78 Simple ablation of the PL/IL region was not associated with significant antidepressant-like effects,79 though other studies have shown antidepressant-like effects with ablation or inactivation of the IL target.83,84 Interestingly, lesions of the local gray matter, while preserving white matter fibers of passage, was associated with antidepressant-like effects.79 Inhibitors,research,lifescience,medical This suggests the mechanism of DBS for TRD may not be simply due to local inhibitory effects, but may involve stimulation of white matter tracts—similar to findings seen in Parkinson’s disease.85 For the NAc target,

it has been shown that continuous stimulation was more effective than intermittent stimulation.86 Consistent with imaging studies in humans, DBS of the NAc has been associated with remote brain activity changes in Inhibitors,research,lifescience,medical the prefrontal cortex,

insula, cingulate, and parahippocampus in a pig model.87 Depletion of serotonin blocks the antidepressantlike effects of medial frontal stimulation in rats, while depletion Inhibitors,research,lifescience,medical of norepinephrine does not79; this suggests a critical role for serotonin (among other monoamines) in the mechanism of action of DBS for TRD. Stimulation of the NAc has been associated with increased monoamine levels in rats corresponding to improvement in depressive- and/or anxiety-like behaviors,86,88,89 though another study showed that internal capsule stimulation resulted Inhibitors,research,lifescience,medical in greater anxiolytic effects.90 Beyond the monoamines, stimulation of the vmPFC, NAc, or ventral tegmental area has been associated with increased Inhibitors,research,lifescience,medical brain-derived neurotrophic factor (BDNF) levels in rats using a chronic

mild stress paradigm80,81,90; prior to stimulation the rats prone to depressive-like behavior showed lower BDNF levels than control rats.91 Therefore, as with Dichloromethane dehalogenase other antidepressant treatments (including medication and ECT), the mechanism of DBS for TRD may involve upregulation of neurotrophic systems.92,93 Ethical concerns associated with deep brain stimulation for treatment-resistant depression Ethical considerations in medicine include beneficence, non-malfeasance, and autonomy.94,95 Consequently, regulations and supervision need to be implemented for clinical trials, especially considering the potential impairment in decision-making Luminespib concentration inherent to neuropsychiatric illnesses and the invasiveness of DBS.96,97 In depression, one must consider the goal of treatment: happiness versus euthymia.