Deep Brain Stimulation of the Habenula: Systematic Review of the Literature and Clinical Trial Registries

Abstract

The habenula is a small bilateral epithalamic structure that plays a key role in the regulation of the main monoaminergic systems. It is implicated in many aspects of behavior such as reward processing, motivational behavior, behavioral adaptation, and sensory integration. A role of the habenula has been indicated in the pathophysiology of a number of neuropsychiatric disorders such as depression, addiction, obsessive-compulsive disorder, and bipolar disorder. Neuromodulation of the habenula using deep brain stimulation (DBS) as potential treatment has been proposed and a first successful case of habenula DBS was reported a decade ago. To provide an overview of the current state of habenula DBS in human subjects for the treatment of neuropsychiatric disorders we conducted a systematic review of both the published literature using PUBMED and current and past registered clinical trials using ClinicalTrials.gov as well as the International Clinical Trials Registry Platform. Using PRISMA guidelines five articles and five registered clinical trials were identified. The published articles detailed the results of habenula DBS for the treatment of schizophrenia, depression, obsessive-compulsive disorder, and bipolar disorder. Four are single case studies; one reports findings in two patients and positive clinical outcome is described in five of the six patients. Of the five registered clinical trials identified, four investigate habenula DBS for the treatment of depression and one for obsessive-compulsive disorder. One trial is listed as terminated, one is recruiting, two are not yet recruiting and the status of the fifth is unknown. The planned enrollment varies between 2 to 13 subjects and four of the five are open label trials. While the published studies suggest a potential role of habenula DBS for a number of indications, future trials and studies are necessary. The outcomes of the ongoing clinical trials will provide further valuable insights. Establishing habenula DBS, however, will depend on successful randomized clinical trials to confirm application and clinical benefit of this promising intervention.

Habenular Involvement in Response to Subcallosal Cingulate Deep Brain Stimulation for Depression

“…Building on existing ECT, ketamine, and standard pharmacotherapy imaging work (23,25), these results strengthen the notion that Hb plays an important role in subserving clinical response to a variety of antidepressant therapies. They also fit with preliminary evidence that DBS directly targeting Hb itself may be a useful therapy for depression (58,59) and various other refractory neuropsychiatric disorders (60).…”

Habenula as a Neural Substrate for Aggressive Behavior

“…Although only a few case studies on Hb deep brain stimulation have been published, they report beneficial outcomes in patients suffering from schizophrenia ( 81 ), depression ( 82 , 83 ), obsessive-compulsive disorder ( 84 ), and bipolar disorder ( 85 ). New clinical trials are currently being performed, demonstrating a growing interest to target this region for the treatment of psychiatric disorders [for a review on deep brain stimulation of the habenula see ( 86 )]. Considering the strong evidence on the involvement of the Hb in the pathophysiology of aggressive behaviors and the possibility of safely targeting this area with deep brain stimulation, it would be interesting to investigate Hb deep brain stimulation in the context of aggressive behaviors.…”

Habenula activation patterns in a preclinical model of neuropathic pain accompanied by depressive-like behaviour

“…It has been shown that patients diagnosed with major depressive disorder [ 64 ] and in psychiatric disorders that present depressive components [ 65 , 66 ] present with altered habenula volume. Furthermore, deep brain stimulation of the habenula results in symptom alleviation in depressive patients [ 67 , 68 ]. It has been shown that the LHb is involved in effort-based decision-making, a key contributor to willingness to exert physical effort in psychiatric conditions [ 69 ].…”