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Figure.
Schematic Representation of Electrode Location
Schematic Representation of Electrode Location

Postoperative computed tomography merged with preoperative T1 images were morphed to the USP-Würzburg atlas of the human brain and normalized to MNI standard space. The trajectory of the electrodes was determined and the volume of tissue activated calculated, as described in the text. Red spheres represent the volume of tissue activated when clinically used cathodes were stimulated at long-term deep brain stimulation settings (2 mA in patient 1 and 3 mA in patients 2, 3, and 4).

Table 1.  
Patient Demographic and Clinical Characteristics
Patient Demographic and Clinical Characteristics
Table 2.  
Preoperative and Postoperative Anthropometry, Bioimpedanciometry, and Calorimetry
Preoperative and Postoperative Anthropometry, Bioimpedanciometry, and Calorimetry
1.
Cassidy  SB, Schwartz  S, Miller  JL, Driscoll  DJ.  Prader-Willi syndrome.  Genet Med. 2012;14(1):10-26. doi:10.1038/gim.0b013e31822bead0PubMedGoogle ScholarCrossref
2.
Brown  FD, Fessler  RG, Rachlin  JR, Mullan  S.  Changes in food intake with electrical stimulation of the ventromedial hypothalamus in dogs.  J Neurosurg. 1984;60(6):1253-1257. doi:10.3171/jns.1984.60.6.1253PubMedGoogle ScholarCrossref
3.
Melega  WP, Lacan  G, Gorgulho  AA, Behnke  EJ, De Salles  AA.  Hypothalamic deep brain stimulation reduces weight gain in an obesity-animal model.  PLoS One. 2012;7(1):e30672. doi:10.1371/journal.pone.0030672PubMedGoogle ScholarCrossref
4.
Sani  S, Jobe  K, Smith  A, Kordower  JH, Bakay  RA.  Deep brain stimulation for treatment of obesity in rats.  J Neurosurg. 2007;107(4):809-813. doi:10.3171/JNS-07/10/0809PubMedGoogle ScholarCrossref
5.
Torres  N, Chabardes  S, Piallat  B, Devergnas  A, Benabid  AL.  Body fat and body weight reduction following hypothalamic deep brain stimulation in monkeys: an intraventricular approach.  Int J Obes (Lond). 2012;36(12):1537-1544. doi:10.1038/ijo.2011.271PubMedGoogle ScholarCrossref
6.
Hamani  C, McAndrews  MP, Cohn  M,  et al.  Memory enhancement induced by hypothalamic/fornix deep brain stimulation.  Ann Neurol. 2008;63(1):119-123. doi:10.1002/ana.21295PubMedGoogle ScholarCrossref
7.
Whiting  DM, Tomycz  ND, Bailes  J,  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. 2013;119(1):56-63. doi:10.3171/2013.2.JNS12903PubMedGoogle ScholarCrossref
8.
Talakoub  O, Paiva  RR, Milosevic  M,  et al.  Lateral hypothalamic activity indicates hunger and satiety states in humans.  Ann Clin Transl Neurol. 2017;4(12):897-901. doi:10.1002/acn3.466PubMedGoogle ScholarCrossref
9.
Alho  EJL, Alho  A, Grinberg  L,  et al.  High thickness histological sections as alternative to study the three-dimensional microscopic human sub-cortical neuroanatomy.  Brain Struct Funct. 2018;223(3):1121-1132. doi:10.1007/s00429-017-1548-2PubMedGoogle Scholar
10.
Franco  R, Fonoff  ET, Alvarenga  P,  et al.  DBS for obesity.  Brain Sci. 2016;6(3):E21. doi:10.3390/brainsci6030021PubMedGoogle ScholarCrossref
11.
Mendelson  J.  Lateral hypothalamic stimulation in satiated rats: the rewarding effects of self-induced drinking.  Science. 1967;157(3792):1077-1079. doi:10.1126/science.157.3792.1077PubMedGoogle ScholarCrossref
12.
Mendelson  J, Chorover  SL.  Lateral hypothalamic stimulation in satiated rats: T-maze learning for food.  Science. 1965;149(3683):559-561. doi:10.1126/science.149.3683.559PubMedGoogle ScholarCrossref
13.
Delgado  JM, Anand  BK.  Increase of food intake induced by electrical stimulation of the lateral hypothalamus.  Am J Physiol. 1953;172(1):162-168.PubMedGoogle Scholar
14.
Stuber  GD, Wise  RA.  Lateral hypothalamic circuits for feeding and reward.  Nat Neurosci. 2016;19(2):198-205. doi:10.1038/nn.4220PubMedGoogle ScholarCrossref
15.
Soto-Montenegro  ML, Pascau  J, Desco  M.  Response to deep brain stimulation in the lateral hypothalamic area in a rat model of obesity: in vivo assessment of brain glucose metabolism.  Mol Imaging Biol. 2014;16(6):830-837. doi:10.1007/s11307-014-0753-0PubMedGoogle ScholarCrossref
16.
Bielajew  C, Stenger  J, Schindler  D.  Factors that contribute to the reduced weight gain following chronic ventromedial hypothalamic stimulation.  Behav Brain Res. 1994;62(2):143-148. doi:10.1016/0166-4328(94)90021-3PubMedGoogle ScholarCrossref
17.
Krasne  FB.  General disruption resulting from electrical stimulus of ventromedial hypothalamus.  Science. 1962;138(3542):822-823. doi:10.1126/science.138.3542.822PubMedGoogle ScholarCrossref
18.
Ruffin  M, Nicolaidis  S.  Electrical stimulation of the ventromedial hypothalamus enhances both fat utilization and metabolic rate that precede and parallel the inhibition of feeding behavior.  Brain Res. 1999;846(1):23-29. doi:10.1016/S0006-8993(99)01922-8PubMedGoogle ScholarCrossref
19.
Stenger  J, Fournier  T, Bielajew  C.  The effects of chronic ventromedial hypothalamic stimulation on weight gain in rats.  Physiol Behav. 1991;50(6):1209-1213. doi:10.1016/0031-9384(91)90584-BPubMedGoogle ScholarCrossref
20.
Ettrup  KS, Sørensen  JC, Rodell  A, Alstrup  AK, Bjarkam  CR.  Hypothalamic deep brain stimulation influences autonomic and limbic circuitry involved in the regulation of aggression and cardiocerebrovascular control in the Göttingen minipig.  Stereotact Funct Neurosurg. 2012;90(5):281-291. doi:10.1159/000338087PubMedGoogle ScholarCrossref
21.
Laćan  G, De Salles  AA, Gorgulho  AA,  et al.  Modulation of food intake following deep brain stimulation of the ventromedial hypothalamus in the vervet monkey: laboratory investigation.  J Neurosurg. 2008;108(2):336-342. doi:10.3171/JNS/2008/108/2/0336PubMedGoogle ScholarCrossref
22.
Zhang  C, Wei  NL, Wang  Y, Wang  X, Zhang  JG, Zhang  K.  Deep brain stimulation of the nucleus accumbens shell induces anti-obesity effects in obese rats with alteration of dopamine neurotransmission.  Neurosci Lett. 2015;589:1-6. doi:10.1016/j.neulet.2015.01.019PubMedGoogle ScholarCrossref
23.
Doucette  WT, Khokhar  JY, Green  AI.  Nucleus accumbens deep brain stimulation in a rat model of binge eating.  Transl Psychiatry. 2015;5:e695. doi:10.1038/tp.2015.197PubMedGoogle ScholarCrossref
24.
Halpern  CH, Tekriwal  A, Santollo  J,  et al.  Amelioration of binge eating by nucleus accumbens shell deep brain stimulation in mice involves D2 receptor modulation.  J Neurosci. 2013;33(17):7122-7129. doi:10.1523/JNEUROSCI.3237-12.2013PubMedGoogle ScholarCrossref
25.
Harat  M, Rudaś  M, Zieliński  P, Birska  J, Sokal  P.  Nucleus accumbens stimulation in pathological obesity.  Neurol Neurochir Pol. 2016;50(3):207-210.PubMedGoogle Scholar
26.
Rezai  AR, Krishna  V, Bogner  J,  et al.  Letter: feasibility of nucleus accumbens deep brain stimulation for morbid, treatment-refractory obesity.  Neurosurgery. 2018;82(5):E136-E137. doi:10.1093/neuros/nyx630PubMedGoogle ScholarCrossref
27.
Fronczek  R, Lammers  GJ, Balesar  R, Unmehopa  UA, Swaab  DF.  The number of hypothalamic hypocretin (orexin) neurons is not affected in Prader-Willi syndrome.  J Clin Endocrinol Metab. 2005;90(9):5466-5470. doi:10.1210/jc.2005-0296PubMedGoogle ScholarCrossref
28.
Manzardo  AM, Johnson  L, Miller  JL, Driscoll  DJ, Butler  MG.  Higher plasma orexin A levels in children with Prader-Willi syndrome compared with healthy unrelated sibling controls.  Am J Med Genet A. 2016;170(8):2097-2102. doi:10.1002/ajmg.a.37749PubMedGoogle ScholarCrossref
29.
Miller  JL, James  GA, Goldstone  AP,  et al.  Enhanced activation of reward mediating prefrontal regions in response to food stimuli in Prader-Willi syndrome.  J Neurol Neurosurg Psychiatry. 2007;78(6):615-619. doi:10.1136/jnnp.2006.099044PubMedGoogle ScholarCrossref
30.
Widge  AS, Licon  E, Zorowitz  S,  et al.  Predictors of hypomania during ventral capsule/ventral striatum deep brain stimulation.  J Neuropsychiatry Clin Neurosci. 2016;28(1):38-44. doi:10.1176/appi.neuropsych.15040089PubMedGoogle ScholarCrossref
31.
Chang  CH, Chen  SY, Hsiao  YL, Tsai  ST, Tsai  HC.  Hypomania with hypersexuality following bilateral anterior limb stimulation in obsessive-compulsive disorder.  J Neurosurg. 2010;112(6):1299-1300. doi:10.3171/2009.10.JNS09918PubMedGoogle ScholarCrossref
32.
Chang  CH, Chen  SY, Tsai  ST, Tsai  HC.  Compulsive skin-picking behavior after deep brain stimulation in a patient with refractory obsessive-compulsive disorder: a case report.  Medicine (Baltimore). 2017;96(36):e8012. doi:10.1097/MD.0000000000008012PubMedGoogle ScholarCrossref
33.
Calandrella  D, Rizzi  M, Ferré  FM, Romito  LM.  Excoriation disorder as a risk factor for deep brain stimulation hardware removal.  J Neurol Sci. 2017;373:342-343. doi:10.1016/j.jns.2017.01.034PubMedGoogle ScholarCrossref
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    Original Investigation
    Neurology
    November 30, 2018

    Assessment of Safety and Outcome of Lateral Hypothalamic Deep Brain Stimulation for Obesity in a Small Series of Patients With Prader-Willi Syndrome

    Author Affiliations
    • 1Children’s Institute, Division of Pediatric Endocrinology, University of São Paulo Medical School, São Paulo, Brazil
    • 2Division of Functional Neurosurgery of Institute of Psychiatry, Department of Neurology, University of São Paulo Medical School, São Paulo, Brazil
    • 3Institute of Psychiatry, Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil
    • 4Harquail Centre for Neuromodulation, Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
    JAMA Netw Open. 2018;1(7):e185275. doi:10.1001/jamanetworkopen.2018.5275
    Key Points

    Question  Is lateral hypothalamic deep brain stimulation (DBS) safe for the treatment of obesity in Prader-Willi syndrome?

    Findings  In this case series of 4 patients with Prader-Willi syndrome treated with lateral hypothalamic DBS, 2 developed stimulation-induced manic symptoms and 2 developed infections, 1 of which was associated with skin picking. No major differences were found when postoperative anthropometric and calorimetric data were compared with baseline; hormonal levels, and results of blood workup, sleep studies, and neuropsychological evaluations also showed no change.

    Meaning  Safety of lateral hypothalamic DBS was in the range of that demonstrated in patients with similar psychiatric conditions receiving DBS; however, in the small cohort of patients with Prader-Willi syndrome treated, DBS seemed largely ineffective for the treatment of obesity.

    Abstract

    Importance  Deep brain stimulation (DBS) has been investigated for treatment of morbid obesity with variable results. Patients with Prader-Willi syndrome (PWS) present with obesity that is often difficult to treat.

    Objective  To test the safety and study the outcome of DBS in patients with PWS.

    Design, Setting, and Participants  This case series was conducted in the Hospital das Clínicas, University of São Paulo, Brazil. Four patients with genetically confirmed PWS presenting with severe obesity were included.

    Exposure  Deep brain stimulation electrodes were bilaterally implanted in the lateral hypothalamic area. After DBS implantation, the treatment included the following phases: titration (1-2 months), stimulation off (2 months), low-frequency DBS (40 Hz; 1 month), washout (15 days), high-frequency DBS (130 Hz; 1 month), and long-term follow-up (6 months).

    Main Outcomes and Measures  Primary outcome measures were adverse events recorded during stimulation and long-term DBS treatment. Secondary outcomes consisted of changes in anthropometric measures (weight, body mass index [calculated as weight in kilograms divided by height in meters squared], and abdominal and neck circumference), bioimpedanciometry, and calorimetry after 6 months of treatment compared with baseline. The following evaluations and measurements were conducted before and after DBS: clinical, neurological, psychiatric, neuropsychological, anthropometry, calorimetry, blood workup, hormonal levels, and sleep studies. Adverse effects were monitored during all follow-up visits.

    Results  Four patients with PWS were included (2 male and 2 female; ages 18-28 years). Baseline mean (SD) body mass index was 39.6 (11.1). Two patients had previous bariatric surgery, and all presented with psychiatric comorbidity, which was well controlled with the use of medications. At 6 months after long-term DBS, patients had a mean 9.6% increase in weight, 5.8% increase in body mass index, 8.4% increase in abdominal circumference, 4.2% increase in neck circumference, 5.3% increase in the percentage of body fat, and 0% change in calorimetry compared with baseline. Also unchanged were hormonal levels and results of blood workup, sleep studies, and neuropsychological evaluations. Two patients developed stimulation-induced manic symptoms. Discontinuation of DBS controlled this symptom in 1 patient. The other required adjustments in medication dosage. Two infections were documented, 1 associated with skin picking.

    Conclusions and Relevance  Safety of lateral hypothalamic area stimulation was in the range of that demonstrated in patients with similar psychiatric conditions receiving DBS. In the small cohort of patients with PWS treated in our study, DBS was largely ineffective.

    Introduction

    Obesity is one of the hallmarks of Prader-Willi Syndrome (PWS) and is largely refractory to medical and surgical therapies in this context.1 Preclinical evidence suggests that hypothalamic stimulation may reduce food consumption and weight gain.2-5 In the clinic, a patient with morbid obesity treated with hypothalamic DBS had transiently lost 12 kg over 5 months.6 Two of 3 patients receiving lateral hypothalamic area (LHA) DBS had significant increases in metabolism at rest.7

    We report the safety and outcome data on the use of LHA DBS in 4 patients with PWS.

    Methods
    Patients

    This nonrandomized study was approved by the research ethics board of the Hospital das Clínicas, University of São Paulo, Brazil, and registered at ClinicalTrials.gov (NCT02297022). Written informed consent was obtained from legally authorized representatives. The study largely followed the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) reporting guideline for nonrandomized trials, except for a few items not applicable to our study (eg, statistical analyses, allocation, patients lost to follow-up, comparison with target population, intention-to-treat analysis).

    Inclusion criteria were (1) age 15 years or older; (2) diagnosis confirmed by genetic analysis; (3) severe obesity, defined as body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) greater than 35 or BMI greater than 30 in patients kept on a strict diet; and (4) legal guardians able to sign the consent. Exclusion criteria were (1) cardiovascular symptoms that could increase surgical risk; (2) clinically relevant brain abnormalities; (3) implanted stimulators; (4) medical condition requiring body magnetic resonance imaging; (5) history of seizures; (6) plans to use diathermy; and (7) currently participating in another trial.

    In total, 5 patients treated in the Division of Pediatric Endocrinology of the Hospital das Clínicas, University of São Paulo, Brazil, were screened by investigators participating in the trial. All received growth hormone during childhood. Patients were living at home with their parents and participated regularly in daily activities. One patient was excluded because his BMI was below 30. Procedures and follow-up appointments were conducted in the Hospital das Clínicas, University of São Paulo, Brazil.

    Baseline Evaluations

    Baseline evaluations included clinical and neurological examinations, psychiatric and neuropsychological assessments, anthropometry (weight, BMI, and abdominal and neck circumference), bioimpedanciometry (Quantum II; RJL Systems, Inc), and calorimetry (CPX/Ultima; MedGraphics). Blood samples to measure the following hormones were collected: growth hormone, follicle stimulating hormone, luteinizing hormone, testosterone, estradiol, cortisol, adrenocorticotropic hormone, prolactin, thyroid-stimulating hormone, free thyroxine, insulin, and insulin-like growth factor 1. Blood workup included measurements of cholesterol and fractions (high-density lipoproteins and low-density lipoproteins), triglycerides, glucose, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, 25-hydroxyvitamin D, and uric acid. Additional examinations were electrocardiogram, echocardiogram, chest radiography, abdominal ultrasound, magnetic resonance imaging, and sleep studies.

    Primary outcome measures were adverse events recorded during stimulation and chronic DBS treatment. Secondary outcomes consisted of changes in anthropometric measures, bioimpedanciometry, and calorimetry after 6 months of chronic DBS compared with baseline. Neither patients nor investigators were blinded as to whether stimulation was being delivered.

    Surgical Procedure

    Surgery was conducted 2 to 4 weeks after baseline assessments (eMethods in the Supplement). The selected target was adjacent to the fornix, anterolateral to the mammillary bodies, and posterior to the optic tract.8 No microrecordings were used. Once electrodes were implanted (model 6149; St Jude Medical), contacts were tested for adverse effects. Stimulation of ventral contacts at 130 Hz, 91 μsec, and 3.5 mA or greater induced significant increases in heart rate with no concomitant changes in blood pressure. While receiving stimulation, patients did not notice changes in hunger or satiety. No memory flashbacks or experiential phenomena were recorded. After testing, electrodes were connected to extension cables externalized through the scalp. A computed tomography scan was then obtained. Five days later, electrodes were connected to a pulse generator (Libra XP6644; St Jude Medical) under general anesthesia.

    To study the location of contacts used for chronic stimulation, postoperative computed tomography merged to preoperative T1 images were morphed to the USP-Würzburg brain atlas9 (eMethods in the Supplement).

    Postoperative Care

    Stimulation was commenced 10 days after surgery at 1.5 mA, 91 μsec, and 40 Hz, a frequency in the range of that associated with weight loss in our previous report.6 Selected cathodes were ventral contacts (case as anode). Patients were initially assessed every 3 to 7 days. If no changes in hunger or weight were noticed, stimulation was increased by 0.5 mA. Once 3 mA was reached, the frequency was increased to 130 Hz, followed by testing of the second most ventral contact. This titration phase lasted 1 to 2 months. Because patients 1 and 2 developed manic symptoms at 3.5 mA and patient 4 had a postoperative skin infection, DBS systems were only activated 2 months after titration (eFigure in the Supplement). Patients were initially given 1 month of low-frequency stimulation (3 mA, 210 μsec, and 40 Hz) followed by 15 days washout and 1 month of high-frequency stimulation (2 mA, 91 μsec, and 130 Hz). Thereafter, DBS was administered at either 40 or 130 Hz for 6 months (frequency selected based on subjective reports provided by caregivers). During chronic stimulation, patient 1 received 2 mA, 91 μsec, and 130 Hz (contacts 2 and 6 as cathodes and the case as anode). Patients 2, 3, and 4 received 3 mA, 210 μsec, and 40 Hz (contacts 1 and 5 as cathodes and the case as anode). Mean (SD) coordinates of the active contacts (midpoint of the cathodes) used for chronic stimulation were 8.3 (2.5) mm lateral, 5.8 (2.1) mm anterior, and 7.3 (1.7) mm inferior to the midcommissural point.

    Anthropometric measures and clinical evaluations were obtained in the end of the off-stimulation, low-frequency stimulation, and high-frequency stimulation phases and 6 months after long-term stimulation. Calorimetry, bioimpedanciometry, neuropsychological assessments, hormonal levels, blood workup, and sleep studies were conducted at baseline and during the 6-month follow-up visit. No activities were done to increase patient compliance.

    Statistical Analysis

    Data in the text and tables are presented as mean (standard deviation). As only 4 patients were treated and our primary outcome was safety, no statistical analyses comparing preoperative and postoperative values were conducted. As this is the first study, to our knowledge, to deliver DBS to patients with PWS, power was not calculated because we could not predict the effect size.

    Results

    Two male and 2 female patients with genetically documented PWS and age ranging from 18 to 28 years were included (Table 1). Mean (SD) baseline BMI was 39.6 (11.1). Two patients had previous bariatric surgery. All presented psychiatric comorbidities, including skin picking, nail biting, aggressive behavior, hypersexuality, episodes of hypomania, psychosis, and impulsiveness. These were well controlled with medications.

    No major differences in preoperative and postoperative anthropometric and calorimetric data were recorded (Table 2). Six months after receiving DBS at best settings, patients had a mean 9.6% increase in weight, 5.8% increase in BMI, 8.4% increase in abdominal circumference, 4.2% increase in neck circumference, 5.3% increase in the percentage of body fat, and 0% change in calorimetry compared with baseline. Also unchanged were hormonal levels and results of blood workup, sleep studies, and neuropsychological evaluations (eTables 1-4 in the Supplement). Individualized data are shown in eTables 5 to 7 in the Supplement. Contacts used for chronic DBS had a volume of tissue activated that encompassed the LHA (Figure).

    Adverse Events

    Patients 1 and 2 developed manic symptoms during the titration phase. Discontinuation of DBS was associated with symptomatic improvement in patient 1 but not in patient 2, who required an increase in topiramate. Patient 1 was receiving preoperative testosterone injections for hypogonadism, which infrequently resulted in priapism. A new episode occurred during the titration phase, requiring drainage.

    Seven months after DBS, patient 1 developed an infection over the connector site likely due to skin picking. As DBS was largely ineffective, the family opted for removing the system. Patient 4 developed a superficial infection over the pulse generator during the first postoperative month that was successfully treated with antibiotics.

    Discussion

    We found that safety of LHA stimulation was in the range of that demonstrated in patients with similar psychiatric conditions treated with DBS. In the small cohort of patients with PWS treated in our study, DBS seemed to be largely ineffective. Recorded adverse effects were hardware-related complications and manic symptoms, which might have occurred because of the recruitment of nearby structures (eg, medial subthalamic nucleus or the medial forebrain bundle).

    Today, the classical concept of specific hypothalamic centers of appetite and satiety is outdated.10 This was supported by early experiments that contributed to our knowledge about mechanisms and circuits involved in these processes. Initial studies targeting the LHA in rodents11,12 and felines13 showed an increase in feeding, an effect partially attributed to the modulation of the medial forebrain bundle.14 In contrast, recent experiments in rodents reported a reduction in weight gain following high-frequency stimulation.4,15 Preclinical work in which the ventromedial nuclei were targeted has also been controversial. While some studies in rodents,16-19 dogs,2 minipigs,3 and nonhuman primates5 have shown altered feeding behavior, changes in type of food ingested, and/or a decrease in weight gain, others reported no substantial changes20 or even an increase in food consumption following stimulation.21

    As feeding involves rewarding aspects, stimulation of the nucleus accumbens (NAc) has also been investigated in animal models. Obese animals receiving NAc shell stimulation had a reduction in weight gain22 associated with increased dopamine levels and the upregulation of D2 receptors.10,22 Reductions in binge eating have also been documented in rodents receiving NAc core23 and NAc shell stimulation,24 the latter effect being mitigated by D2 receptor antagonists.

    To date, a few clinical studies have been conducted using DBS to treat patients with obesity. In 2008, a single patient was treated with hypothalamic DBS with electrodes implanted near the fornix.6 When stimulated at 50 Hz he lost 12 kg over 5 months.6 When required to turn off the device at night, the patient binged and regained the weight he had lost.6 In more recent work, 3 obese patients were treated with LHA stimulation and followed up for an average of 35 months.7 Deep brain stimulation significantly increased resting metabolic state in 2 patients but induced no substantial changes in weight. The outcome of NAc DBS was described in 2 recent trials. A patient who developed hypothalamic obesity following the onset of and surgery to treat a craniopharyngioma lost more than 13 kg in 14 months.25 Rezai and colleagues26 treated 3 obese patients with BMI greater than 40 for whom treatment with Rou-en-Y bypass failed. One patient successfully completed the DBS trial and lost 100 pounds. One patient required the system to be explanted, and the other committed suicide. The authors mentioned that all patients had a history of psychiatric comorbidity and were exposed to important psychosocial stressors during the trial. Deep brain stimulation itself was not thought to be the reason for study withdrawal or suicide.

    Target selection in our study was based on preclinical4,15 and clinical7 evidence. In addition, the LHA has unique neural elements and anatomical connections, serving as an interface between food consumption and reward.14 In PWS, postmortem studies suggest a relative preservation of orexin-positive cells in LHA.27 As patients with PWS have increased plasmatic levels of orexin A,28 we hypothesized that the modulation of local neuronal firing following DBS could have reduced orexin levels and food intake.

    Limitations

    Our study was preliminary in nature and not without limitations. Only 4 patients were included. Despite this fact, recorded changes after DBS were of small magnitude and little variability. The main exception was the documented reduction in testosterone. We believe this was not stimulation induced for several reasons. First, only 1 of 2 patients experienced this event. Second, similar hormonal variability had been documented in that same patient during pretrial examinations. This was attributed to the time of blood collection, which was always done in the morning but not in the same hour. Although the reduction of testosterone in patient 3 was approximately 60%, we note that both preoperative and postoperative levels were substantially lower than the normal value for men of the patient’s age, reflecting his hypogonadotropic hypogonadism. A second aspect that needs to be discussed is the selected hypothalamic target. It is possible that DBS delivered to different hypothalamic nuclei (eg, ventromedial)2,3,5 or brain structures (eg, NAc or ventral internal capsule) might have yielded different results.25,26 This is important if one takes into account neuroimaging studies showing an increased activation of reward circuits when patients with PWS are presented with food stimuli.29 A third aspect involves adverse effects. Stimulation-induced manic symptoms have been reported in patients with psychiatric disorders receiving DBS.30,31 In our study, this occurred only after a certain current threshold was reached. Manic symptoms were reversible in 1 patient following stimulation offset, while the other required medication adjustments. As for infections, patients with PWS may be at particular risk, especially when presenting comorbid skin picking.32,33 Although this diagnosis cannot be considered a surgical contraindication, its presence requires and extra degree of caution to avoid erosions and subsequent infections of the system. As a final remark, patients with PWS present hypothalamic dysfunction (although not particularly in the LHA) and structural abnormalities that might have precluded a positive therapeutic response.

    In a recent study, we have recorded LHA activity in a patient with PWS and tested DBS effects during food intake.8 After eating, the patient described a sensation of fullness but continued to crave food. Rewarding components and craving are associated with a subjective desire to gain pleasure and not directly related to homeostatic feeding. We cannot rule out that hypothalamic stimulation might regulate physiological aspects without affecting craving, which would be an important mechanism for increased food intake in PWS.

    Conclusions

    This study found that LHA DBS was relatively safe but largely ineffective for improving anthropometric measures in a cohort of 4 patients with PWS.

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    Article Information

    Accepted for Publication: October 9, 2018.

    Published: November 30, 2018. doi:10.1001/jamanetworkopen.2018.5275

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Franco RR et al. JAMA Network Open.

    Corresponding Author: Clement Hamani, MD, PhD, Harquail Centre for Neuromodulation, Sunnybrook Research Institute, 2075 Bayview Ave S126, Toronto, ON M4N3M5, Canada (clement.hamani@sunnybrook.ca).

    Author Contributions: Drs Franco and Hamani had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Franco, Fonoff, Lopes, Miguel, Teixeira, Damiani, Hamani.

    Acquisition, analysis, or interpretation of data: Franco, Fonoff, Alvarenga, Alho, Lopes, Hoexter, Batistuzzo, Paiva, Taub, Shavitt, Damiani, Hamani.

    Drafting of the manuscript: Franco, Alvarenga, Shavitt, Hamani.

    Critical revision of the manuscript for important intellectual content: Fonoff, Alho, Lopes, Hoexter, Batistuzzo, Paiva, Taub, Miguel, Teixeira, Damiani.

    Statistical analysis: Franco, Hamani.

    Administrative, technical, or material support: Franco, Fonoff, Alvarenga, Alho, Hoexter, Batistuzzo, Paiva, Taub, Shavitt, Miguel, Teixeira, Damiani.

    Supervision: Fonoff, Alvarenga, Shavitt, Miguel, Damiani, Hamani.

    Conflict of Interest Disclosures: Dr Hamani received honoraria from Medtronic unrelated to this work. No other disclosures were reported.

    Funding/ Support: St. Jude Medical donated deep brain stimulation devices.

    Role of the Funder/Sponsor: St. Jude Medical had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Cassidy  SB, Schwartz  S, Miller  JL, Driscoll  DJ.  Prader-Willi syndrome.  Genet Med. 2012;14(1):10-26. doi:10.1038/gim.0b013e31822bead0PubMedGoogle ScholarCrossref
    2.
    Brown  FD, Fessler  RG, Rachlin  JR, Mullan  S.  Changes in food intake with electrical stimulation of the ventromedial hypothalamus in dogs.  J Neurosurg. 1984;60(6):1253-1257. doi:10.3171/jns.1984.60.6.1253PubMedGoogle ScholarCrossref
    3.
    Melega  WP, Lacan  G, Gorgulho  AA, Behnke  EJ, De Salles  AA.  Hypothalamic deep brain stimulation reduces weight gain in an obesity-animal model.  PLoS One. 2012;7(1):e30672. doi:10.1371/journal.pone.0030672PubMedGoogle ScholarCrossref
    4.
    Sani  S, Jobe  K, Smith  A, Kordower  JH, Bakay  RA.  Deep brain stimulation for treatment of obesity in rats.  J Neurosurg. 2007;107(4):809-813. doi:10.3171/JNS-07/10/0809PubMedGoogle ScholarCrossref
    5.
    Torres  N, Chabardes  S, Piallat  B, Devergnas  A, Benabid  AL.  Body fat and body weight reduction following hypothalamic deep brain stimulation in monkeys: an intraventricular approach.  Int J Obes (Lond). 2012;36(12):1537-1544. doi:10.1038/ijo.2011.271PubMedGoogle ScholarCrossref
    6.
    Hamani  C, McAndrews  MP, Cohn  M,  et al.  Memory enhancement induced by hypothalamic/fornix deep brain stimulation.  Ann Neurol. 2008;63(1):119-123. doi:10.1002/ana.21295PubMedGoogle ScholarCrossref
    7.
    Whiting  DM, Tomycz  ND, Bailes  J,  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. 2013;119(1):56-63. doi:10.3171/2013.2.JNS12903PubMedGoogle ScholarCrossref
    8.
    Talakoub  O, Paiva  RR, Milosevic  M,  et al.  Lateral hypothalamic activity indicates hunger and satiety states in humans.  Ann Clin Transl Neurol. 2017;4(12):897-901. doi:10.1002/acn3.466PubMedGoogle ScholarCrossref
    9.
    Alho  EJL, Alho  A, Grinberg  L,  et al.  High thickness histological sections as alternative to study the three-dimensional microscopic human sub-cortical neuroanatomy.  Brain Struct Funct. 2018;223(3):1121-1132. doi:10.1007/s00429-017-1548-2PubMedGoogle Scholar
    10.
    Franco  R, Fonoff  ET, Alvarenga  P,  et al.  DBS for obesity.  Brain Sci. 2016;6(3):E21. doi:10.3390/brainsci6030021PubMedGoogle ScholarCrossref
    11.
    Mendelson  J.  Lateral hypothalamic stimulation in satiated rats: the rewarding effects of self-induced drinking.  Science. 1967;157(3792):1077-1079. doi:10.1126/science.157.3792.1077PubMedGoogle ScholarCrossref
    12.
    Mendelson  J, Chorover  SL.  Lateral hypothalamic stimulation in satiated rats: T-maze learning for food.  Science. 1965;149(3683):559-561. doi:10.1126/science.149.3683.559PubMedGoogle ScholarCrossref
    13.
    Delgado  JM, Anand  BK.  Increase of food intake induced by electrical stimulation of the lateral hypothalamus.  Am J Physiol. 1953;172(1):162-168.PubMedGoogle Scholar
    14.
    Stuber  GD, Wise  RA.  Lateral hypothalamic circuits for feeding and reward.  Nat Neurosci. 2016;19(2):198-205. doi:10.1038/nn.4220PubMedGoogle ScholarCrossref
    15.
    Soto-Montenegro  ML, Pascau  J, Desco  M.  Response to deep brain stimulation in the lateral hypothalamic area in a rat model of obesity: in vivo assessment of brain glucose metabolism.  Mol Imaging Biol. 2014;16(6):830-837. doi:10.1007/s11307-014-0753-0PubMedGoogle ScholarCrossref
    16.
    Bielajew  C, Stenger  J, Schindler  D.  Factors that contribute to the reduced weight gain following chronic ventromedial hypothalamic stimulation.  Behav Brain Res. 1994;62(2):143-148. doi:10.1016/0166-4328(94)90021-3PubMedGoogle ScholarCrossref
    17.
    Krasne  FB.  General disruption resulting from electrical stimulus of ventromedial hypothalamus.  Science. 1962;138(3542):822-823. doi:10.1126/science.138.3542.822PubMedGoogle ScholarCrossref
    18.
    Ruffin  M, Nicolaidis  S.  Electrical stimulation of the ventromedial hypothalamus enhances both fat utilization and metabolic rate that precede and parallel the inhibition of feeding behavior.  Brain Res. 1999;846(1):23-29. doi:10.1016/S0006-8993(99)01922-8PubMedGoogle ScholarCrossref
    19.
    Stenger  J, Fournier  T, Bielajew  C.  The effects of chronic ventromedial hypothalamic stimulation on weight gain in rats.  Physiol Behav. 1991;50(6):1209-1213. doi:10.1016/0031-9384(91)90584-BPubMedGoogle ScholarCrossref
    20.
    Ettrup  KS, Sørensen  JC, Rodell  A, Alstrup  AK, Bjarkam  CR.  Hypothalamic deep brain stimulation influences autonomic and limbic circuitry involved in the regulation of aggression and cardiocerebrovascular control in the Göttingen minipig.  Stereotact Funct Neurosurg. 2012;90(5):281-291. doi:10.1159/000338087PubMedGoogle ScholarCrossref
    21.
    Laćan  G, De Salles  AA, Gorgulho  AA,  et al.  Modulation of food intake following deep brain stimulation of the ventromedial hypothalamus in the vervet monkey: laboratory investigation.  J Neurosurg. 2008;108(2):336-342. doi:10.3171/JNS/2008/108/2/0336PubMedGoogle ScholarCrossref
    22.
    Zhang  C, Wei  NL, Wang  Y, Wang  X, Zhang  JG, Zhang  K.  Deep brain stimulation of the nucleus accumbens shell induces anti-obesity effects in obese rats with alteration of dopamine neurotransmission.  Neurosci Lett. 2015;589:1-6. doi:10.1016/j.neulet.2015.01.019PubMedGoogle ScholarCrossref
    23.
    Doucette  WT, Khokhar  JY, Green  AI.  Nucleus accumbens deep brain stimulation in a rat model of binge eating.  Transl Psychiatry. 2015;5:e695. doi:10.1038/tp.2015.197PubMedGoogle ScholarCrossref
    24.
    Halpern  CH, Tekriwal  A, Santollo  J,  et al.  Amelioration of binge eating by nucleus accumbens shell deep brain stimulation in mice involves D2 receptor modulation.  J Neurosci. 2013;33(17):7122-7129. doi:10.1523/JNEUROSCI.3237-12.2013PubMedGoogle ScholarCrossref
    25.
    Harat  M, Rudaś  M, Zieliński  P, Birska  J, Sokal  P.  Nucleus accumbens stimulation in pathological obesity.  Neurol Neurochir Pol. 2016;50(3):207-210.PubMedGoogle Scholar
    26.
    Rezai  AR, Krishna  V, Bogner  J,  et al.  Letter: feasibility of nucleus accumbens deep brain stimulation for morbid, treatment-refractory obesity.  Neurosurgery. 2018;82(5):E136-E137. doi:10.1093/neuros/nyx630PubMedGoogle ScholarCrossref
    27.
    Fronczek  R, Lammers  GJ, Balesar  R, Unmehopa  UA, Swaab  DF.  The number of hypothalamic hypocretin (orexin) neurons is not affected in Prader-Willi syndrome.  J Clin Endocrinol Metab. 2005;90(9):5466-5470. doi:10.1210/jc.2005-0296PubMedGoogle ScholarCrossref
    28.
    Manzardo  AM, Johnson  L, Miller  JL, Driscoll  DJ, Butler  MG.  Higher plasma orexin A levels in children with Prader-Willi syndrome compared with healthy unrelated sibling controls.  Am J Med Genet A. 2016;170(8):2097-2102. doi:10.1002/ajmg.a.37749PubMedGoogle ScholarCrossref
    29.
    Miller  JL, James  GA, Goldstone  AP,  et al.  Enhanced activation of reward mediating prefrontal regions in response to food stimuli in Prader-Willi syndrome.  J Neurol Neurosurg Psychiatry. 2007;78(6):615-619. doi:10.1136/jnnp.2006.099044PubMedGoogle ScholarCrossref
    30.
    Widge  AS, Licon  E, Zorowitz  S,  et al.  Predictors of hypomania during ventral capsule/ventral striatum deep brain stimulation.  J Neuropsychiatry Clin Neurosci. 2016;28(1):38-44. doi:10.1176/appi.neuropsych.15040089PubMedGoogle ScholarCrossref
    31.
    Chang  CH, Chen  SY, Hsiao  YL, Tsai  ST, Tsai  HC.  Hypomania with hypersexuality following bilateral anterior limb stimulation in obsessive-compulsive disorder.  J Neurosurg. 2010;112(6):1299-1300. doi:10.3171/2009.10.JNS09918PubMedGoogle ScholarCrossref
    32.
    Chang  CH, Chen  SY, Tsai  ST, Tsai  HC.  Compulsive skin-picking behavior after deep brain stimulation in a patient with refractory obsessive-compulsive disorder: a case report.  Medicine (Baltimore). 2017;96(36):e8012. doi:10.1097/MD.0000000000008012PubMedGoogle ScholarCrossref
    33.
    Calandrella  D, Rizzi  M, Ferré  FM, Romito  LM.  Excoriation disorder as a risk factor for deep brain stimulation hardware removal.  J Neurol Sci. 2017;373:342-343. doi:10.1016/j.jns.2017.01.034PubMedGoogle ScholarCrossref
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