Deep Brain Stimulation for Obesity: From a Theoretical Framework to Practical Application.

Obesity remains a pervasive global health problem. While there are a number of nonsurgical and surgical options for treatment, the incidence of obesity continues to increase at an alarming rate. The inability to curtail the growing rise of the obesity epidemic may be related to a combination of increased food availability and palatability. Research into feeding behavior has yielded a number of insights into the homeostatic and reward mechanisms that govern feeding. However, there remains a gap between laboratory investigations of feeding physiology in animals and translation into meaningful treatment options for humans. In addition, laboratory investigation may not be able to recapitulate all aspects of human food consumption. In a landmark pilot study of deep brain stimulation (DBS) of the lateral hypothalamic area for obesity, we found that there was an increase in resting metabolic rate as well as a decreased urge to eat. In this review, the authors will review some of the work relating to feeding physiology and research surrounding two nodes involved in feeding homeostasis, nucleus accumbens (NAc) and hypothalamus, and use this to provide a framework for future investigations of DBS as a viable therapeutic modality for obesity.

Wakefulness-Promoting Effects of Lateral Hypothalamic Area-Deep Brain Stimulation in Traumatic Brain Injury-Induced Comatose Rats: Upregulation of α1-Adrenoceptor Subtypes and Downregulation of Gamma-Aminobutyric Acid ß Receptor Expression Via the Orexins Pathway.

OBJECTIVE: Previous studies have shown that deep brain stimulation (DBS) can improve the level of consciousness of comatose patients with traumatic brain injuries (TBIs). However, the most suitable targets for DBS are unknown, and the mechanisms underlying recovery remain to be determined. The aim of the present study was to assess the effects of lateral hypothalamic area-DBS (LHA-DBS) in comatose rats with TBIs. METHODS: A total of 55 Sprague-Dawley rats were randomly assigned to 5 groups: the control group, TBI group, stimulated (TBI+LHA-DBS) group, antagonist (TBI+SB334867+LHA-DBS) group, and antagonist control (TBI+saline+LHA-DBS) group. The rats in the control group had undergone a sham operation and anesthesia, without coma induction. Coma was induced using a free-fall drop method. The rats in the stimulated group received bilateral LHA stimulation (frequency, 200 Hz; voltage, 2-4 V; pulse width, 0.1 ms) for 1 hour, with 5-minute intervals between subsequent stimulations, which were applied alternately to the left and right sides of the lateral hypothalamus. The comatose rats in the antagonist group received an intracerebroventricular injection with an orexins receptor type 1 (OX1R) antagonist (SB334867) and then received LHA-DBS. A I-VI consciousness scale and electroencephalography were used to assess the level of consciousness in each group of rats after LHA-DBS. Western blotting and immunofluorescence were used to detect OX1R expression in the LHA and α1-adrenoceptor (α1-AR) subtype and gamma-aminobutyric acid ß receptor (GABABR) expression in the prefrontal cortex. RESULTS: In the TBI, stimulated, antagonist, and antagonist control groups, 5, 10, 6, and 9 rats were awakened. The electroencephalographic readings indicated that the proportion of δ waves was lower in the stimulated group than in the TBI and antagonist groups (P < 0.05). Western blotting and immunofluorescence analysis showed that OX1R expression was greater in the stimulated group than in the TBI group (P < 0.05). The expression of α1-AR was also greater in the stimulated group than in the TBI and antagonist groups (P < 0.05). In contrast, the GABABR levels in the stimulated group were lower than those in the TBI and antagonist groups (P < 0.05). A statistically significant difference was found between the antagonist and antagonist control groups. CONCLUSIONS: Taken together, these results suggest that LHA-DBS promotes the recovery of consciousness in comatose rats with TBIs. Upregulation of α1-AR expression and downregulation of GABABR expression in the prefrontal cortex via the orexins and OX1R pathways might be involved in the wakefulness-promoting effects of LHA-DBS.

Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice.

Gene transfer has proven to be an effective neurobiological tool in a number of neurodegenerative diseases, but it is not known if it can correct a sleep disorder. Narcolepsy is a neurodegenerative sleep disorder linked to the loss of neurons containing the neuropeptide orexin, also known as hypocretin. Here, a replication-defective herpes simplex virus-1 amplicon-based vector was constructed to transfer the gene for mouse prepro-orexin into mice with a genetic deletion of the orexin gene. After in vitro tests confirmed successful gene transfer into cells, the gene vector was delivered to the lateral hypothalamus of orexin knockout (KO) mice where the orexin peptide was robustly expressed in the somata and processes of numerous neurons, and the peptide product was detected in the cerebrospinal fluid. During the 4-day life-span of the vector the incidence of cataplexy declined by 60%, and the levels of rapid eye movement sleep during the second half of the night were similar to levels in wild-type mice, indicating that narcoleptic sleep-wake behavior in orexin KO mice can be improved by targeted gene transfer.

Electrical stimulation in the lateral hypothalamus in rats in the activity-based anorexia model.

OBJECT: One quarter of patients with anorexia nervosa have a poor outcome and continue to suffer chronically or die. Electrical brain stimulation may be of therapeutic benefit in some of these patients; however, the brain target for inducing symptom relief is unknown. In this study, the authors evaluated the effects of acute and chronic electrical stimulation in the lateral hypothalamus on food intake, locomotor activity, and survival time in rats in an activity-based anorexia model. METHODS: In an acute experiment, the authors electrically stimulated at 100 Hz and 0, 25, 50 and 75% of the maximal stimulation amplitude (that is, the amplitude leading to severe side effects) in the lateral hypothalamus on consecutive days during 4 test sessions in 10 rats and evaluated food intake and locomotor activity. In a chronic experiment, they compared food intake, wheel revolutions, and survival time between 6 rats that underwent electrical stimulation in the lateral hypothalamus (50% of maximal stimulation amplitude) and 8 rats that did not undergo stimulation. RESULTS: In the acute experiment, overall electrical stimulation (25, 50, and 75% combined) and stimulation at 75% of the maximal stimulation amplitude significantly decreased the locomotor activity. However, if the authors omitted results of 1 rat, in which the electrode tip was not located in the lateral hypothalamus on one side but rather in the supraoptic chiasm, the remaining results did not yield significance. No other differences were observed. CONCLUSIONS: When the findings of the current study are extrapolated to patients with anorexia nervosa, the authors do not expect major effects on symptoms with electrical stimulation at high frequency in the lateral hypothalamus.

Deep brain stimulation for treatment of obesity in rats.

OBJECT: Given the success of deep brain stimulation (DBS) in a variety of applications (for example, Parkinson disease and essential tremor), other indications for which there is currently little effective therapy are being evaluated for clinical use of DBS. Obesity may be one such indication. Studies of the control of feeding and appetite by neurosurgical lesioning have been completed previously. This study was conducted to test the authors' hypothesis that continuous bilateral stimulatory inhibition of the rat lateral hypothalamic nucleus (LH) would lead to significant and sustained decrease in food intake and subsequent weight loss. METHODS: Sixteen Sprague-Dawley rats were maintained on a high-fat diet. Daily food intake and weight gain were measured for 7 days, at which time the animals underwent stereotactic placement of 0.25-mm-diameter bipolar stimulating electrodes bilaterally in the LH. On postoperative Day 7, eight animals began to receive continuous stimulation of the LH. The remaining eight animals were left unstimulated as the control group. Individual animal weight, food intake, and water intake were monitored daily and continuously throughout the experiment until postoperative Day 24. RESULTS: There was a decreased rate of weight gain after surgery in all animals, but the unstimulated group recovered and resumed a linear weight gain curve. The stimulated group, however, failed to show weight gain and remained below the mean baseline for body mass. There was a significant weight loss between the stimulated and unstimulated groups. On postoperative Day 24, compared with the day of surgery (Day 0), the unstimulated group had a mean weight gain of 13.8%, whereas the stimulated group had a 2.3% weight loss on average (p = 0.001), yielding a 16.1% weight difference between the two groups. CONCLUSIONS: Bilateral electrical stimulatory inhibition of the LH is effective in causing significant and sustained weight loss in rats.

Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells.

Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. The bar-pressing rate was determined at a range of frequencies each day to evaluate the effects of infusions on reward. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Two control oligos had only slight effects (means of 5 and 11% for missense and sense oligos, respectively). After the infusion, the required frequency shifted back to baseline levels gradually over 1-5 d. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward.

Modulation of cellular immunity by a lesion of the lateral hypothalamic area (LHA) in rats.

The subject of our investigation was the effect of bilateral damage to the lateral hypothalamic area (LHA) on the cellular immune response (CIR), assessed by measuring the diameter of skin infiltration (DSI) 24 and 48 h after intradermal administration of tuberculin in adult male Wistar rats, previously immunized with BCG vaccine. It has been shown that: 1) in the hypothalamo-lesioned rats (HLR) DSI measured 24 and 48 h after tuberculinization did not differ, 2) in the sham-operated rats (SOR) DSI measured 48 h after tuberculin injection was significantly higher (p < 0.02) than that found 24 h after the antigen administration, 3) the damage-induced loss of body weight and the 24-48 h difference in DSI in the responders of the HLR group correlated negatively with each other (r = -0.806, p < 0.05). These results indicate that damage to the LHA enhances the rate of formation, but not the maximal size, of the tuberculin-induced skin infiltration. Thus, the LHA seems to be involved in the regulation/modulation of processes engaged in the expression of tuberculin reaction.

[The organization of instrumental food-procuring movements in rats]. / Organizatsiia instrumental'nykh pishchedobyvatel'nykh dvizhenii u krys.

The roles of the lateral hypothalamus, basolateral nucleus of the amygdalar complex, the second field of the frontal cortex, and ventromedial thalamic nucleus in organization of the fast ballistic food-procuring movements were studied in albino rats. Sequences of uni- and bilateral destruction of the brain structures were assessed by photorecording. Movement-related neuronal activity in these structures was recorded in freely moving animals. A specific involvement of each of the above listed structures in organization of food-procuring movements was shown. The lateral hypothalamus seems to participate in initiation of the motor program and its efficient realization, the basolateral amygdala appears to produce activatory, training, and stabilizing effects. The second field of the motor cortex leads in movement acquisition (i.e., in memorizing) and decision making about triggering the program. The idea about the relay role of the thalamic motor nucleus is supplemented by understanding of its more complex integrative function.

Expression of gastrointestinal nesfatin-1 and gastric emptying in ventromedial hypothalamic nucleus- and ventrolateral hypothalamic nucleus-lesioned rats.

AIM: To determine the expression levels of gastrointestinal nesfatin-1 in ventromedial hypothalamic nucleus (VMH)-lesioned (obese) and ventrolateral hypothalamic nucleus (VLH)-lesioned (lean) rats that exhibit an imbalance in their energy metabolism and gastric mobility. METHODS: Male Wistar rats were randomly divided into a VMH-lesioned group, a VLH-lesioned group, and their respective sham-operated groups. The animals had free access to food and water, and their diets and weights were monitored after surgery. Reverse transcription-polymerase chain reaction and immunostaining were used to analyse the levels of NUCB2 mRNA and nesfatin-1 immunoreactive (IR) cells in the stomach, duodenum, small intestine, and colon, respectively. Gastric emptying was also assessed using a modified phenol red-methylcellulose recovery method. RESULTS: The VMH-lesioned rats fed normal chow exhibited markedly greater food intake and body weight gain, whereas the VLH-lesioned rats exhibited markedly lower food intake and body weight gain. NUCB2/nesfatin-1 IR cells were localised in the lower third and middle portion of the gastric mucosal gland and in the submucous layer of the enteric tract. Compared with their respective controls, gastric emptying was enhanced in the VMH-lesioned rats (85.94% ± 2.27%), whereas the VLH lesions exhibited inhibitory effects on gastric emptying (29.12% ± 1.62%). In the VMH-lesioned rats, the levels of NUCB2 mRNA and nesfatin-1 protein were significantly increased in the stomach and duodenum and reduced in the small intestine. In addition, the levels of NUCB2 mRNA and nesfatin-1 protein in the VLH-lesioned rats were decreased in the stomach, duodenum, and small intestine. CONCLUSION: Our study demonstrated that nesfatin-1 level in the stomach and duodenum is positively correlated with body mass. Additionally, there is a positive relationship between gastric emptying and body mass. The results of this study indicate that gastrointestinal nesfatin-1 may play a significant role in gastric mobility and energy homeostasis.

Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism.

OBJECT: Deep brain stimulation (DBS) of the lateral hypothalamic area (LHA) has been suggested as a potential treatment for intractable obesity. The authors present the 2-year safety results as well as early efficacy and metabolic effects in 3 patients undergoing bilateral LHA DBS in the first study of this approach in humans. METHODS: Three patients meeting strict criteria for intractable obesity, including failed bariatric surgery, underwent bilateral implantation of LHA DBS electrodes as part of an institutional review board- and FDA-approved pilot study. The primary focus of the study was safety; however, the authors also received approval to collect data on early efficacy including weight change and energy metabolism. RESULTS: No serious adverse effects, including detrimental psychological consequences, were observed with continuous LHA DBS after a mean follow-up of 35 months (range 30-39 months). Three-dimensional nonlinear transformation of postoperative imaging superimposed onto brain atlas anatomy was used to confirm and study DBS contact proximity to the LHA. No significant weight loss trends were seen when DBS was programmed using standard settings derived from movement disorder DBS surgery. However, promising weight loss trends have been observed when monopolar DBS stimulation has been applied via specific contacts found to increase the resting metabolic rate measured in a respiratory chamber. CONCLUSIONS: Deep brain stimulation of the LHA may be applied safely to humans with intractable obesity. Early evidence for some weight loss under metabolically optimized settings provides the first "proof of principle" for this novel antiobesity strategy. A larger follow-up study focused on efficacy along with a more rigorous metabolic analysis is planned to further explore the benefits and therapeutic mechanism behind this investigational therapy.

Medial forebrain bundle lesions fail to structurally and functionally disconnect the ventral tegmental area from many ipsilateral forebrain nuclei: implications for the neural substrate of brain stimulation reward.

Lesions in the medial forebrain bundle rostral to a stimulating electrode have variable effects on the rewarding efficacy of self-stimulation. We attempted to account for this variability by measuring the anatomical and functional effects of electrolytic lesions at the level of the lateral hypothalamus (LH) and by correlating these effects to postlesion changes in threshold pulse frequency (pps) for self-stimulation in the ventral tegmental area (VTA). We implanted True Blue in the VTA and compared cell labeling patterns in forebrain regions of intact and lesioned animals. We also compared stimulation-induced regional [14C]deoxyglucose (DG) accumulation patterns in the forebrains of intact and lesioned animals. As expected, postlesion threshold shifts varied: threshold pps remained the same or decreased in eight animals, increased by small but significant amounts in three rats, and increased substantially in six subjects. Unexpectedly, LH lesions did not anatomically or functionally disconnect all forebrain nuclei from the VTA. Most septal and preoptic regions contained equivalent levels of True Blue label in intact and lesioned animals. In both intact and lesioned groups, VTA stimulation increased metabolic activity in the fundus of the striatum (FS), the nucleus of the diagonal band, and the medial preoptic area. On the other hand, True Blue labeling demonstrated anatomical disconnection of the accumbens, FS, substantia innominata/magnocellular preoptic nucleus (SI/MA), and bed nucleus of the stria terminalis. [14C]DG autoradiography indicated functional disconnection of the lateral preoptic area and SI/MA. Correlations between patterns of True Blue labeling or [14C]deoxyglucose accumulation and postlesion shifts in threshold pulse frequency were weak and generally negative. These direct measures of connectivity concord with the behavioral measures in suggesting a diffuse net-like connection between forebrain nuclei and the VTA.