Letter to the Editor: Deep brain stimulation for obesity

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To The Editor: With great interest we have studied the article by Whiting et al.10 (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. Clinical article. J Neurosurg 119:56–63, July 2013). This article is critical, primarily because it is a well-designed pilot study that explores a new application for deep brain stimulation (DBS) coupled with results that may give evidence of an ability to modulate metabolic rate.4,10 These results further support the existence of a hidden metabolic circuit buried in our brain. Herein, we raise some concerns regarding certain aspects of the theoretical framework design of such a study. Our concerns are mainly because, even though the aim of this study was safety, we still do not see the robust results as seen in DBS for Parkinson's disease (the main aspiration of this kind of study). Furthermore, there is still no strong explanation for why we did not observe results as impressive as those originally seen in animal models.7,9

Our comments on this paper are an attempt to highlight and address some aspects that, as we believe, should be considered when a larger study is conducted for the sake of efficacy. These concerns are summarized in the following points:

1) The stimulation strategies and parameters. The intimate relationship between circadian system and feed homeostasis makes the neurocircuit of feeding a complicated one, and it becomes even more so in humans when we add the effect of higher centers in eating habits.2 On one hand, this makes finding the optimal target for DBS a challenging mission. On the other hand, using stimulation parameters that are basically driven from the stimulation parameters utilized in movement disorders (with the ignorance of the circadian component) is a questionable strategy in achieving the wanted efficacy.

2) Patient selection. One criterion of patient selection in this study is based on nonresponse to bariatric surgery. We believe it is important to know more details about this selection criterion in terms of why this type of surgery failed in the patients and the pattern of failure. Recently published data show that the patient's genetic profile may play an important role in the success of bariatric surgery.6,8 This factor (the genetic profile) should be considered and addressed when exploring DBS for obesity. It may play a role in the results of DBS as it does in bariatric surgery. In this group of patients the cause of obesity may not simply be high food intake, which makes the ultimate goal of treatment to remedy this cause irrelevant. In fact, it has been shown that several genetic defects could lead to refractory obesity.2 Pairing the complicated organization of appetite control with genetic factors raises the possibility that refractory obesity (in patients in whom bariatric surgery has failed) may be associated with different types of corrupted neurocircuits. The possibility of different types of corrupted neurocircuits may imply that we may have to utilize different targets (on a case by case basis, which raises a question about the reasonability of investigating a novel application for DBS in this group of patients) rather than utilizing 1 target for all cases.

3) What really is the physiological function of the lateral hypothalamus? Even though targeting the lateral hypothalamus is based on animal studies that have shown high-frequency stimulation or lesioning leading to weight loss, this somehow counteracts with other reports about the physiological function of this part of the hypothalamus. To clarify this point, the orexinergic neurons of the lateral thalamus have a main role in wakefulness and arousal.1 It is considered that they affect feeding through modulating arousal levels.2,3,5 It was found that under food restriction, the activity of orexinergic neurons increases in anticipation of food. That being said, we can speculate that modulating these neurons by high-frequency stimulation should lead to less anticipation of food, less arousal, and a lower metabolic rate, or more specifically, as seen in orexinergic neuron–ablated mice, to narcolepsy in a study conducted by Chemelli et al.3 or to narcolepsy, hypophagia, and late-onset obesity in a study done by Hara et al.5 Interestingly, the last effect contradicts what is shown by inhibiting the lateral hypothalamus by DBS (high-frequency stimulation) or by lesioning in rats.7,9 However, orexinergic neuron–ablated mice seem more reliably to mimic the effect of inhibiting the lateral hypothalamus than does trying to inhibit this small area of the brain in the small animals surgically. This makes the article by Hara et al. worth reading and thinking about to explain why the effect of high-frequency stimulation does match the effect of genetic ablation for neurons specifically located in the lateral hypothalamus. This is important to determine that we really understand the physiology of this area of the hypothalamus and that we really have a strong theoretical basis.

Finally, we would like to congratulate Whiting and colleagues on their pioneering work. Since the impact of such studies is profound, especially on other future applications for DBS, it should be reviewed and discussed from several angles and perspectives to guarantee optimal progress.

Disclosure

The authors report no conflict of interest.

References

  • 1

    Abrahamson EELeak RKMoore RY: The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12:4354402001

  • 2

    Bechtold DALoudon AS: Hypothalamic clocks and rhythms in feeding behaviour. Trends Neurosci 36:74822013

  • 3

    Chemelli RMWillie JTSinton CMElmquist JKScammell TLee C: Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:4374511999

  • 4

    Eskandar E: Editorial. Deep brain stimulation and obesity. J Neurosurg 119:542013

  • 5

    Hara JBeuckmann CTNambu TWillie JTChemelli RMSinton CM: Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:3453542001

  • 6

    Harrell LEDecastro JMBalagura S: A critical evaluation of body weight loss following lateral hypothalamic lesions. Physiol Behav 15:1331361975

  • 7

    Hatoum IJGreenawalt DMCotsapas CDaly MJReitman MLKaplan LM: Weight loss after gastric bypass is associated with a variant at 15q26.1. Am J Hum Genet 92:8278342013

  • 8

    Moleres ACampion JMilagro FIMarcos ACampoy CGaragorri JM: Differential DNA methylation patterns between high and low responders to a weight loss intervention in overweight or obese adolescents: the EVASYON study. FASEB J 27:250425122013

  • 9

    Sani SJobe KSmith AKordower JHBakay RA: Deep brain stimulation for treatment of obesity in rats. J Neurosurg 107:8098132007

  • 10

    Whiting DMTomycz NDBailes Jde Jonge LLecoultre VWilent B: Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism. Clinical article. J Neurosurg 119:56632013

Response

We appreciate the thoughtful analysis Drs. Salma and Al-Otaibi have provided on our article. Our comments to their concerns with the paper are summarized below. First, we reiterate that the primary focus was one of safety given that this is the first reported series of humans implanted with chronic lateral hypothalamic DBS. The fact that the FDA regards DBS as a significant risk device puts significant constraints on clinical studies of new DBS targets and indications.3 Our efforts to secondarily look at efficacy are clearly limited by the sample size and primary outcome design of the study. The small sample size (n = 3) in this pilot study is a lamentable but unavoidable reality of such government oversight into certain medical device research. Nevertheless, we hope that by demonstrating safety (with more than 2 years of follow-up) this study has surmounted the first hurdle in considering lateral hypothalamic DBS as a treatment for refractory cases of obesity.

Our choice of standard movement disorder DBS parameters as starting points for programming lateral hypothalamic DBS in our patients was also based on the welle-stablished long-term safety of these parameters for DBS in patients with movement disorders. We agree with Dr. Salma and Dr. Al-Otaibi that future studies of DBS for refractory obesity may benefit from a more complex patient selection process in which patients in whom bariatric surgery has failed are preoperatively characterized by baseline resting metabolic studies and genetic studies. However, despite the fact that dozens of obesity-related genes have been identified, a genotype with high penetrance and high risk for obesity has not been uncovered.1 Moreover, the growing pandemic of obesity in the developed world is not likely attributable to genetic changes or mutations but more likely to environmental factors.

Finally, we defend our choice of the lateral hypothalamus as the best investigational target of DBS in obesity. Drs. Salma and Al-Otaibi correctly point out that the physiology of the lateral hypothalamus remains largely unknown and many of the neurons in the lateral hypothalamus have been primarily shown to be involved with arousal. Interestingly, with certain DBS contacts and stimulation parameters we did observe rapid changes in arousal in our patients undergoing lateral hypothalamic DBS. Similar to the dichotomy between the rational drug designers who want to fashion specific drugs based on shapes of known receptors and the combinatorial chemists who aim to find treatments regardless of mechanism by rapidly screening through massive libraries of compounds, it remains to be seen if future new target DBS surgery is encouraged more from new knowledge regarding the physiology of the brain or more from a continued curiosity about whether electrical stimulation can mimic or augment the historical consequences of brain ablation. Clearly, the lateral hypothalamus has been shown under conditions of both lesioning and stimulation in animals and humans to affect body weight, appetite, and metabolism. Similar to what movement disorder DBS and microelectrode recording has done for basal ganglia physiology, DBS may prove to be a powerful tool for expanding our knowledge of hypothalamic physiology and neural circuits.2 In fact, less invasive, ablative neurosurgery such as single-session radiosurgery may someday be reconsidered for obesity once DBS has been used as a mapping tool for brain function and physiology. We feel that the brain-obesity link is strong enough to encourage continued study of DBS in this disease and hope our safety data provide the green light for a larger efficacy-focused study.

References

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Please include this information when citing this paper: published online December 20, 2013; DOI: 10.3171/2013.9.JNS131887.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Abrahamson EELeak RKMoore RY: The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12:4354402001

  • 2

    Bechtold DALoudon AS: Hypothalamic clocks and rhythms in feeding behaviour. Trends Neurosci 36:74822013

  • 3

    Chemelli RMWillie JTSinton CMElmquist JKScammell TLee C: Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:4374511999

  • 4

    Eskandar E: Editorial. Deep brain stimulation and obesity. J Neurosurg 119:542013

  • 5

    Hara JBeuckmann CTNambu TWillie JTChemelli RMSinton CM: Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:3453542001

  • 6

    Harrell LEDecastro JMBalagura S: A critical evaluation of body weight loss following lateral hypothalamic lesions. Physiol Behav 15:1331361975

  • 7

    Hatoum IJGreenawalt DMCotsapas CDaly MJReitman MLKaplan LM: Weight loss after gastric bypass is associated with a variant at 15q26.1. Am J Hum Genet 92:8278342013

  • 8

    Moleres ACampion JMilagro FIMarcos ACampoy CGaragorri JM: Differential DNA methylation patterns between high and low responders to a weight loss intervention in overweight or obese adolescents: the EVASYON study. FASEB J 27:250425122013

  • 9

    Sani SJobe KSmith AKordower JHBakay RA: Deep brain stimulation for treatment of obesity in rats. J Neurosurg 107:8098132007

  • 10

    Whiting DMTomycz NDBailes Jde Jonge LLecoultre VWilent B: Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism. Clinical article. J Neurosurg 119:56632013

  • 1

    Bircan I: Genetics of obesity. J Clin Res Ped Endo Suppl 154572009

  • 2

    Lozano AMSnyder BJHamani CHutchison WDDostrovsky JO: Basal ganglia physiology and deep brain stimulation. Mov Disorder 25:Suppl 1S71S752010

  • 3

    Tomycz NDCheng BCCantella DAngle COh MYWhiting DM: Pursuing new targets and indications for deep brain stimulation: considerations for device-related clinical research in the United States. Neuromodulation 14:3893922011

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