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Deep Brain Stimulation for Obesity.

Ho AL, Sussman ES, Zhang M, Pendharkar AV, Azagury DE, Bohon C, Halpern CH - Cureus (2015)

Bottom Line: Obesity is now the third leading cause of preventable death in the US, accounting for 216,000 deaths annually and nearly 100 billion dollars in health care costs.Despite advancements in bariatric surgery, substantial weight regain and recurrence of the associated metabolic syndrome still occurs in almost 20-35% of patients over the long-term, necessitating the development of novel therapies.We will also briefly review ethical considerations for such an intervention, and discuss genetic secondary-obesity syndromes that may also benefit from DBS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, Stanford University School of Medicine.

ABSTRACT
Obesity is now the third leading cause of preventable death in the US, accounting for 216,000 deaths annually and nearly 100 billion dollars in health care costs. Despite advancements in bariatric surgery, substantial weight regain and recurrence of the associated metabolic syndrome still occurs in almost 20-35% of patients over the long-term, necessitating the development of novel therapies. Our continually expanding knowledge of the neuroanatomic and neuropsychiatric underpinnings of obesity has led to increased interest in neuromodulation as a new treatment for obesity refractory to current medical, behavioral, and surgical therapies. Recent clinical trials of deep brain stimulation (DBS) in chronic cluster headache, Alzheimer's disease, and depression and obsessive-compulsive disorder have demonstrated the safety and efficacy of targeting the hypothalamus and reward circuitry of the brain with electrical stimulation, and thus provide the basis for a neuromodulatory approach to treatment-refractory obesity. In this study, we review the literature implicating these targets for DBS in the neural circuitry of obesity. We will also briefly review ethical considerations for such an intervention, and discuss genetic secondary-obesity syndromes that may also benefit from DBS. In short, we hope to provide the scientific foundation to justify trials of DBS for the treatment of obesity targeting these specific regions of the brain.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram depicting the deep brain stimulation (DBS) targets for obesity and their role in homeostatic pathway of energy balanceThe LH is responsible for providing anabolic feedback onto the autonomic nervous system effectors. The nucleus accumbens (NAc) is the center of the reward pathway in the brain integrating inputs from various high cortical brain areas and the limbic system to reinforce certain beneficial behaviors, such as feeding. Integration of the reward pathways with feeding behavior begins with dopamine release from the ventral tegmental area (VTA) neurons that project onto the nucleus accumbens (NAc). Within the NAc, there are neurons that projection onto the lateral hypothalamus (LH) which contain neurons that stimulate food intake. These nuclei also respond to various hormonal peptides, such as leptin, that are released by the the metabolic systems of the body that link food intake and energy metabolism to the reward pathways within the brain.
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FIG1: Schematic diagram depicting the deep brain stimulation (DBS) targets for obesity and their role in homeostatic pathway of energy balanceThe LH is responsible for providing anabolic feedback onto the autonomic nervous system effectors. The nucleus accumbens (NAc) is the center of the reward pathway in the brain integrating inputs from various high cortical brain areas and the limbic system to reinforce certain beneficial behaviors, such as feeding. Integration of the reward pathways with feeding behavior begins with dopamine release from the ventral tegmental area (VTA) neurons that project onto the nucleus accumbens (NAc). Within the NAc, there are neurons that projection onto the lateral hypothalamus (LH) which contain neurons that stimulate food intake. These nuclei also respond to various hormonal peptides, such as leptin, that are released by the the metabolic systems of the body that link food intake and energy metabolism to the reward pathways within the brain.

Mentions: The hypothalamus is divided into multiple distinct functional regions; the main subregion that has received the most focus as a target for DBS is the lateral hypothalamus (LH). The LH has classically been recognized as the feeding center, providing anabolic control over the body's metabolism (Figure 1) [25]. The LH contains neurons that produce two orexinergic neuropeptides known as orexin and melanin-concentrating hormone (MHC). Intracerebroventricular infusion of either peptide elicits feeding [33]. Orexin-containing neurons project to various brain areas regulating feeding behavior. Over-expression of MCH in experimental models of obesity has been associated with insulin resistance and obesity, whereas MCH-knockout mice tend to be hypophagic and lean [34]. A variety of other peptides in addition to orexins have been implicated in LH activity, such as neuropeptide Y68, and agouti-related protein [35-39]. Moreover, the LH is one of the main regions within the hypothalamus that expresses the leptin receptor. Indeed, the activity of these orexin-containing neurons is mitigated by the presence of leptin, as endogenous leptin signaling in the hypothalamus restrains the overconsumption of calorically dense foods [40]. Animal studies and human genetic studies have confirmed that leptin deficiency is associated with a predisposition to obesity [41-43]. Whether by an inability of leptin to reach its neural target, a decrease in leptin isoforms, or decreased expression of leptin receptor [44-45], this “leptin resistance” lends further evidence that the LH is dysregulated, leading to the hypothesis that targeting this region with DBS may disrupt this aberrant circuitry and ameliorate the obese state [46-48]. 


Deep Brain Stimulation for Obesity.

Ho AL, Sussman ES, Zhang M, Pendharkar AV, Azagury DE, Bohon C, Halpern CH - Cureus (2015)

Schematic diagram depicting the deep brain stimulation (DBS) targets for obesity and their role in homeostatic pathway of energy balanceThe LH is responsible for providing anabolic feedback onto the autonomic nervous system effectors. The nucleus accumbens (NAc) is the center of the reward pathway in the brain integrating inputs from various high cortical brain areas and the limbic system to reinforce certain beneficial behaviors, such as feeding. Integration of the reward pathways with feeding behavior begins with dopamine release from the ventral tegmental area (VTA) neurons that project onto the nucleus accumbens (NAc). Within the NAc, there are neurons that projection onto the lateral hypothalamus (LH) which contain neurons that stimulate food intake. These nuclei also respond to various hormonal peptides, such as leptin, that are released by the the metabolic systems of the body that link food intake and energy metabolism to the reward pathways within the brain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494510&req=5

FIG1: Schematic diagram depicting the deep brain stimulation (DBS) targets for obesity and their role in homeostatic pathway of energy balanceThe LH is responsible for providing anabolic feedback onto the autonomic nervous system effectors. The nucleus accumbens (NAc) is the center of the reward pathway in the brain integrating inputs from various high cortical brain areas and the limbic system to reinforce certain beneficial behaviors, such as feeding. Integration of the reward pathways with feeding behavior begins with dopamine release from the ventral tegmental area (VTA) neurons that project onto the nucleus accumbens (NAc). Within the NAc, there are neurons that projection onto the lateral hypothalamus (LH) which contain neurons that stimulate food intake. These nuclei also respond to various hormonal peptides, such as leptin, that are released by the the metabolic systems of the body that link food intake and energy metabolism to the reward pathways within the brain.
Mentions: The hypothalamus is divided into multiple distinct functional regions; the main subregion that has received the most focus as a target for DBS is the lateral hypothalamus (LH). The LH has classically been recognized as the feeding center, providing anabolic control over the body's metabolism (Figure 1) [25]. The LH contains neurons that produce two orexinergic neuropeptides known as orexin and melanin-concentrating hormone (MHC). Intracerebroventricular infusion of either peptide elicits feeding [33]. Orexin-containing neurons project to various brain areas regulating feeding behavior. Over-expression of MCH in experimental models of obesity has been associated with insulin resistance and obesity, whereas MCH-knockout mice tend to be hypophagic and lean [34]. A variety of other peptides in addition to orexins have been implicated in LH activity, such as neuropeptide Y68, and agouti-related protein [35-39]. Moreover, the LH is one of the main regions within the hypothalamus that expresses the leptin receptor. Indeed, the activity of these orexin-containing neurons is mitigated by the presence of leptin, as endogenous leptin signaling in the hypothalamus restrains the overconsumption of calorically dense foods [40]. Animal studies and human genetic studies have confirmed that leptin deficiency is associated with a predisposition to obesity [41-43]. Whether by an inability of leptin to reach its neural target, a decrease in leptin isoforms, or decreased expression of leptin receptor [44-45], this “leptin resistance” lends further evidence that the LH is dysregulated, leading to the hypothesis that targeting this region with DBS may disrupt this aberrant circuitry and ameliorate the obese state [46-48]. 

Bottom Line: Obesity is now the third leading cause of preventable death in the US, accounting for 216,000 deaths annually and nearly 100 billion dollars in health care costs.Despite advancements in bariatric surgery, substantial weight regain and recurrence of the associated metabolic syndrome still occurs in almost 20-35% of patients over the long-term, necessitating the development of novel therapies.We will also briefly review ethical considerations for such an intervention, and discuss genetic secondary-obesity syndromes that may also benefit from DBS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, Stanford University School of Medicine.

ABSTRACT
Obesity is now the third leading cause of preventable death in the US, accounting for 216,000 deaths annually and nearly 100 billion dollars in health care costs. Despite advancements in bariatric surgery, substantial weight regain and recurrence of the associated metabolic syndrome still occurs in almost 20-35% of patients over the long-term, necessitating the development of novel therapies. Our continually expanding knowledge of the neuroanatomic and neuropsychiatric underpinnings of obesity has led to increased interest in neuromodulation as a new treatment for obesity refractory to current medical, behavioral, and surgical therapies. Recent clinical trials of deep brain stimulation (DBS) in chronic cluster headache, Alzheimer's disease, and depression and obsessive-compulsive disorder have demonstrated the safety and efficacy of targeting the hypothalamus and reward circuitry of the brain with electrical stimulation, and thus provide the basis for a neuromodulatory approach to treatment-refractory obesity. In this study, we review the literature implicating these targets for DBS in the neural circuitry of obesity. We will also briefly review ethical considerations for such an intervention, and discuss genetic secondary-obesity syndromes that may also benefit from DBS. In short, we hope to provide the scientific foundation to justify trials of DBS for the treatment of obesity targeting these specific regions of the brain.

No MeSH data available.


Related in: MedlinePlus