Deep brain stimulation for obesity: past, present, and future targets

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  • Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania
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The authors review the history of deep brain stimulation (DBS) in patients for treating obesity, describe current DBS targets in the brain, and discuss potential DBS targets and nontraditional stimulation parameters that may improve the effectiveness of DBS for ameliorating obesity. Deep brain stimulation for treating obesity has been performed both in animals and in humans with intriguing preliminary results. The brain is an attractive target for addressing obesity because modulating brain activity may permit influencing both sides of the energy equation—caloric intake and energy expenditure.

ABBREVIATIONS

BMI = body mass index; DA = dopamine; DBS = deep brain stimulation; HFS = high-frequency stimulation; LHA = lateral hypothalamic area; LHb = lateral habenula; NAc = nucleus accumbens; OCD = obsessive-compulsive disorder; OFC = orbitofrontal cortex; ON = orexinergic neuron; PFC = prefrontal cortex; SCC = subcallosal cingulate cortex; VMH = ventromedial hypothalamus; VS = ventral striatum; VTA = ventral tegmental area.

The authors review the history of deep brain stimulation (DBS) in patients for treating obesity, describe current DBS targets in the brain, and discuss potential DBS targets and nontraditional stimulation parameters that may improve the effectiveness of DBS for ameliorating obesity. Deep brain stimulation for treating obesity has been performed both in animals and in humans with intriguing preliminary results. The brain is an attractive target for addressing obesity because modulating brain activity may permit influencing both sides of the energy equation—caloric intake and energy expenditure.

ABBREVIATIONS

BMI = body mass index; DA = dopamine; DBS = deep brain stimulation; HFS = high-frequency stimulation; LHA = lateral hypothalamic area; LHb = lateral habenula; NAc = nucleus accumbens; OCD = obsessive-compulsive disorder; OFC = orbitofrontal cortex; ON = orexinergic neuron; PFC = prefrontal cortex; SCC = subcallosal cingulate cortex; VMH = ventromedial hypothalamus; VS = ventral striatum; VTA = ventral tegmental area.

Obesity is often defined as a body mass index (BMI) of > 30 kg/m2, with a healthy BMI ranging from 18.5–24.9 kg/m2.18, 66 Using this definition, the WHO estimates that approximately 600 million people worldwide are obese.106 Sedentary lifestyles, urbanization, genetics, and an abundance of processed, high-calorie foods have contributed to a 4-fold increase in the prevalence of obesity in many countries across the world over the past 3 decades.35 The risks for increased morbidity and mortality rates associated with this condition, as well as the immense burden on health care systems coping with an increasing number of obese individuals, are at an all-time high and will likely worsen in years to come.35, 62 For example, in the United States, the prevalence of obesity in adults has increased by nearly 50% in the past 2 decades. Moreover, this increase approaches 300% in American children.35, 62 With 17% of adolescents being obese, and with 44% of those adolescents having metabolic syndrome, the prevalence of chronic diseases and burdensome pressures on health care systems will inevitably surge in the coming decades.62 Because of the consequences of this pandemic for society, investigators have intensified programs geared toward alleviating the burden of this debilitating disease.

Thanks to recent advances in molecular genetics and functional neuroimaging, functional neurosurgery is one of the most recently developed tools used to treat morbid obesity. Deep brain stimulation (DBS) in particular has been shown to improve symptoms in neurological disorders such as Parkinson’s disease, essential tremor, and dystonia in both adults and children.15, 47, 53, 55, 64, 68, 69, 76, 98, 102 Additionally, increasing evidence points to DBS as an effective modality in the treatment of neuropsychiatric and degenerative disorders such as Tourette’s syndrome, obsessive-compulsive disorder (OCD), Alzheimer’s disease, anddepression.5, 16, 29, 48, 49, 54, 55, 59, 82, 84

Leading theories for how DBS effects beneficial treatment outcomes suggest that it may disrupt abnormal oscillations in brain signaling and restore normal synchronization and coupling between various areas of the brain.40 As such, DBS targets for most currently treated disorders are not limited to one area because stimulation of several different targets may yield similar therapeutic efficacy.1, 11, 19, 29, 48, 87, 102 As currently used, DBS is effective when administered at what is considered high-frequency stimulation (HFS; that is, at > 100 Hz); however, there is evidence that the parameters of stimulation used in treating movement disorders may not be optimal for treating diseases such as obesity.96, 104 In addition, targeting several brain structures with DBS to treat neuropsychiatric disorders has been shown to engender weight loss and reduce addiction, 45, 57 lending further evidence to the notion that multinodal circuits rather than a localized area of the brain are involved in many of these disorders. In this review, we discuss the targets and outcomes of DBS for managing obesity and the progression of the field. We also review the neurobiology and molecular physiology indicating potential novel targets in humans and discuss recent animal DBS and human functional imaging and neuropsychiatric studies.

Past and Present DBS Targets for Obesity

Ventromedial Hypothalamus

In 2008, Hamani and colleagues implanted bilateral DBS electrodes into the ventromedial hypothalamus (VMH) of a morbidly obese man who did not wish to undergo gastric bypass surgery because he knew he would still have the desire to eat.26 Stimulation of the VMH in this patient produced several unexpected side effects, including déjà vu and feelings of being in an alternate environment, yet had no effect on appetite. Confirming that stimulation of the VMH leads to undesirable effects, Wilent et al. reported that DBS induced panic attacks in a graded manner during HFS of the VMH, demonstrating that its stimulation causes adverse psychogenic manifestations.105 Since publication of these results, no additional trials involving DBS of the VMH have been reported.

Lateral Hypothalamic Area

In an FDA-approved pilot study by Whiting et al. to determine the safety of DBS of the lateral hypothalamic area (LHA), 3 morbidly obese patients in whom gastric bypass surgery had failed to control their condition underwent bilateral DBS of the LHA.104 While undergoing HFS of the LHA over 4 consecutive days, the patients were placed in a metabolic chamber that measured energy expenditure through gas exchange. The resting metabolic rate increased in 2 of the 3 patients during the treatment, and all 3 individuals reported a decreased urge to eat, as well as increased energy levels during active stimulation. These feelings reproducibly waned when the stimulation ceased. Follow-up examinations at 9 and 11 months under optimized settings indicated a weight loss of 12.3%-16.4% in 2 patients, and a 0.9% weight loss at the 16-month follow-up in the third patient. Although these reductions in weight were modest, defining effective outcomes by using absolute measures may be misleading for several reasons. For instance, more accurate measures of obesity exist, including body shape, BMI, waist-to-hip ratio, waist circumference, waist-to-stature ratio, and fat distribution, each of which predicts and reflects the associations to other medical comorbidities.101 Two-year follow-up metabolic analysis is currently ongoing in these 3 patients.

Future DBS Targets for Obesity

Serendipitous outcomes after DBS of various targets for the treatment of neuropsychiatric diseases, such as OCD and Tourette’s syndrome, has led researchers to investigate the role of various nuclei in the treatment of obesity. The brain circuits responsible for cravings associated with obesity due to overeating or with drug addiction share extensive overlap.20, 21, 73 Perhaps the most convincing account of such overlap was demonstrated by Mantione et al., who reported that stimulation of the nucleus accumbens (NAc) in a patient with OCD led to weight loss and enabled him to quit his long-standing nicotine habit.57 Similarly, other researchers documented remission of alcohol dependency in a patient who underwent DBS of the NAc for severe anxiety.45 In addition to such coincidental outcomes in DBS treatments of patients, animal models and advances in functional neuroimaging, molecular genetics, and neurobiology have yielded insight into targets whose stimulation could be of potential benefit in the obesity treatments based on DBS, and these will be discussed in the following.

Three broad categories of circuits are described below, each with unique, as well as with overlapping, roles in eating behaviors. The 3 categories are further subdivided into primary anatomical and physiological nodes. These target nodes are summarized in Table 1.

TABLE 1.

Potential DBS targets for treating obesity

Predominant Role in ObesityTargetKey Modulatory Components & Pathways
Integration of nutritional status & energy stateLHA (feeding center), VMH (satiety center), area postrema, & NTSOrexins, MCH, NPY, leptin, insulin, glucose, amino acids, POMC, CART, & AGRP: mediators integrating the satiety & feeding centers w/the reward system.

Area postrema associated w/ variations in meal sizes in rat models.3

NTS is primary satiety relay center to CNS from Gl tract.9, 13, 36, 94
Hedonic food drive/incentive salience; primary limbic & striatal structuresNAc,* VMPFC (medial OFC, SCC, anteriorcingulate), DMmc, GPi* STN,* ALIC,* VPT, SNpr, Al, & FOInput from various homeostatic nuclei w/ integration into reward center (primarily DA mediated).
Cognitive control of feedingdIPFC, LOFC, DMpc, & VATAssociative system responsible for executive decisions involved in eating habits & nutritional valuation.
Integration of food-seeking behavior w/ caloric needsPPN, IdTA, SI, & median eminencePeripheral integration of feeding control, primarily ACh-mediated influence on DA & Glu signaling.6, 63, 72, 74, 107, 108 Connectivity w/ hypothalamus.
OthersST & amygdalaConnections to limbic circuits (SCC, NAc shell) and LHA. Integration of associative, homeostatic, and reward mechanisms.80, 90, 103
ITPConnections via amygdalofugal pathway to & from DMmc/SI.
LHb,* MHb,* & SMT*Limbic/BG input, output to DRN. Integration of reward w/ cognition & emotion (VBDM), implicated in depression & obesity.31, 32, 34, 86, 109

ACh = acetylcholine; AGRP = agouti-related peptide; AI = anterior insula; ALIC = anterior limb of internal capsule; BG = basal ganglia; CART = cocaine- and amphetamine-regulated transcript; dIPFC = dorsolateral prefrontal cortex; DMmc = dorsomedial magnocellular thalamus; DMpc = dorsomedial parvocellular thalamus; DRN = dorsal raphe nucleus; FO = frontal operculum; GI = gastrointestinal; Glu = glutamate; GPi = globus pallidus internus; ITP = inferior thalamic peduncle; IdTA = lateral dorsal tegmental area; LOFC = lateral orbitofrontal cortex; MCH = melanin-concentrating hormone; MHb = medial habenular nucleus; NPY = neuropeptide Y; NTS = nucleus of tractus solitarius; POMC = pro-opiomelanocortin; PPN = pedunculopontine nucleus; SI = substantia innominata; SMT = stria medullaris of thalamus; ST = stria terminalis; STN = subthalamic nucleus; VAT = ventral anterior thalamus; VBDM = value-based decision making; VPT = ventral posterior thalamus.

This brain region involves both limbic and cognitive circuits.

Reward Circuitry, Cravings, and Addiction

Nucleus Accumbens

The NAc is functionally divided into core and shell, the latter of which has been the primary focus of DBS. Studies using animal models of DBS have reported that the NAc affects activity in several brain centers involved in neuropsychiatric disorders.44 Electrical stimulation of the NAc in humans is safe and feasible, as demonstrated by studies in which the NAc was targeted for treating OCD, depression, Tourette’s syndrome, or alcoholism.21, 29, 44, 64, 82 Besides coincidental weight loss observed in a study in which the NAc was targeted to treat a different neuropsychiatric disorder, 57 robust animal data support the NAc as a potential target for DBS in people with obesity.

For example, dopamine (DA) levels in the NAc of mice significantly decrease after highly palatable foods are removed from their diets.91 Furthermore, rodent NAc-lesioning models indicate significant reductions in weight and in binge-eating and food-hoarding behaviors.25, 42 Activity in the NAc is increased in individuals who imagine eating highly palatable foods, and visual cues disproportionately stimulate the reinforcement circuits in obese and leptin-deficient individuals in anticipation of these visualized rewards.17, 65, 79, 89 Interestingly, both HFS and low-frequency stimulation (≤ 50 Hz) effectively stimulate the NAc. As shown by Hamilton et al., stimulating the NAc with both DBS modalities attenuates drug-seeking behavior in rodents.27 In addition, activation of cannabinoid receptors in the NAc shell of rodents induces the expression of genes that are associated with increased food intake.70

Subgenual/Subcallosal Cingulate Cortex

Several trials involving DBS of the subcallosal cingulate cortex (SCC) to address treatment-resistant depression and refractory anorexia nervosa have been reported.40, 52, 54, 56 In a prospective trial involving 6 anorexic individuals, half of the patients achieved a 50% sustained increase in the BMI. Although this is the opposite effect of that intended in the treatment of obesity, the results are promising because they support DBS as a means for modifying the BMI.52 Interestingly, in the primary instrument for rating outcomes of DBS for treating depression (that is, the Hamilton Rating Scale for Depression), 8% of the questions ask about appetite, food intake, or weight.54, 56 With its abundant functional connections to the NAc, hypothalamus, amygdala, insula, and orbitofrontal cortex (OFC), the SCC appears to be an appropriate target for treating neuropsychiatric disorders involving any of the possibly dysregulated pathways in this white matter tract convergence zone, 55 including refractory obesity due to hedonistic food-seeking behavior or to mood-related feeding.

Anterior Insula and Frontal Operculum

The anterior insula and frontal operculum are 2 areas that are involved in both food cravings and anticipatory food reward.22, 85, 88 Functional neuroimaging studies have reported hyperactivity in the anterior insula, as well as in other areas described below, in individuals who are obese. Addiction studies have identified a strong correlation between insular hyperactivity and addiction, suggesting that the insula could be a DBS target in obese patients who have eating habits resembling an addiction. In contrast, hypoactivity in the frontal operculum (and in the lateral OFC and striatum) observed in individuals who imagine consuming highly palatable foods is a predictor of future weight gain in some of these individuals.88

Ventral Striatum, Dorsal Striatum, and Other Limbic System Nodes

Although the hypothalamus has long been known to govern homeostatic control of eating, recent evidence suggests that the striatum initiates the initial drive or motivation to seek nutrition. The ventral striatum (VS) is involved in those DA pathways dysregulated in obesity that are related to pleasure, reward, and addiction; normally, these phylogenetically preserved pathways may provide the impetus to invest energy into seeking out food.46 Once the homeostatic aspect of the VS activates food-seeking behavior, it uses outputs from the dorsal striatum to other areas that couple goal-directed behavior to motor responses.46, 86, 93 The hedonic aspect of obesity, also known as incentive salience, is a product of this circuit’s malad-aptation.7, 12 Interestingly, recent data suggest that certain hormones involved in feeding (insulin, ghrelin, and leptin) directly alter DA activity to increase or decrease feeding behaviors.46

Teegarden et al. provided evidence of the adverse and maladaptive consequences of obesity by demonstrating that rodents are willing to be exposed to an adverse environment and to forgo some foods in order to obtain a more palatable meal.91, 92 The reward of eating highly palatable foods has been repeatedly linked to the limbic system. It therefore follows that DBS at varying points along the circuit should counteract the hedonic drive to eat. In particular, such targets would prove most useful in individuals who have developed aberrant DA signaling in structures that have been physiologically altered after years of exposure to highly palatable foods.92

Using functional MRI, Stice et al. not only demonstrated increased DA activity in the frontal operculum, lateral OFC, and striatum when human subjects thought of consuming highly palatable foods, but also that these altered DA activities help predict individuals at risk for future weight gain.88 Further support of the DA dysregulation theory in obesity comes from molecular studies that indicated that a decreased striatal DA2 receptor availability is proportional to changes in BMI in obese individuals.100 Additional potential DBS targets along the limbic circuit include the anterior limb of the internal capsule, the ventromedial caudate and ventromedial prefrontal cortex (PFC) (including the medial OFC, and anterior cingulate), the putamen and ventral pallidum, the dorsomedial mag-nocellular thalamus, the hippocampus and subthalamic nucleus, the ventral posterior thalamus and ventral tegmental area (VTA), and the substantia nigra pars reticulata.

While the signaling cascades involved in the limbic system traverse many nodes, it is likely that only a handful of these nodes may be useful targets for DBS. For example, among several areas implicated in food cravings and reward, the OFC, amygdala, and striatum appear to encode the reward value of food.22, 85, 88 A recent pilot study verified the safety and feasibility in accurately targeting the VS in patients with OCD, 95 supporting the safety and accessibility of the VS as a potential DBS target for treating obesity.

An interesting effect produced through stimulation of the VS is smiling and laughter, which highlights the involvement of emotional components in certain types of obesity. It reaffirms that eating disorders are linked to emotions; therefore, if stimulation affects mood, it may affect eating as well, and vice versa. In addition to being the primary reward center involved in DA transmission, the VTA (and NAc) have increased activity associated with cravings in response to nutrients such as lipids and sugars.97 Indeed, there is a growing consensus that targeting areas such as the VTA, NAc, and SCC could produce successful clinical outcomes in DBS for obesity.40, 90

Satiety Signaling

Ventromedial Hypothalamus

Lesioning (or HFS) of the well-known “satiety” center, the VMH, diminishes feeding in animal models.33, 41, 75 Kullmann and colleagues recently showed how the LHA and VMH are functionally connected to other brain regions in both healthy-weight and obese individuals.46 The authors reported that the LHA network was more robustly connected to the anterior cingulum, dorsal striatum, and frontal operculum, while the VMH made stronger connections to the medial OFC and the NAc. These observations suggest that food-mediated activation of components of the dopaminergic reward system affect the VMH and LHA differently and that stimulation of the VMH and stimulation of the LHA activate distinct circuits. The VMH is smaller and more challenging to access than the

LHA, and previous trials involving VMH stimulation resulted in side effects due to spread of current to adjacent nuclei.26, 105 With the advent of new DBS technologies, 29, 58 more precise targeting of the VMH with smaller micro-contacts to reduce the spread of current could lead to a resurgence in the interest of targeting the VMH for obesity treatment.

Amygdala, Stria Terminalis, and Inferior Thalamic Peduncle

Orexinergic neurons (ONs), located primarily in the LHA, have long been known to modulate feeding behavior through homeostatic and associative mechanisms.80, 103 Recent rodent studies have unveiled novel downstream effects of ONs. The amygdala is the prime target of the LHA ONs, and the stria terminalis accounts for much of the connectivity between the amygdala and the VMH.8, 103 Findings in many animal models have implicated this major pathway in the valuation of highly palatable foods.97, 103 Certain neuropeptides of the ONs, such as orexins, have also been shown to be linked to drug seeking and addiction, including food addictions that contribute to obesity.14, 103 Furthermore, ONs respond not only to internal energy states, but also to external food-related cues, particularly when they override satiety.103 Another major modulatory nucleus of thalamocortical projections to and from the OFC is the inferior thalamic peduncle, which lies in close proximity to the stria terminalis and has been shown to elicit behavioral modifications in patients who have had DBS of the inferior thalamic peduncle for treating OCD.37

Energy Homeostasis and Nutritional Gauging

Habenula and Stria Medullaris of Thalamus

The lateral habenula (LHb) regulates several essential physiological features, such as sleep patterns and responses to stress and pain, and it also plays a critical role in the neurobiological underpinnings of several psychiatric illnesses.32, 109 By integrating DA-reward pathways (via the stria medullaris of thalamus) with cognitive processes and emotion (that is, via connections to, and modulation of, serotonergic output of the dorsal raphe nucleus), 109 the LHb participates in motivational or value-based decision making.32, 34 Nonhuman primate models have provided insight into the major reward inputs of the LHb, which are likely also present in humans. By stimulating varying areas of the striatum and globus pallidus, Hong and Hikosaka identified alternating excitatory and inhibitory inputs to the LHb from the basal ganglia.34

Interestingly, rodent obesity models implicate the medial habenula in diet-induced obesity.86 Smith et al. have postulated a homeostatic mechanism that normally limits overeating (and eventual obesity) as a behavior that is mediated through the medial habenula.86 The LHb is currently a DBS target of interest in patients with severe refractory depression, 31, 83 and its role in value-based decision making may potentially have significant implications for using it as a target in DBS to treat obesity.

Area Postrema and Nucleus of Tractus Solitarius

Orexins and melanin-concentrating hormone are produced in the LHA and mediate feeding behavior in different ways.50, 81 Findings in animal models indicate that the area postrema and the nucleus of tractus solitarius have links to the LHA indirectly through the orexin-mediated pathways and that the hyperphagic effects of melanin-concentrating hormone rely on stimulation of the fore-brain, whereas those of orexin-A and also of neuropeptide Y do not.3, 51 Additionally, the area postrema and nucleus of tractus solitarius have effects on meal size, but not on meal frequency.3 The area postrema and the nucleus of tractus solitarius both promote orexin-mediated feeding behaviors, suggesting that they represent a robust link to the feeding centers in the LHA. The nucleus of tractus solitarius is the primary satiety relay center to the CNS from the gastrointestinal tract via N-methyl-d-aspartic acid (NMDA) receptor-mediated activation by vagal afferents, 9, 13, 36, 94 making DBS of this region an attractive proposition. In addition, some neurons within the nucleus of tractus solitarius selectively respond to essential amino acids according to various nutritional states.97 Because both of these structures are surrounded by critical structures of the brainstem, cannulating them may increase the risk for injury of the critical structures, which may account for a lack of interest in this procedure.

Conscious Rationalization of Food-Eating Behavior

Cognitive Circuit Targets

The limbic system is largely responsible for the emotional and rewarding components of eating,60, 90 and the cognitive, or “associative, ” loop is mainly engaged in the processes involved in the conscious decisions about eating.90 The cognitive loop may be responsible for overriding the reward aspect of eating and may be dysfunctional or overcome by the limbic system in obese individuals who overeat because of a lack of self-control.46, 90 Candidate DBS nodes in these regions for treating obesity include the dorsolateral PFC, dorsomedial parvocellular thalamus, globus pallidus internus, lateral OFC, and ventral anterior thalamus. Multiple imaging studies have indicated that obese individuals have increased responses to food in areas such as the striatum, operculum, and medial OFC and decreased responses in regions involved in inhibitory control, such as the PFC.28, 46, 79

Additional Brain Targets

Nicotinic and muscarinic acetylcholine signaling is largely responsible for learned maladaptive behaviors, including overeating.72 The long-term modulatory activity of acetylcholine accounts for the regulatory release of, and responsiveness to, the more acute functions of other neurotransmitters (namely DA and glutamate) implicated in the central dysregulation observed in obesity.6, 10, 63, 72, 74, 107, 108 The neuromodulatory effects of acetylcholine on these other circuits and its significant role in coordinating food-seeking behavior and caloric needs39 all suggest cholinergic signaling as another potential avenue of DBS treatment. Various nuclei related to the peripheral integration of feeding control exhibit abrupt adaptation in response to environmental cues.71, 72 The laterodorsal tegmental and pedunculopontine areas are prime examples of such targets and supply cholinergic input to the hypothalamus, 24, 38 and DBS of the pedunculopontine areas was accomplished in 2 patients with progressive supranuclear palsy.30

A source of cholinergic signaling and an area that has been safely targeted in the treatment of individuals with cognitive decline4, 48 is the nucleus basalis of Meynert. The potentiating effects of these cholinergic pathways are partially responsible for the learned behaviors and adaptive changes associated with eating disorders, which makes these pathways strong candidates for DBS in the treatment of obesity. Other examples of nodes with functional connectivity to the hypothalamus through cholinergic signaling include the substantia innominata, which is activated by food presentation in primates subjected to fasting, 72, 77 and the median eminence, which releases corticotropin-releasing hormone, leading to downstream effects on metabolism.72

Discussion

Compound Obesity

Compound obesity is defined here as obesity due to the maladaptive processes produced by dysfunction in one or more signaling pathways, for example, in those originating from the LHA and leading to a domino effect resulting in aberrant signaling in multiple circuits and nodes. This irregular signaling leads to dysregulation of the limbic and associative circuits involved in the hedonic and homeostatic aspects of food-seeking behaviors. Examples of this type of dysregulation in obesity may include those arising from genetic defects in the insulin pathway or from nutritional deficiency, leading to increased food consumption to counteract the underlying signaling defects. In this setting, hyperphagia might lead to increased activity in the dopaminergic reward system, which has roles in addiction and craving not only for drugs, but also for lipids and sugars.99

Multiplicity

Last, we propose a multipronged approach to the treatment of compound obesity with DBS. Given the high number of connections among the various nuclei associated with obesity, simultaneous DBS of more than one brain target has shown some efficacy in patients with co-occurring essential tremor or with Parkinson’s disease.1, 2, 11, 96 Therefore, because compound obesity by definition is the result of a malfunction in more than one bodily system, effective treatment of this condition likely requires modulation at both individual and multiple nodes. Concomitant stimulation of the LHA and NAc, ventromedial PFC, or of various combinations thereof may be beneficial in patients with a long history of compound obesity and whose neural networks have structurally and functionally adapted to the disease through long-term plasticity.

The LHA remains the primary DBS target for treating obesity because the LHA is the central hub for all circuits involved in the drive to eat.80, 97, 103 In addition to the robust connectivity between the LHA and the limbic system, data supporting it as a DBS target include the modulatory effects of DBS on the resting metabolic rate in patients,104 the recent discovery of amino acid-sensing pathways that connect the stomach to the LHA,97 and the discovery of obesity-related genes expressed exclusively by ONs in the LHA.103 Because the ONs of the LHA control diet-induced thermogenesis, reward circuits, energy homeostasis, and satiety,80 the LHA continues to be the target of choice for addressing obesity due to metabolic dysregulation (in peripheral and central areas), genetics, or food addiction.

Rapid technological and engineering advances are molding the future of DBS. The availability of new electrodes is popularizing systems with constant current (as opposed to constant voltage, regardless of impedance), directional or steerable current, and closed-loop devices that activate via aberrant signaling when needed.29, 58, 67, 78 These advances are contributing to improved outcomes and new applications for DBS.23 Adoption of DBS by multidisciplinary teams responsible for the treatment of various neuropsychiatric disorders continues to increase, and the number of prospectively controlled trials for these disorders is also increasing.40 Although many clinicians are aware of the life-changing effects of neuromodulation, reports of the placebo effects of DBS (up to 39%)61 likely contribute to the reluctance of skeptical practitioners to accept this intervention as valid and effective. The community must therefore remain steadfast in the objective and accurate reporting of the clinical benefits and possible shortcomings that such surgeries may yield.

Conclusions

Electrical stimulation of various combinations of brain targets may ultimately improve willpower, decrease hedonic drive, increase metabolic rate, and enhance or inhibit, as necessary, the functionality of those nodes and pathways that are altered in individuals with obesity. Although many imaging, molecular, and animal studies implicate various neural nodes in modifying the pathogenesis of obesity, DBS of the LHA remains the neurosurgical treatment of choice in the treatment of this disease.

Author Contributions

Conception and design: Dupré, Whiting. Acquisition of data: Dupré. Analysis and interpretation of data: Dupré. Drafting the article: Dupré. Critically revising the article: Dupré, Tomycz, Oh. Reviewed submitted version of manuscript: all authors. Administrative/technical/material support: Whiting. Study supervision: Whiting.

References

  • 1

    Anderson VC, , Burchiel KJ, , Hogarth P, , Favre J, & Hammerstad JP: Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 62:554560, 2005

    • Search Google Scholar
    • Export Citation
  • 2

    Bahgat D, , Raslan AM, , McCartney S, & Burchiel KJ: Lesioning and stimulation in tremor-predominant movement disorder patients: an institutional case series and patient-reported outcome. Stereotact Funct Neurosurg 90:181187, 2012

    • Search Google Scholar
    • Export Citation
  • 3

    Baird JP, , Choe A, , Loveland JL, , Beck J, , Mahoney CE, & Lord JS, et al. : Orexin-A hyperphagia: hindbrain participation in consummatory feeding responses. Endocrinology 150:12021216, 2009

    • Search Google Scholar
    • Export Citation
  • 4

    Barnikol TT, , Pawelczyk NB, , Barnikol UB, , Kuhn J, , Lenartz D, & Sturm V, et al. : Changes in apraxia after deep brain stimulation of the nucleus basalis Meynert in a patient with Parkinson dementia syndrome. Mov Disord 25:15191520, 2010

    • Search Google Scholar
    • Export Citation
  • 5

    Benabid AL, & Torres N: New targets for DBS. Parkinsonism Relat Disord 18:Suppl 1 S21S23, 2012

  • 6

    Benagiano V, , Virgintino D, , Flace P, , Girolamo F, , Errede M, & Roncali L, et al. : Choline acetyltransferase-containing neurons in the human parietal neocortex. Eur J Histochem 47:253256, 2003

    • Search Google Scholar
    • Export Citation
  • 7

    Berridge KC, & Robinson TE: What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?. Brain Res Brain Res Rev 28:309369, 1998

    • Search Google Scholar
    • Export Citation
  • 8

    Bisetti A, , Cvetkovic V, , Serafin M, , Bayer L, , Machard D, & Jones BE, et al. : Excitatory action of hypocretin/orexin on neurons of the central medial amygdala. Neuroscience 142:9991004, 2006

    • Search Google Scholar
    • Export Citation
  • 9

    Blevins JE, , Schwartz MW, & Baskin DG: Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol 287:R87R96, 2004

    • Search Google Scholar
    • Export Citation
  • 10

    Bonelli RM, & Cummings JL: Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 9:141151, 2007

  • 11

    Burchiel KJ, , Anderson VC, , Favre J, & Hammerstad JP: Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson’s disease: results of a randomized, blinded pilot study. Neurosurgery 45:13751384, 1999

    • Search Google Scholar
    • Export Citation
  • 12

    Burger KS, & Stice E: Greater striatopallidal adaptive coding during cue-reward learning and food reward habituation predict future weight gain. Neuroimage 99:122128, 2014

    • Search Google Scholar
    • Export Citation
  • 13

    Campos CA, , Shiina H, , Silvas M, , Page S, & Ritter RC: Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats. Endocrinology 154:26132625, 2013

    • Search Google Scholar
    • Export Citation
  • 14

    Cason AM, , Smith RJ, , Tahsili-Fahadan P, , Moorman DE, , Sartor GC, & Aston-Jones G: Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav 100:419428, 2010

    • Search Google Scholar
    • Export Citation
  • 15

    Cleary DR, , Raslan AM, , Rubin JE, , Bahgat D, , Viswanathan A, & Heinricher MM, et al. : Deep brain stimulation entrains local neuronal firing in human globus pallidus internus. J Neurophysiol 109:978987, 2013

    • Search Google Scholar
    • Export Citation
  • 16

    Denys D, , Mantione M, , Figee M, , van den Munckhof P, , Koerselman F, & Westenberg H, et al. : Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 67:10611068, 2010

    • Search Google Scholar
    • Export Citation
  • 17

    Farooqi IS, , Bullmore E, , Keogh J, , Gillard J, , O'Rahilly S, & Fletcher PC: Leptin regulates striatal regions and human eating behavior. Science 317:1355, 2007

    • Search Google Scholar
    • Export Citation
  • 18

    Flegal KM, , Carroll MD, , Kit BK, & Ogden CL: Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307:491497, 2012

    • Search Google Scholar
    • Export Citation
  • 19

    Fox MD, , Buckner RL, , Liu H, , Chakravarty MM, , Lozano AM, & Pascual-Leone A: Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases. Proc Natl Acad Sci U S A 111:E4367E4375, 2014

    • Search Google Scholar
    • Export Citation
  • 20

    Gearhardt AN, , White MA, , Masheb RM, , Morgan PT, , Crosby RD, & Grilo CM: An examination of the food addiction construct in obese patients with binge eating disorder. Int J Eat Disord 45:657663, 2012

    • Search Google Scholar
    • Export Citation
  • 21

    Goodman WK, , Foote KD, , Greenberg BD, , Ricciuti N, , Bauer R, & Ward H, et al. : Deep brain stimulation for intractable obsessive compulsive disorder: pilot study using a blinded, staggered-onset design. Biol Psychiatry 67:535542, 2010

    • Search Google Scholar
    • Export Citation
  • 22

    Gottfried JA, , O'Doherty J, & Dolan RJ: Encoding predictive reward value in human amygdala and orbitofrontal cortex. Science 301:11041107, 2003

    • Search Google Scholar
    • Export Citation
  • 23

    Gunduz A, , Morita H, , Rossi J, , Allen WL, , Alterman RL, & Bronte-Stewart H, et al. : Proceedings of the Second Annual Deep Brain Stimulation Think Tank: What’s in the Pipeline. Int J Neurosci epub ahead of print 2014

    • Search Google Scholar
    • Export Citation
  • 24

    Hallanger AE, & Wainer BH: Ascending projections from the pedunculopontine tegmental nucleus and the adjacent mesopontine tegmentum in the rat. J Comp Neurol 274:483515, 1988

    • Search Google Scholar
    • Export Citation
  • 25

    Halpern CH, , Torres N, , Hurtig HI, , Wolf JA, , Stephen J, & Oh MY, et al. : Expanding applications of deep brain stimulation: a potential therapeutic role in obesity and addiction management. Acta Neurochir (Wien) 153:22932306, 2011

    • Search Google Scholar
    • Export Citation
  • 26

    Hamani C, , McAndrews MP, , Cohn M, , Oh M, , Zumsteg D, & Shapiro CM, et al. : Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 63:119123, 2008

    • Search Google Scholar
    • Export Citation
  • 27

    Hamilton J, , Lee J, & Canales JJ: Chronic unilateral stimulation of the nucleus accumbens at high or low frequencies attenuates relapse to cocaine seeking in an animal model. Brain Stimulat 8:5763, 2015

    • Search Google Scholar
    • Export Citation
  • 28

    Hare TA, , Malmaud J, & Rangel A: Focusing attention on the health aspects of foods changes value signals in vmPFC and improves dietary choice. J Neurosci 31:1107711087, 2011

    • Search Google Scholar
    • Export Citation
  • 29

    Hariz M, , Blomstedt P, & Zrinzo L: Future of brain stimulation: new targets, new indications, new technology. Mov Disord 28:17841792, 2013

    • Search Google Scholar
    • Export Citation
  • 30

    Hazrati LN, , Wong JC, , Hamani C, , Lozano AM, , Poon YY, & Dostrovsky JO, et al. : Clinicopathological study in progressive supranuclear palsy with pedunculopontine stimulation. Mov Disord 27:13041307, 2012

    • Search Google Scholar
    • Export Citation
  • 31

    Hauptman JS, , DeSalles AA, , Espinoza R, , Sedrak M, & Ishida W: Potential surgical targets for deep brain stimulation in treatment-resistant depression. Neurosurg Focus 25:1 E3, 2008

    • Search Google Scholar
    • Export Citation
  • 32

    Hikosaka O: The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci 11:503513, 2010

  • 33

    Hoebel BG, & Thompson RD: Aversion to lateral hypothalamic stimulation caused by intragastric feeding or obesity. J Comp Physiol Psychol 68:536543, 1969

    • Search Google Scholar
    • Export Citation
  • 34

    Hong S, & Hikosaka O: Diverse sources of reward value signals in the basal ganglia nuclei transmitted to the lateral habenula in the monkey. Front Hum Neurosci 7:778, 2013

    • Search Google Scholar
    • Export Citation
  • 35

    Hruby A, & Hu FB: The epidemiology of obesity: a big picture. Pharmacoeconomics epub ahead of print 2014

  • 36

    Hung CY, , Covasa M, , Ritter RC, & Burns GA: Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat. Am J Physiol Regul Integr Comp Physiol 290:R642R651, 2006

    • Search Google Scholar
    • Export Citation
  • 37

    Jiménez-Ponce F, , Velasco-Campos F, , Castro-Farfán G, , Nicolini H, , Velasco AL, & Salín-Pascual R, et al. : Preliminary study in patients with obsessive-compulsive disorder treated with electrical stimulation in the inferior thalamic peduncle. Neurosurgery 65:6 Suppl 203209, 2009

    • Search Google Scholar
    • Export Citation
  • 38

    Jones BE, & Beaudet A: Retrograde labeling of neurones in the brain stem following injections of [3H]choline into the fore-brain of the rat. Exp Brain Res 65:437448, 1987

    • Search Google Scholar
    • Export Citation
  • 39

    Kaizer RR, , da Silva AC, , Morsch VM, , Corrêa MC, & Schetinger MR: Diet-induced changes in AChE activity after long-term exposure. Neurochem Res 29:22512255, 2004

    • Search Google Scholar
    • Export Citation
  • 40

    Karas PJ, , Mikell CB, , Christian E, , Liker MA, & Sheth SA: Deep brain stimulation: a mechanistic and clinical update. Neurosurg Focus 35:5 E1E16, 2013

    • Search Google Scholar
    • Export Citation
  • 41

    Keesey RE, & Lindholm EP: Differential rates of discrimination learning reinforced by medial versus lateral hypothalamic stimulation. J Comp Physiol Psychol 68:544551, 1969

    • Search Google Scholar
    • Export Citation
  • 42

    Kelley AE, & Stinus L: Disappearance of hoarding behavior after 6-hydroxydopamine lesions of the mesolimbic dopamine neurons and its reinstatement with L-dopa. Behav Neurosci 99:531545, 1985

    • Search Google Scholar
    • Export Citation
  • 43

    Knight EJ, , Min HK, , Hwang SC, , Marsh MP, , Paek S, & Kim I, et al. : Nucleus accumbens deep brain stimulation results in insula and prefrontal activation: a large animal FMRI study. PLoS ONE 8:e56640, 2013

    • Search Google Scholar
    • Export Citation
  • 44

    Kuhn J, , Bauer R, , Pohl S, , Lenartz D, , Huff W, & Kim EH, et al. : Observations on unaided smoking cessation after deep brain stimulation of the nucleus accumbens. Eur Addict Res 15:196201, 2009

    • Search Google Scholar
    • Export Citation
  • 45

    Kuhn J, , Lenartz D, , Huff W, , Lee S, , Koulousakis A, & Klosterkoetter J, et al. : Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?. J Neurol Neurosurg Psychiatry 78:11521153, 2007

    • Search Google Scholar
    • Export Citation
  • 46

    Kullmann S, , Heni M, , Linder K, , Zipfel S, , Häring HU, & Veit R, et al. : Resting-state functional connectivity of the human hypothalamus. Hum Brain Mapp 35:60886096, 2014

    • Search Google Scholar
    • Export Citation
  • 47

    Laxton AW, , Lipsman N, & Lozano AM: Deep brain stimulation for cognitive disorders. Handb Clin Neurol 116:307311, 2013

  • 48

    Laxton AW, & Lozano AM: Deep brain stimulation for the treatment of Alzheimer disease and dementias. World Neurosurg 80:e1e8, 2013

  • 49

    Laxton AW, , Tang-Wai DF, , McAndrews MP, , Zumsteg D, , Wennberg R, & Keren R, et al. : A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 68:521534, 2010

    • Search Google Scholar
    • Export Citation
  • 50

    Li AJ, , Dinh TT, & Ritter S: Hyperphagia and obesity produced by arcuate injection of NPY-saporin do not require upregulation of lateral hypothalamic orexigenic peptide genes. Peptides 29:17321739, 2008

    • Search Google Scholar
    • Export Citation
  • 51

    Li N, , Wang J, , Wang XL, , Chang CW, , Ge SN, & Gao L, et al. : Nucleus accumbens surgery for addiction. World Neurosurg 80:e9e19, 2013

  • 52

    Lipsman N, , Woodside DB, , Giacobbe P, , Hamani C, , Carter JC, & Norwood SJ, et al. : Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. Lancet 381:13611370, 2013

    • Search Google Scholar
    • Export Citation
  • 53

    Lozano AM: Vim thalamic stimulation for tremor. Arch Med Res 31:266269, 2000

  • 54

    Lozano AM, , Giacobbe P, , Hamani C, , Rizvi SJ, , Kennedy SH, & Kolivakis TT, et al. : A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg 116:315322, 2012

    • Search Google Scholar
    • Export Citation
  • 55

    Lozano AM, & Lipsman N: Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 77:406424, 2013

  • 56

    Lozano AM, , Mayberg HS, , Giacobbe P, , Hamani C, , Craddock RC, & Kennedy SH: Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 64:461467, 2008

    • Search Google Scholar
    • Export Citation
  • 57

    Mantione M, , van de Brink W, , Schuurman PR, & Denys D: Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report. Neurosurgery 66:E218, 2010

    • Search Google Scholar
    • Export Citation
  • 58

    Martens HC, , Toader E, , Decré MM, , Anderson DJ, , Vetter R, & Kipke DR, et al. : Spatial steering of deep brain stimulation volumes using a novel lead design. Clin Neurophysiol 122:558566, 2011

    • Search Google Scholar
    • Export Citation
  • 59

    Mayberg HS, , Lozano AM, , Voon V, , McNeely HE, , Seminowicz D, & Hamani C, et al. : Deep brain stimulation for treatment-resistant depression. Neuron 45:651660, 2005

    • Search Google Scholar
    • Export Citation
  • 60

    McClure SM, , Laibson DI, , Loewenstein G, & Cohen JD: Separate neural systems value immediate and delayed monetary rewards. Science 306:503507, 2004

    • Search Google Scholar
    • Export Citation
  • 61

    McRae C, , Cherin E, , Yamazaki TG, , Diem G, , Vo AH, & Russell D, et al. : Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry 61:412420, 2004

    • Search Google Scholar
    • Export Citation
  • 62

    Messiah SE, , Lipshultz SE, , Natale RA, & Miller TL: The imperative to prevent and treat childhood obesity: why the world cannot afford to wait. Clin Obes 3:163171, 2013

    • Search Google Scholar
    • Export Citation
  • 63

    Mesulam MM, Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain. Bloom FE, & Kupfer DJ: Psychopharmacology: the Fourth Generation of Progress New York, Raven Press, 1995

    • Search Google Scholar
    • Export Citation
  • 64

    Müller UJ, , Sturm V, , Voges J, , Heinze HJ, , Galazky I, & Heldmann M, et al. : Successful treatment of chronic resistant alcoholism by deep brain stimulation of nucleus accumbens: first experience with three cases. Pharmacopsychiatry 42:288291, 2009

    • Search Google Scholar
    • Export Citation
  • 65

    O’Doherty JP, , Deichmann R, , Critchley HD, & Dolan RJ: Neural responses during anticipation of a primary taste reward. Neuron 33:815826, 2002

    • Search Google Scholar
    • Export Citation
  • 66

    Ogden CL, , Carroll MD, , Curtin LR, , McDowell MA, , Tabak CJ, & Flegal KM: Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 295:15491555, 2006

    • Search Google Scholar
    • Export Citation
  • 67

    Okun MS, , Gallo BV, , Mandybur G, , Jagid J, , Foote KD, & Revilla FJ, et al. : Subthalamic deep brain stimulation with a constant-current device in Parkinson’s disease: an open-label randomised controlled trial. Lancet Neurol 11:140149, 2012

    • Search Google Scholar
    • Export Citation
  • 68

    Olaya JE, , Christian E, , Ferman D, , Luc Q, , Krieger MD, & Sanger TD, et al. : Deep brain stimulation in children and young adults with secondary dystonia: the Children’s Hospital Los Angeles experience. Neurosurg Focus 35:5 E7, 2013

    • Search Google Scholar
    • Export Citation
  • 69

    Pereira EA, & Aziz TZ: Neuropathic pain and deep brain stimulation. Neurotherapeutics 11:496507, 2014

  • 70

    Pérez-Morales M, , López-Colomé AM, , Méndez-Díaz M, , Ruiz-Contreras AE, & Prospéro-García O: Inhibition of diacylglycerol lipase (DAGL) in the lateral hypothalamus of rats prevents the increase in REMS and food ingestion induced by PAR1 stimulation. Neurosci Lett 578:117121, 2014

    • Search Google Scholar
    • Export Citation
  • 71

    Phillis JW: Acetylcholine release from the central nervous system: a 50-year retrospective. Crit Rev Neurobiol 17:161217, 2005

  • 72

    Picciotto MR, , Higley MJ, & Mineur YS: Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76:116129, 2012

    • Search Google Scholar
    • Export Citation
  • 73

    Pursey KM, , Stanwell P, , Gearhardt AN, , Collins CE, & Burrows TL: The prevalence of food addiction as assessed by the Yale Food Addiction Scale: a systematic review. Nutrients 6:45524590, 2014

    • Search Google Scholar
    • Export Citation
  • 74

    Ren J, , Qin C, , Hu F, , Tan J, , Qiu L, & Zhao S, et al. : Habenula “cholinergic” neurons co-release glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes. Neuron 69:445452, 2011

    • Search Google Scholar
    • Export Citation
  • 75

    Quaade F, , Vaernet K, & Larsson S: Stereotaxic stimulation and electrocoagulation of the lateral hypothalamus in obese humans. Acta Neurochir (Wien) 30:111117, 1974

    • Search Google Scholar
    • Export Citation
  • 76

    Rocchi L, , Carlson-Kuhta P, , Chiari L, , Burchiel KJ, , Hogarth P, & Horak FB: Effects of deep brain stimulation in the subthalamic nucleus or globus pallidus internus on step initiation in Parkinson disease: laboratory investigation. J Neurosurg 117:11411149, 2012

    • Search Google Scholar
    • Export Citation
  • 77

    Rolls ET, , Sanghera MK, & Roper-Hall A: The latency of activation of neurones in the lateral hypothalamus and substantia innominata during feeding in the monkey. Brain Res 164:121135, 1979

    • Search Google Scholar
    • Export Citation
  • 78

    Rosin B, , Slovik M, , Mitelman R, , Rivlin-Etzion M, , Haber SN, & Israel Z, et al. : Closed-loop deep brain stimulation is superior in ameliorating parkinsonism. Neuron 72:370384, 2011

    • Search Google Scholar
    • Export Citation
  • 79

    Rothemund Y, , Preuschhof C, , Bohner G, , Bauknecht HC, , Klingebiel R, & Flor H, et al. : Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals. Neuroimage 37:410421, 2007

    • Search Google Scholar
    • Export Citation
  • 80

    Sakurai T: Roles of orexins in the regulation of body weight homeostasis. Obes Res Clin Pract 8:e414e420, 2014

  • 81

    Sano H, & Yokoi M: Striatal medium spiny neurons terminate in a distinct region in the lateral hypothalamic area and do not directly innervate orexin/hypocretin- or melanin-concentrating hormone-containing neurons. J Neurosci 27:69486955, 2007

    • Search Google Scholar
    • Export Citation
  • 82

    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. Neuropsychopharmacology 33:368377, 2008

    • Search Google Scholar
    • Export Citation
  • 83

    Schneider TM, , Beynon C, , Sartorius A, , Unterberg AW, & Kiening KL: Deep brain stimulation of the lateral habenular complex in treatment-resistant depression: traps and pitfalls of trajectory choice. Neurosurgery 72:2 Suppl Operative ons184ons193, 2013

    • Search Google Scholar
    • Export Citation
  • 84

    Schrock LE, , Mink JW, , Woods DW, , Porta M, , Servello D, & Visser-Vandewalle V, et al. : Tourette syndrome deep brain stimulation: A review and updated recommendations. Mov Disord 00:124, 2014

    • Search Google Scholar
    • Export Citation
  • 85

    Small DM, , Veldhuizen MG, , Felsted J, , Mak YE, & McGlone F: Separable substrates for anticipatory and consummatory food chemosensation. Neuron 57:786797, 2008

    • Search Google Scholar
    • Export Citation
  • 86

    Smith SL, , Harrold JA, & Williams G: Diet-induced obesity increases mu opioid receptor binding in specific regions of the rat brain. Brain Res 953:215222, 2002

    • Search Google Scholar
    • Export Citation
  • 87

    St George RJ, , Carlson-Kuhta P, , Nutt JG, , Hogarth P, , Burchiel KJ, & Horak FB: The effect of deep brain stimulation randomized by site on balance in Parkinson’s disease. Mov Disord 29:949953, 2014

    • Search Google Scholar
    • Export Citation
  • 88

    Stice E, , Yokum S, , Bohon C, , Marti N, & Smolen A: Reward circuitry responsivity to food predicts future increases in body mass: moderating effects of DRD2 and DRD4. Neuroimage 50:16181625, 2010

    • Search Google Scholar
    • Export Citation
  • 89

    Stoeckel LE, & Weller RE: Widespread reward-system activation in obese women in response to pictures of high-calorie foods. Neuroimage 41:636647, 2008

    • Search Google Scholar
    • Export Citation
  • 90

    Taghva A, , Corrigan JD, & Rezai AR: Obesity and brain addiction circuitry: implications for deep brain stimulation. Neurosurgery 71:224238, 2012

    • Search Google Scholar
    • Export Citation
  • 91

    Teegarden SL, & Bale TL: Decreases in dietary preference produce increased emotionality and risk for dietary relapse. Biol Psychiatry 61:10211029, 2007

    • Search Google Scholar
    • Export Citation
  • 92

    Teegarden SL, , Scott AN, & Bale TL: Early life exposure to a high fat diet promotes long-term changes in dietary preferences and central reward signaling. Neuroscience 162:924932, 2009

    • Search Google Scholar
    • Export Citation
  • 93

    Tomasi D, & Volkow ND: Striatocortical pathway dysfunction in addiction and obesity: differences and similarities. Crit Rev Biochem Mol Biol 48:119, 2013

    • Search Google Scholar
    • Export Citation
  • 94

    Treece BR, , Covasa M, , Ritter RC, & Burns GA: Delay in meal termination follows blockade of N-methyl-D-aspartate receptors in the dorsal hindbrain. Brain Res 810:3440, 1998

    • Search Google Scholar
    • Export Citation
  • 95

    Tsai HC, , Chang CH, , Pan JI, , Hsieh HJ, , Tsai ST, & Hung HY, et al. : Acute stimulation effect of the ventral capsule/ventral striatum in patients with refractory obsessive-compulsive disorder - a double-blinded trial. Neuropsychiatr Dis Treat 10:6369, 2014

    • Search Google Scholar
    • Export Citation
  • 96

    Tsang EW, , Hamani C, , Moro E, , Mazzella F, , Saha U, & Lozano AM, et al. : Subthalamic deep brain stimulation at individualized frequencies for Parkinson disease. Neurology 78:19301938, 2012

    • Search Google Scholar
    • Export Citation
  • 97

    Tsurugizawa T, , Uneyama H, & Torii K: Brain amino acid sensing. Diabetes Obes Metab 16:Suppl 1 4148, 2014

  • 98

    Vayssiere N, , van der Gaag N, , Cif L, , Hemm S, , Verdier R, & Frerebeau P, et al. : Deep brain stimulation for dystonia confirming a somatotopic organization in the globus pallidus internus. J Neurosurg 101:181188, 2004

    • Search Google Scholar
    • Export Citation
  • 99

    Volkow ND, , Wang GJ, , Tomasi D, & Baler RD: The addictive dimensionality of obesity. Biol Psychiatry 73:811818, 2013

  • 100

    Wang GJ, , Volkow ND, , Logan J, , Pappas NR, , Wong CT, & Zhu W, et al. : Brain dopamine and obesity. Lancet 357:354357, 2001

  • 101

    Wang S, , Liu Y, , Li F, , Jia H, , Liu L, & Xue F: A novel quantitative body shape score for detecting association between obesity and hypertension in China. BMC Public Health 15:7, 2015

    • Search Google Scholar
    • Export Citation
  • 102

    Weaver FM, , Follett KA, , Stern M, , Luo P, , Harris CL, & Hur K, et al. : Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes. Neurology 79:5565, 2012

    • Search Google Scholar
    • Export Citation
  • 103

    Wheeler DS, , Wan S, , Miller A, , Angeli N, , Adileh B, & Hu W, et al. : Role of lateral hypothalamus in two aspects of attention in associative learning. Eur J Neurosci 40:23592377, 2014

    • Search Google Scholar
    • Export Citation
  • 104

    Whiting DM, , Tomycz ND, , Bailes J, , de Jonge L, , Lecoultre V, & Wilent B, et al. : Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism. J Neurosurg 119:5663, 2013

    • Search Google Scholar
    • Export Citation
  • 105

    Wilent WB, , Oh MY, , Buetefisch CM, , Bailes JE, , Cantella D, & Angle C, et al. : Induction of panic attack by stimulation of the ventromedial hypothalamus. J Neurosurg 112:12951298, 2010

    • Search Google Scholar
    • Export Citation
  • 106

    World Health Organization: Obesity and Overweight, Fact Sheet No. 311 (http://www.who.int/mediacentre/factsheets/fs311/en/index.html) Accessed April 7, 2015

    • Search Google Scholar
    • Export Citation
  • 107

    Zaborszky L: The modular organization of brain systems. Basal forebrain: the last frontier. Prog Brain Res 136:359372, 2002

  • 108

    Zaborszky L, , Hoemke L, , Mohlberg H, , Schleicher A, , Amunts K, & Zilles K: Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. Neuroimage 42:11271141, 2008

    • Search Google Scholar
    • Export Citation
  • 109

    Zhao H, , Zhang BL, , Yang SJ, & Rusak B: The role of lateral habenula-dorsal raphe nucleus circuits in higher brain functions and psychiatric illness. Behav Brain Res 277:8998, 2015

    • Search Google Scholar
    • Export Citation

Contributor Notes

Correspondence Derrick A. Dupré, Department of Neurosurgery, Allegheny General Hospital, 420 E. North Ave., Ste. 302, Pittsburgh, PA 15212. email: ddupre@wpahs.org.

INCLUDE WHEN CITING DOI: 10.3171/2015.3.FOCUS1542.

DISCLOSURE The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Anderson VC, , Burchiel KJ, , Hogarth P, , Favre J, & Hammerstad JP: Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 62:554560, 2005

    • Search Google Scholar
    • Export Citation
  • 2

    Bahgat D, , Raslan AM, , McCartney S, & Burchiel KJ: Lesioning and stimulation in tremor-predominant movement disorder patients: an institutional case series and patient-reported outcome. Stereotact Funct Neurosurg 90:181187, 2012

    • Search Google Scholar
    • Export Citation
  • 3

    Baird JP, , Choe A, , Loveland JL, , Beck J, , Mahoney CE, & Lord JS, et al. : Orexin-A hyperphagia: hindbrain participation in consummatory feeding responses. Endocrinology 150:12021216, 2009

    • Search Google Scholar
    • Export Citation
  • 4

    Barnikol TT, , Pawelczyk NB, , Barnikol UB, , Kuhn J, , Lenartz D, & Sturm V, et al. : Changes in apraxia after deep brain stimulation of the nucleus basalis Meynert in a patient with Parkinson dementia syndrome. Mov Disord 25:15191520, 2010

    • Search Google Scholar
    • Export Citation
  • 5

    Benabid AL, & Torres N: New targets for DBS. Parkinsonism Relat Disord 18:Suppl 1 S21S23, 2012

  • 6

    Benagiano V, , Virgintino D, , Flace P, , Girolamo F, , Errede M, & Roncali L, et al. : Choline acetyltransferase-containing neurons in the human parietal neocortex. Eur J Histochem 47:253256, 2003

    • Search Google Scholar
    • Export Citation
  • 7

    Berridge KC, & Robinson TE: What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?. Brain Res Brain Res Rev 28:309369, 1998

    • Search Google Scholar
    • Export Citation
  • 8

    Bisetti A, , Cvetkovic V, , Serafin M, , Bayer L, , Machard D, & Jones BE, et al. : Excitatory action of hypocretin/orexin on neurons of the central medial amygdala. Neuroscience 142:9991004, 2006

    • Search Google Scholar
    • Export Citation
  • 9

    Blevins JE, , Schwartz MW, & Baskin DG: Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol 287:R87R96, 2004

    • Search Google Scholar
    • Export Citation
  • 10

    Bonelli RM, & Cummings JL: Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 9:141151, 2007

  • 11

    Burchiel KJ, , Anderson VC, , Favre J, & Hammerstad JP: Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson’s disease: results of a randomized, blinded pilot study. Neurosurgery 45:13751384, 1999

    • Search Google Scholar
    • Export Citation
  • 12

    Burger KS, & Stice E: Greater striatopallidal adaptive coding during cue-reward learning and food reward habituation predict future weight gain. Neuroimage 99:122128, 2014

    • Search Google Scholar
    • Export Citation
  • 13

    Campos CA, , Shiina H, , Silvas M, , Page S, & Ritter RC: Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats. Endocrinology 154:26132625, 2013

    • Search Google Scholar
    • Export Citation
  • 14

    Cason AM, , Smith RJ, , Tahsili-Fahadan P, , Moorman DE, , Sartor GC, & Aston-Jones G: Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav 100:419428, 2010

    • Search Google Scholar
    • Export Citation
  • 15

    Cleary DR, , Raslan AM, , Rubin JE, , Bahgat D, , Viswanathan A, & Heinricher MM, et al. : Deep brain stimulation entrains local neuronal firing in human globus pallidus internus. J Neurophysiol 109:978987, 2013

    • Search Google Scholar
    • Export Citation
  • 16

    Denys D, , Mantione M, , Figee M, , van den Munckhof P, , Koerselman F, & Westenberg H, et al. : Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 67:10611068, 2010

    • Search Google Scholar
    • Export Citation
  • 17

    Farooqi IS, , Bullmore E, , Keogh J, , Gillard J, , O'Rahilly S, & Fletcher PC: Leptin regulates striatal regions and human eating behavior. Science 317:1355, 2007

    • Search Google Scholar
    • Export Citation
  • 18

    Flegal KM, , Carroll MD, , Kit BK, & Ogden CL: Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307:491497, 2012

    • Search Google Scholar
    • Export Citation
  • 19

    Fox MD, , Buckner RL, , Liu H, , Chakravarty MM, , Lozano AM, & Pascual-Leone A: Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases. Proc Natl Acad Sci U S A 111:E4367E4375, 2014

    • Search Google Scholar
    • Export Citation
  • 20

    Gearhardt AN, , White MA, , Masheb RM, , Morgan PT, , Crosby RD, & Grilo CM: An examination of the food addiction construct in obese patients with binge eating disorder. Int J Eat Disord 45:657663, 2012

    • Search Google Scholar
    • Export Citation
  • 21

    Goodman WK, , Foote KD, , Greenberg BD, , Ricciuti N, , Bauer R, & Ward H, et al. : Deep brain stimulation for intractable obsessive compulsive disorder: pilot study using a blinded, staggered-onset design. Biol Psychiatry 67:535542, 2010

    • Search Google Scholar
    • Export Citation
  • 22

    Gottfried JA, , O'Doherty J, & Dolan RJ: Encoding predictive reward value in human amygdala and orbitofrontal cortex. Science 301:11041107, 2003

    • Search Google Scholar
    • Export Citation
  • 23

    Gunduz A, , Morita H, , Rossi J, , Allen WL, , Alterman RL, & Bronte-Stewart H, et al. : Proceedings of the Second Annual Deep Brain Stimulation Think Tank: What’s in the Pipeline. Int J Neurosci epub ahead of print 2014

    • Search Google Scholar
    • Export Citation
  • 24

    Hallanger AE, & Wainer BH: Ascending projections from the pedunculopontine tegmental nucleus and the adjacent mesopontine tegmentum in the rat. J Comp Neurol 274:483515, 1988

    • Search Google Scholar
    • Export Citation
  • 25

    Halpern CH, , Torres N, , Hurtig HI, , Wolf JA, , Stephen J, & Oh MY, et al. : Expanding applications of deep brain stimulation: a potential therapeutic role in obesity and addiction management. Acta Neurochir (Wien) 153:22932306, 2011

    • Search Google Scholar
    • Export Citation
  • 26

    Hamani C, , McAndrews MP, , Cohn M, , Oh M, , Zumsteg D, & Shapiro CM, et al. : Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 63:119123, 2008

    • Search Google Scholar
    • Export Citation
  • 27

    Hamilton J, , Lee J, & Canales JJ: Chronic unilateral stimulation of the nucleus accumbens at high or low frequencies attenuates relapse to cocaine seeking in an animal model. Brain Stimulat 8:5763, 2015

    • Search Google Scholar
    • Export Citation
  • 28

    Hare TA, , Malmaud J, & Rangel A: Focusing attention on the health aspects of foods changes value signals in vmPFC and improves dietary choice. J Neurosci 31:1107711087, 2011

    • Search Google Scholar
    • Export Citation
  • 29

    Hariz M, , Blomstedt P, & Zrinzo L: Future of brain stimulation: new targets, new indications, new technology. Mov Disord 28:17841792, 2013

    • Search Google Scholar
    • Export Citation
  • 30

    Hazrati LN, , Wong JC, , Hamani C, , Lozano AM, , Poon YY, & Dostrovsky JO, et al. : Clinicopathological study in progressive supranuclear palsy with pedunculopontine stimulation. Mov Disord 27:13041307, 2012

    • Search Google Scholar
    • Export Citation
  • 31

    Hauptman JS, , DeSalles AA, , Espinoza R, , Sedrak M, & Ishida W: Potential surgical targets for deep brain stimulation in treatment-resistant depression. Neurosurg Focus 25:1 E3, 2008

    • Search Google Scholar
    • Export Citation
  • 32

    Hikosaka O: The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci 11:503513, 2010

  • 33

    Hoebel BG, & Thompson RD: Aversion to lateral hypothalamic stimulation caused by intragastric feeding or obesity. J Comp Physiol Psychol 68:536543, 1969

    • Search Google Scholar
    • Export Citation
  • 34

    Hong S, & Hikosaka O: Diverse sources of reward value signals in the basal ganglia nuclei transmitted to the lateral habenula in the monkey. Front Hum Neurosci 7:778, 2013

    • Search Google Scholar
    • Export Citation
  • 35

    Hruby A, & Hu FB: The epidemiology of obesity: a big picture. Pharmacoeconomics epub ahead of print 2014

  • 36

    Hung CY, , Covasa M, , Ritter RC, & Burns GA: Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat. Am J Physiol Regul Integr Comp Physiol 290:R642R651, 2006

    • Search Google Scholar
    • Export Citation
  • 37

    Jiménez-Ponce F, , Velasco-Campos F, , Castro-Farfán G, , Nicolini H, , Velasco AL, & Salín-Pascual R, et al. : Preliminary study in patients with obsessive-compulsive disorder treated with electrical stimulation in the inferior thalamic peduncle. Neurosurgery 65:6 Suppl 203209, 2009

    • Search Google Scholar
    • Export Citation
  • 38

    Jones BE, & Beaudet A: Retrograde labeling of neurones in the brain stem following injections of [3H]choline into the fore-brain of the rat. Exp Brain Res 65:437448, 1987

    • Search Google Scholar
    • Export Citation
  • 39

    Kaizer RR, , da Silva AC, , Morsch VM, , Corrêa MC, & Schetinger MR: Diet-induced changes in AChE activity after long-term exposure. Neurochem Res 29:22512255, 2004

    • Search Google Scholar
    • Export Citation
  • 40

    Karas PJ, , Mikell CB, , Christian E, , Liker MA, & Sheth SA: Deep brain stimulation: a mechanistic and clinical update. Neurosurg Focus 35:5 E1E16, 2013

    • Search Google Scholar
    • Export Citation
  • 41

    Keesey RE, & Lindholm EP: Differential rates of discrimination learning reinforced by medial versus lateral hypothalamic stimulation. J Comp Physiol Psychol 68:544551, 1969

    • Search Google Scholar
    • Export Citation
  • 42

    Kelley AE, & Stinus L: Disappearance of hoarding behavior after 6-hydroxydopamine lesions of the mesolimbic dopamine neurons and its reinstatement with L-dopa. Behav Neurosci 99:531545, 1985

    • Search Google Scholar
    • Export Citation
  • 43

    Knight EJ, , Min HK, , Hwang SC, , Marsh MP, , Paek S, & Kim I, et al. : Nucleus accumbens deep brain stimulation results in insula and prefrontal activation: a large animal FMRI study. PLoS ONE 8:e56640, 2013

    • Search Google Scholar
    • Export Citation
  • 44

    Kuhn J, , Bauer R, , Pohl S, , Lenartz D, , Huff W, & Kim EH, et al. : Observations on unaided smoking cessation after deep brain stimulation of the nucleus accumbens. Eur Addict Res 15:196201, 2009

    • Search Google Scholar
    • Export Citation
  • 45

    Kuhn J, , Lenartz D, , Huff W, , Lee S, , Koulousakis A, & Klosterkoetter J, et al. : Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?. J Neurol Neurosurg Psychiatry 78:11521153, 2007

    • Search Google Scholar
    • Export Citation
  • 46

    Kullmann S, , Heni M, , Linder K, , Zipfel S, , Häring HU, & Veit R, et al. : Resting-state functional connectivity of the human hypothalamus. Hum Brain Mapp 35:60886096, 2014

    • Search Google Scholar
    • Export Citation
  • 47

    Laxton AW, , Lipsman N, & Lozano AM: Deep brain stimulation for cognitive disorders. Handb Clin Neurol 116:307311, 2013

  • 48

    Laxton AW, & Lozano AM: Deep brain stimulation for the treatment of Alzheimer disease and dementias. World Neurosurg 80:e1e8, 2013

  • 49

    Laxton AW, , Tang-Wai DF, , McAndrews MP, , Zumsteg D, , Wennberg R, & Keren R, et al. : A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 68:521534, 2010

    • Search Google Scholar
    • Export Citation
  • 50

    Li AJ, , Dinh TT, & Ritter S: Hyperphagia and obesity produced by arcuate injection of NPY-saporin do not require upregulation of lateral hypothalamic orexigenic peptide genes. Peptides 29:17321739, 2008

    • Search Google Scholar
    • Export Citation
  • 51

    Li N, , Wang J, , Wang XL, , Chang CW, , Ge SN, & Gao L, et al. : Nucleus accumbens surgery for addiction. World Neurosurg 80:e9e19, 2013

  • 52

    Lipsman N, , Woodside DB, , Giacobbe P, , Hamani C, , Carter JC, & Norwood SJ, et al. : Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. Lancet 381:13611370, 2013

    • Search Google Scholar
    • Export Citation
  • 53

    Lozano AM: Vim thalamic stimulation for tremor. Arch Med Res 31:266269, 2000

  • 54

    Lozano AM, , Giacobbe P, , Hamani C, , Rizvi SJ, , Kennedy SH, & Kolivakis TT, et al. : A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg 116:315322, 2012

    • Search Google Scholar
    • Export Citation
  • 55

    Lozano AM, & Lipsman N: Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 77:406424, 2013

  • 56

    Lozano AM, , Mayberg HS, , Giacobbe P, , Hamani C, , Craddock RC, & Kennedy SH: Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 64:461467, 2008

    • Search Google Scholar
    • Export Citation
  • 57

    Mantione M, , van de Brink W, , Schuurman PR, & Denys D: Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report. Neurosurgery 66:E218, 2010

    • Search Google Scholar
    • Export Citation
  • 58

    Martens HC, , Toader E, , Decré MM, , Anderson DJ, , Vetter R, & Kipke DR, et al. : Spatial steering of deep brain stimulation volumes using a novel lead design. Clin Neurophysiol 122:558566, 2011

    • Search Google Scholar
    • Export Citation
  • 59

    Mayberg HS, , Lozano AM, , Voon V, , McNeely HE, , Seminowicz D, & Hamani C, et al. : Deep brain stimulation for treatment-resistant depression. Neuron 45:651660, 2005

    • Search Google Scholar
    • Export Citation
  • 60

    McClure SM, , Laibson DI, , Loewenstein G, & Cohen JD: Separate neural systems value immediate and delayed monetary rewards. Science 306:503507, 2004

    • Search Google Scholar
    • Export Citation
  • 61

    McRae C, , Cherin E, , Yamazaki TG, , Diem G, , Vo AH, & Russell D, et al. : Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry 61:412420, 2004

    • Search Google Scholar
    • Export Citation
  • 62

    Messiah SE, , Lipshultz SE, , Natale RA, & Miller TL: The imperative to prevent and treat childhood obesity: why the world cannot afford to wait. Clin Obes 3:163171, 2013

    • Search Google Scholar
    • Export Citation
  • 63

    Mesulam MM, Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain. Bloom FE, & Kupfer DJ: Psychopharmacology: the Fourth Generation of Progress New York, Raven Press, 1995

    • Search Google Scholar
    • Export Citation
  • 64

    Müller UJ, , Sturm V, , Voges J, , Heinze HJ, , Galazky I, & Heldmann M, et al. : Successful treatment of chronic resistant alcoholism by deep brain stimulation of nucleus accumbens: first experience with three cases. Pharmacopsychiatry 42:288291, 2009

    • Search Google Scholar
    • Export Citation
  • 65

    O’Doherty JP, , Deichmann R, , Critchley HD, & Dolan RJ: Neural responses during anticipation of a primary taste reward. Neuron 33:815826, 2002

    • Search Google Scholar
    • Export Citation
  • 66

    Ogden CL, , Carroll MD, , Curtin LR, , McDowell MA, , Tabak CJ, & Flegal KM: Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 295:15491555, 2006

    • Search Google Scholar
    • Export Citation
  • 67

    Okun MS, , Gallo BV, , Mandybur G, , Jagid J, , Foote KD, & Revilla FJ, et al. : Subthalamic deep brain stimulation with a constant-current device in Parkinson’s disease: an open-label randomised controlled trial. Lancet Neurol 11:140149, 2012

    • Search Google Scholar
    • Export Citation
  • 68

    Olaya JE, , Christian E, , Ferman D, , Luc Q, , Krieger MD, & Sanger TD, et al. : Deep brain stimulation in children and young adults with secondary dystonia: the Children’s Hospital Los Angeles experience. Neurosurg Focus 35:5 E7, 2013

    • Search Google Scholar
    • Export Citation
  • 69

    Pereira EA, & Aziz TZ: Neuropathic pain and deep brain stimulation. Neurotherapeutics 11:496507, 2014

  • 70

    Pérez-Morales M, , López-Colomé AM, , Méndez-Díaz M, , Ruiz-Contreras AE, & Prospéro-García O: Inhibition of diacylglycerol lipase (DAGL) in the lateral hypothalamus of rats prevents the increase in REMS and food ingestion induced by PAR1 stimulation. Neurosci Lett 578:117121, 2014

    • Search Google Scholar
    • Export Citation
  • 71

    Phillis JW: Acetylcholine release from the central nervous system: a 50-year retrospective. Crit Rev Neurobiol 17:161217, 2005

  • 72

    Picciotto MR, , Higley MJ, & Mineur YS: Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76:116129, 2012

    • Search Google Scholar
    • Export Citation
  • 73

    Pursey KM, , Stanwell P, , Gearhardt AN, , Collins CE, & Burrows TL: The prevalence of food addiction as assessed by the Yale Food Addiction Scale: a systematic review. Nutrients 6:45524590, 2014

    • Search Google Scholar
    • Export Citation
  • 74

    Ren J, , Qin C, , Hu F, , Tan J, , Qiu L, & Zhao S, et al. : Habenula “cholinergic” neurons co-release glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes. Neuron 69:445452, 2011

    • Search Google Scholar
    • Export Citation
  • 75

    Quaade F, , Vaernet K, & Larsson S: Stereotaxic stimulation and electrocoagulation of the lateral hypothalamus in obese humans. Acta Neurochir (Wien) 30:111117, 1974

    • Search Google Scholar
    • Export Citation
  • 76

    Rocchi L, , Carlson-Kuhta P, , Chiari L, , Burchiel KJ, , Hogarth P, & Horak FB: Effects of deep brain stimulation in the subthalamic nucleus or globus pallidus internus on step initiation in Parkinson disease: laboratory investigation. J Neurosurg 117:11411149, 2012

    • Search Google Scholar
    • Export Citation
  • 77

    Rolls ET, , Sanghera MK, & Roper-Hall A: The latency of activation of neurones in the lateral hypothalamus and substantia innominata during feeding in the monkey. Brain Res 164:121135, 1979

    • Search Google Scholar
    • Export Citation
  • 78

    Rosin B, , Slovik M, , Mitelman R, , Rivlin-Etzion M, , Haber SN, & Israel Z, et al. : Closed-loop deep brain stimulation is superior in ameliorating parkinsonism. Neuron 72:370384, 2011

    • Search Google Scholar
    • Export Citation
  • 79

    Rothemund Y, , Preuschhof C, , Bohner G, , Bauknecht HC, , Klingebiel R, & Flor H, et al. : Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals. Neuroimage 37:410421, 2007

    • Search Google Scholar
    • Export Citation
  • 80

    Sakurai T: Roles of orexins in the regulation of body weight homeostasis. Obes Res Clin Pract 8:e414e420, 2014

  • 81

    Sano H, & Yokoi M: Striatal medium spiny neurons terminate in a distinct region in the lateral hypothalamic area and do not directly innervate orexin/hypocretin- or melanin-concentrating hormone-containing neurons. J Neurosci 27:69486955, 2007

    • Search Google Scholar
    • Export Citation
  • 82

    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. Neuropsychopharmacology 33:368377, 2008

    • Search Google Scholar
    • Export Citation
  • 83

    Schneider TM, , Beynon C, , Sartorius A, , Unterberg AW, & Kiening KL: Deep brain stimulation of the lateral habenular complex in treatment-resistant depression: traps and pitfalls of trajectory choice. Neurosurgery 72:2 Suppl Operative ons184ons193, 2013

    • Search Google Scholar
    • Export Citation
  • 84

    Schrock LE, , Mink JW, , Woods DW, , Porta M, , Servello D, & Visser-Vandewalle V, et al. : Tourette syndrome deep brain stimulation: A review and updated recommendations. Mov Disord 00:124, 2014

    • Search Google Scholar
    • Export Citation
  • 85

    Small DM, , Veldhuizen MG, , Felsted J, , Mak YE, & McGlone F: Separable substrates for anticipatory and consummatory food chemosensation. Neuron 57:786797, 2008

    • Search Google Scholar
    • Export Citation
  • 86

    Smith SL, , Harrold JA, & Williams G: Diet-induced obesity increases mu opioid receptor binding in specific regions of the rat brain. Brain Res 953:215222,