

87. Poschel BPH: Comparison of reinforcing effects yielded by lat-eral versus medial hypothalamic stimulation. J Comp Physiol Psychol 61:346–352, 1966

88. Predy PA, Kokkindis L: Sensitization to the effects of repeated amphetamine administration on intracranial self-stimulation: evidence for changes in reward processes. Behav Brain Res 13: 251–259, 1984

89. Purves D, Augustine GJ, Fitzpatrick D, Katz L, LaMantia A, McNamara JO, et al (eds): Neuroscience, ed 2. Sunderland, MA: Sinauer Associated, Inc., 2001

90. Quaade F, Vaernet K, Larsson S: Stereotaxic stimulation and electrocoagulation of the lateral hypothalamus in obese hu-mans. Acta Neurochir (Wien) 30:111–117, 1974

91. Rauch SL: Neuroimaging and neurocircuitry models pertain-ing to the neurosurgical treatment of psychiatric disorders. Neurosurg Clin N Am 14:213–223, vii–viii, 2003

92. Roe DA, Eickwort KR: Relationships between obesity and as-sociated health factors with unemployment 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 Sup- pl):139–150, 1984

94. Ruffin M, Nicolaidis S: Electrical stimulation of the ventro-medial hypothalamus enhances both fat utilization and meta-bolic rate that precede and parallel the inhibition of feeding behavior. Brain Res 846:23–29, 1999

95. Saito M, Minokoshi Y, Shimazu T: Accelerated norepineph-rine turnover in peripheral tissues after ventromedial hypo-thalamic 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 orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585, 1998

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

98. Sani SB, Jobe KW, Kordower J, Bakay RA: Deep brain stimu-lation for the treatment of obesity in the rat, in 73rd Annual Meeting, American Association of Neurological Surgeons. Rolling Meadows, 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 brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsy-cho pharmacology 33:368-377, 2007

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

102. Shimizu H, Shimomura Y, Takahashi M, Uehara Y, Fukat- su A, Sato N: Altered ambulatory activity and related brain mono amine metabolism in genetically obese Zucker rats. Exp Clin Endocrinol 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 inhibiting memory specifically related to learned fear. Cell 111:905–918, 2002

104. Smith KS, Berridge KC: Opioid limbic circuit for reward: in teraction between hedonic hotspots of 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 major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res 604:304–317, 1993

106. Stenger J, Fournier T, Bielajew C: The effects of chronic ventro-medial hypothalamic stimulation 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

108. Sturm V, Lenartz D, Koulousakis A, Treuer H, Herholz K, Klein JC, et al: The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders. J Chem Neuroanat 26:293–299, 2003

109. Taha SA, Fields HL: Encoding of palatability and appetitive behaviors by distinct neuronal populations in the nucleus accum-bens. J Neurosci 25:1193–1202, 2005

110. Teegarden SL, Bale TL: Decreases in dietary preference pro-duce increased emotionality and risk for dietary relapse. Biol Psychiatry 61:1021-1029, 2007

111. Toleikis JR, Toleikis SC, Barborica A, Verhagen L, Sturaitis MK, Bakay R: Analysis of human single unit activity acquired during deep brain stimulation, in Proceedings of the American Association 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 depressive disorder re vealed by a dopaminergic probe. Arch Gen Psychiatry 62:1228–1236, 2005

113. Valenstein ES, Cox VC, Kakolewski JW: Modification of moti-vated behavior elicited by electrical stimulation of the hypothala-mus. Science 159:1119–1121, 1968

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

115. van Kuyck K, Gabriëls L, Cosyns P, Arckens L, Sturm V, Ras mussen S, et al: Behavioural and physiological effects of electrical stimulation in the nucleus accumbens: a review. Acta Neurochir Suppl 97:375–391, 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 mammillothalam ic area in patients with chronic refractory epilepsy. Epilepsia 45: 164, 2004

117. Velley L, Cardo B: Long-term improvement of learning after

early electrical stimulation of some central nervous structures: is the effect structure and age-dependent? Brain Res Bull 4: 459–466, 1979

118. Voges J, Waerzeggers Y, Maarouf M, Lehrke R, Koulousakis A, Lenartz D, et al: Deep-brain stimulation: long-term analysis of complications caused by hardware and surgery–experiences from a single centre. J Neurol Neurosurg Psychiatry 77:868– 872, 2006

119. Volkow ND, O’Brien CP: Issues for DSM-V: 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 addiction as assessed by neurofunc-tional 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 gastric bypass is superior to laparoscopic gastric banding for treatment of morbid obesity. Ann Surg 240: 975–983, 2004

122. Will MJ, Pratt WE, Kelley AE: Pharmacological characterization of high-fat feeding induced by opioid 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, Benoit-Marand M, O’Donnell P, et al: NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computa-tional model of the nucleus accumbens medium spiny projection neuron. J Neurosci 25:9080–9095, 2005

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

126. Wright J, Kelly DF, Mitchell-Heggs N, Frankel R: Respiratory changes induced by intracranial stimulation: anatomical local-izing value and related functional effects in rhesus monkeys, in Sweet WH, Obrador S, Martin-Rodriguez JG (eds): Neu rosurgical Treatment in Psychiatry, Pain, and Epilepsy. Bal ti-more: University Park Press, 1977, pp 751–756

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

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

129. Zahm DS: An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens. Neurosci Biobehav Rev 24:85– 105, 2000

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

131. Zhang M, Gosnell BA, Kelley AE: Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation with in the nucleus accumbens. J Pharmacol Exp Ther 285: 908–914, 1998

Manuscript submitted August 27, 2007.Accepted February 21, 2008.Address correspondence to: Casey H. Halpern, M.D., Department

of Neurosurgery, 3 Silverstein, Hospital of the University of Penn-sylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. email: [email protected].

Deep brain stimulation in the treatment of...

Documents

Transcript of Deep brain stimulation in the treatment of...