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

Abstract

The habenula (Hb) is a small, evolutionarily conserved epithalamic structure implicated in functions such as reward and mood regulation. Prior imaging work suggests that Hb's structural and functional properties may relate to treatment response in depression and other mood disorders. We used multimodal MRI techniques to investigate the potential involvement of Hb in response to subcallosal cingulate area deep brain stimulation (SCC-DBS) for treatment-resistant mood disorders. Using an automated segmentation technique, we compared Hb volume at baseline and at a subsequent post-operative timepoint (4.4 ± 3.0 years after surgery) in a cohort of 32 patients who received SCC-DBS. Clinical response to treatment (≥50% decrease in HAMD-17 from baseline to 12 months post-operation) was significantly associated with longitudinal Hb volume change: responders tended to have increased Hb volume over time, while non-responders showed decreased Hb volume (t = 2.4, p = 0.021). We additionally used functional MRI (fMRI) in a subcohort of SCC-DBS patients (n = 12) to investigate immediate within-patient changes in Hb functional connectivity associated with SCC-DBS stimulation. Active DBS was significantly associated with increased Hb connectivity to several prefrontal and corticolimbic regions (TFCE-adjusted p _Bonferroni < 0.0001), many of which have been previously implicated in the neurocircuitry of depression. Taken together, our results suggest that Hb may play an important role in the antidepressant effect of SCC-DBS.

Keywords: deep brain stimulation; depression; habenula; neuroimaging; neuromodulation; treatment biomarker.

Figure 1

SCC-DBS and the habenula. (A) Sagittal and coronal structural T1-weighted MRI slices from an exemplar patient showing the position of the implanted bilateral electrodes. These are placed in the white matter bordering the subcallosal cingulate cortex. (B) Coronal slices of the asymmetrical MNI152 template (42) illustrating the location of the habenula and surrounding structures. The habenula appears bright (hyperintense) on T1-weighted MRI. DBS, deep brain stimulation; MNI, Montreal Neurological Institute; SCC, subcallosal cingulate area.

Figure 2

Response-related trajectories of change in habenular volume over time following SCC-DBS. (A) Outline of the habenula—as per automated MAGeT segmentation—shown on two different coronal slices of the MNI152 template brain for illustrative purposes. (B) Changes in bilateral habenula volume over time following SCC-DBS surgery are shown for each patient (follow-up is cut off at 2,500 days post-surgery for visualization purposes, although some post-operative scans were acquired at later timepoints). The dotted lines indicate the change in habenular volume over time in individual patients, while the thick solid lines indicate the estimated change in habenular volume over time for each cohort overall. The gray shaded zones surrounding the solid lines denote the 95% confidence interval. A significant difference in trajectory of change was found in responders (≥50% HAMD improvement) compared to non-responders: habenula volume decreased over time in non-responders but increased in responders (t = 2.4, p < 0.021 for interaction of time and response status). DBS: deep brain stimulation; HAMD-17: 17-item Hamilton rating scale for depression; MNI, Montreal Neurological Institute; SCC, subcallosal cingulate area.

Figure 3

Habenular functional connectivity changes with active SCC-DBS. Change in habenular functional connectivity between DBS-ON and DBS-OFF states. Brain areas that showed a significant change in functional connectivity [TFCE-adjusted p_Bonferroni < 0.0001 (52)] between these states are superimposed on axial slices of a high resolution, high contrast brain template (53) in MNI standard space (42). Red/yellow colors denote areas that were more functionally connected with the bilateral habenula in the DBS-ON condition, while blue colors denote areas that showed less habenular connectivity in the DBS-ON state. Many of the areas whose habenular connectivity changed with SCC-DBS are known to be part of the “brain-wide network of depression.” c., cortex; DBS, deep brain stimulation; DLPFC, dorsolateral prefrontal cortex; g., gyrus; MNI, Montreal Neurological Institute; SCC, subcallosal cingulate area; TFCE, threshold-free cluster enhancement.