Deep Brain Stimulation for Obesity: A Review and Future Directions

Abstract

The global prevalence of obesity has been steadily increasing. Although pharmacotherapy and bariatric surgeries can be useful adjuvants in the treatment of morbid obesity, they may lose long-term effectiveness. Obesity result largely from unbalanced energy homeostasis. Palatable and densely caloric foods may affect the brain overlapped circuits involved with homeostatic hypothalamus and hedonic feeding. Deep brain stimulation (DBS) consists of delivering electrical impulses to specific brain targets to modulate a disturbed neuronal network. In selected patients, DBS has been shown to be safe and effective for movement disorders. We review all the cases reports and series of patients treated with DBS for obesity using a PubMed search and will address the following obesity-related issues: (i) the hypothalamic regulation of homeostatic feeding; (ii) the reward mesolimbic circuit and hedonic feeding; (iii) basic concepts of DBS as well as the rationale for obesity treatment; (iv) perspectives and challenges in obesity DBS. The small number of cases provides preliminary evidence for the safety and the tolerability of a potential DBS approach. The ventromedial ( n = 2) and lateral ( n = 8) hypothalamic nuclei targets have shown mixed and disappointing outcomes. Although nucleus accumbens ( n = 7) targets were more encouraging for the outcomes of body weight reduction and behavioral control for eating, there was one suicide reported after 27 months of follow-up. The authors did not attribute the suicide to DBS therapy. The identification of optimal brain targets, appropriate programming strategies and the development of novel technologies will be important as next steps to move DBS closer to a clinical application. The identification of electrical control signals may provide an opportunity for closed-loop adaptive DBS systems to address obesity. Metabolic and hormonal sensors such as glycemic levels, leptin, and ghrelin levels are candidate control signals for DBS. Focused excitation or alternatively inhibition of regions of the hypothalamus may provide better outcomes compared to non-selective DBS. Utilization of the NA delta oscillation or other physiological markers from one or multiple regions in obesity-related brain network is a promising approach. Experienced multidisciplinary team will be critical to improve the risk-benefit ratio for this approach.

The Phantom Satiation Hypothesis of Bariatric Surgery

“…In agreement with the hypothesis presented in this article, the aforementioned observations strongly support the idea that derangements in the integrity of key brain sites involved in GI viscerosensory processing can cause weight loss with reduced food intake. In fact, deep brain stimulation for the treatment of human obesity is an active area of research ( Nangunoori et al, 2016 ; Formolo et al, 2019 ), but is almost entirely focused on brain regions involved in energy balance and reward. Based on the hypothesis presented here, modulating brain regions directly involved in satiation, including the insula and parabrachial complex, may also be considered as an appropriate strategy against obesity.…”

Cognitive Task Performance During Titration Predicts Deep Brain Stimulation Treatment Efficacy: Evidence From a Case Study

“…For a disorder like obesity that is characterized by a hypoactive frontal-thalamic pathway (19), however, an approach geared toward targeted upregulation rather than attenuation appears to be more appropriate. Weight-loss alongside low-amplitude DBS of the NAcc was also recently observed in a handful of case studies [(40-42) see (43) for recent review].…”

Pleiotropic role of melatonin in brain mitochondria of obese mice

“…Mitochondral alterations occur in the brain during obesity but their damage is not well defined. The coincidence, well established, between obesity and chronic oxidative stress (45), including in the brain (46), supports changes in mitochondrial function. Although melatonin is considered an essential molecule in the preservation of mitochondria, its role in brain energy balance in obesity in general and in morbid obesity induced by leptin resistance, in particular, is also not well known.…”