Neurochemical mechanisms of deep brain stimulation for depression in animal models.

Deep brain stimulation (DBS) has emerged as a neuromodulation therapy for treatment-resistant depression, but its actual efficacy and mechanisms of action are still unclear. Changes in neurochemical transmission are important mechanisms of antidepressant therapies. Here, we review the preclinical DBS literature reporting behavioural and neurochemical data associated with its antidepressant-like effects. The most commonly studied target in preclinical models was the ventromedial prefrontal cortex (vmPFC). In rodents, DBS delivered to this target induced serotonin (5-HT) release and increased 5-HT1B receptor expression. The antidepressant-like effects of vmPFC DBS seemed to be independent of the serotonin transporter and potentially mediated by the direct modulation of prefrontal projections to the raphe. Adenosinergic and glutamatergic transmission might have also play a role. Medial forebrain bundle (MFB) DBS increased dopamine levels and reduced D2 receptor expression, whereas nucleus accumbens (NAcc), and lateral habenula (LHb) stimulation increased catecholamine levels in different brain regions. In rodents, subthalamic nucleus (STN) DBS induced robust depression-like responses associated with a reduction in serotonergic transmission, as revealed by a decrease in serotonin release. Some of these effects seemed to be mediated by 5HT1A receptors. In conclusion, the antidepressant-like effects of DBS in preclinical models have been well documented in multiple targets. Though variable mechanisms have been proposed, DBS-induced acute and long-term changes in neurochemical substrates seem to play an important role in the antidepressant-like effects of this therapy.

Serotonin 5-HT1B receptors mediate the antidepressant- and anxiolytic-like effects of ventromedial prefrontal cortex deep brain stimulation in a mouse model of social defeat.

BACKGROUND: Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) induces antidepressant- and anxiolytic-like responses in various animal models. Electrophysiology and neurochemical studies suggest that these effects may be dependent, at least in part, on the serotonergic system. In rodents, vmPFC DBS reduces raphe cell firing and increases serotonin (5-HT) release and the expression of serotonergic receptors in different brain regions. METHODS: We examined whether the behavioural responses of chronic vmPFC DBS are mediated by 5-HT1A or 5-HT1B receptors through a series of experiments. First, we delivered stimulation to mice undergoing chronic social defeat stress (CSDS), followed by a battery of behavioural tests. Second, we measured the expression of 5-HT1A and 5-HT1B receptors in different brain regions with western blot. Finally, we conducted pharmacological experiments to mitigate the behavioural effects of DBS using the 5-HT1A antagonist, WAY-100635, or the 5-HT1B antagonist, GR-127935. RESULTS: We found that chronic DBS delivered to stressed animals reduced the latency to feed in the novelty suppressed feeding test (NSF) and immobility in the forced swim test (FST). Though no significant changes were observed in receptor expression, 5-HT1B levels in DBS-treated animals were found to be non-significantly increased in the vmPFC, hippocampus, and nucleus accumbens and reduced in the raphe compared to non-stimulated controls. Finally, while animals given vmPFC stimulation along with WAY-100635 still presented significant responses in the NSF and FST, these were mitigated following GR-127935 administration. CONCLUSIONS: The antidepressant- and anxiolytic-like effects of DBS in rodents may be partially mediated by 5-HT1B receptors.

A systematic review on neuromodulation therapies for reducing body weight in patients with obesity.

The global prevalence of obesity increases yearly along with a rising demand for efficacious, safe, and accessible treatments. Neuromodulation interventions (i.e., deep brain stimulation [DBS], transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS], percutaneous neurostimulation [PENS], vagus nerve stimulation [VNS], and gastric electrical stimulation [GES]) have been proposed as novel therapies. This systematic review sought to examine the safety and efficacy of neuromodulation therapies in reducing body weight in patients with obesity. Using PRISMA guidelines, we performed a systematic review for studies on neuromodulation for the treatment of obesity, resulting in 60 trials included (7 DBS, 5 TMS, 7 tDCS, 17 PENS and VNS, and 24 GES; a total of 3,042 participants). While promising results have been reported in open label studies, double-blinded randomized clinical trials often did not reach their primary endpoints, with no technique inducing a striking reduction in body weight. Bearing in mind the complexity and multifactorial nature of obesity, it is possible that a single treatment may not be enough for patients to lose or maintain the weight lost at long term.