Deep brain stimulation of habenula reduces depressive symptoms and modulates brain activities in treatment-resistant depression

The habenula (Hb) is a phylogenetically old structure connecting forebrain and brainstem monoaminergic nuclei that has been implicated in the pathogenesis of depression. Here, to investigate the clinical efficacy and neural mechanisms of stimulating the Hb for alleviating depression symptoms in humans, we bilaterally implanted electrodes in six patients with treatment-resistant depression and delivered high-frequency stimulation. Compared to baseline, we observed a substantial reduction in Hamilton Depression Rating Scale scores: 62.1% at 1-month, 64.0% at 3-month and 66.2% at 6-month follow-up. Local field potential data showed that acute Hb stimulation increased theta-band power, especially in the right side, which was related to the following clinical remission. Moreover, functional magnetic resonance imaging data showed that acute Hb stimulation enhanced blood oxygen level-dependent responses of the medial orbitofrontal cortex, raphe and substantia nigra, which are important components of the dopaminergic and serotonergic systems. Our findings demonstrated that Hb stimulation can alleviate depressive symptoms and modulate the activity of the medial orbitofrontal cortex, raphe and substantia nigra in treatment-resistant depression patients. This trial was registered under the clinical trial numbers NCT03667872 and ChiCTR2100045363. Using deep brain stimulation of the habenula with implanted electrodes in patients with treatment-resistant depression, this study found a substantial reduction in depression scores at follow-up over multiple time points.