The Role of the Lateral Habenula in Suicide: A Call for Further Exploration

Abstract

Despite decades of significant effort in research, policy, and prevention, suicide rates have continued to rise to the current peak of 14.6 per 100,000 deaths. This has resulted in a concerted effort to identify biomarkers associated with suicidal behavior in the brain, to provide predictions that are better than the chance of discerning who will die by suicide. We propose that the lateral habenula (LHb), and its dysfunction during a suicidal crisis, is a critical component of the transition from suicidal ideations to self-harm. Moreover, the LHb—a key functional node in brain reward circuitry—has not been ascribed a contributory role in suicidal behavior. We argue that the LHb anchors a “suicide circuit” and call for suicide researchers to directly examine the role of the LHb, and its long-term modulation, in response to the negative affect in suicidal behavior. Discerning the neural mechanisms of this contribution will require the collaboration of neuroscientists and psychologists. Consequently, we highlight and discuss research on LHb as it relates to suicidal ideation, suicidal behavior, or death by suicide. In so doing we hope to address the bench-to-bedside translational issues currently involved in suicide research and suggest a developmental framework that focuses on specific structures motivated by theoretical anchors as a way to incorporate neurobiological findings within the context of clinical theory.

The circadian neurobiology of reward

“…The latter has been consistently shown to be hyperactive in depression 24 and has been theorized to be a critical player in suicide. 25 It receives projections from the NAc, the ventral pallidum (VP), the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vlGN/ IGL) and the basal forebrain, among others, and it is activated by negative events, absence of reward and punishment. Its glutamatergic projections reach the VTA where they inhibit the DA and GABAergic neurons.…”

Suicide prevention and ketamine: insights from computational modeling

“…Finally, the lateral habenula (LHb) plays a critical role in processing aversive experiences ( 118 ) and encoding reward prediction errors ( 119 ), and has been implicated in the pathophysiology of STBs ( 120 , 121 ). As outlined in Marguilho et al ( 58 ) model of ketamine action (see Section 3), ketamine blocks LHb activity ( 28 , 122 ) and in turn disinhibits downstream monoaminergic reward centers through a relay in GABAergic interneurons in the dopaminergic VTA or the serotonergic DRN.…”