Abstract
The habenula is an epithalamic structure implicated in negative reward mechanisms and plays a downstream modulatory role in regulation of dopaminergic and serotonergic functions. Human and animal studies show its hyperactivity in depression which is curtailed by the antidepressant response of ketamine. Deep brain stimulation of habenula (DBS) for major depression have also shown promising results. However, direct neuronal activity of habenula in human studies have rarely been reported. Here, in a cross-sectional design, we acquired both spontaneous resting state and emotional task-induced neuronal recordings from habenula from treatment resistant depressed patients undergoing DBS surgery. We first characterise the aperiodic component (1/f slope) of the power spectrum, interpreted to signify excitation-inhibition balance, in resting and task state. This aperiodicity for left habenula correlated between rest and task and which was significantly positively correlated with depression severity. Time-frequency responses to the emotional picture viewing task show condition differences in beta and gamma frequencies for left habenula and alpha for right habenula. Notably, alpha activity for right habenula was negatively correlated with depression severity. Overall, from direct habenular recordings, we thus show findings convergent with depression models of aberrant excitatory glutamatergic output of the habenula driving inhibition of monoaminergic systems.
Highlights
Major depressive disorder is a major public health issue representing the greatest global burden of disability [1]
The aperiodic component values were significantly correlated between rest and task data for the left habenula (r = 0.94, P = 0.004) (Bonferroni significance P < 0.025) but not for right habenula (r = 0.54, P = 0.26) (Fig. 2b, middle and right panel)
We characterised the power signatures of human habenular recordings demonstrating that the non-oscillatory aperiodic component of the left habenula predicts depression severity
Summary
Major depressive disorder is a major public health issue representing the greatest global burden of disability [1]. Deep brain stimulation (DBS) holds promise for treating resistant depression with potential targeting of brain structures such as the subcallosal cingulate cortex (scCing), anterior limb of the internal capsule [3] and medial forebrain bundle [4, 5]. Another brain region, the habenula, a small evolutionarily conserved epithalamic structure, is a plausible DBS target with two previous pilot clinical case studies demonstrating its therapeutic utility with DBS [6, 7]. It further regulates downstream serotonergic raphe neurons [13] and relays a powerful inhibitory influence on downstream midbrain structures which include both the dopaminergic and serotonergic systems [14, 15] (Fig. 1a)
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