From darkness to light Exploring deep brain stimulation for treatment-resistant depression

Deep brain stimulation (DBS) is a promising intervention for treatment-resistant depression (TRD). This thesis explores its neurobiological mechanisms, symptom trajectories, effects on cognitive functioning, and response predictors. Findings from a systematic review of neuroimaging studies indicate that TRD may be a distinct major depressive disorder subtype, characterized by abnormalities in default mode network and occipital lobe functioning. Furthermore, we show that DBS effectively reduces depressive symptoms across all dimensions in TRD, although insomnia symptoms may improve at a slower rate. Additionally, patients with more anxiety symptoms, who typically tend to have worse pharmacological treatment outcomes, may particularly benefit from DBS. Using a meta-analytic approach, we further show that DBS for TRD does not lead to a decline in cognitive functioning. Two neuroimaging studies show that vALIC DBS normalizes amygdala hyporesponsivity and modifies amygdala functional connectivity in TRD. In addition, findings indicate that baseline and changes in reward circuit activity is associated with DBS outcome, although there was no significant effect of vALIC DBS on reward circuit functioning in patients compared to healthy controls. A systematic review and meta-analysis of preoperative predictors found no reliable predictors of response to DBS in TRD. Although further research is necessary, some findings suggests that a less chronic, more treatment-responsive course of depression may be associated with response, as well as hyperactivity in the subcallosal cingulate gyrus. In order to improve and personalize DBS treatment in TRD, future research should focus on personalizing DBS targets, identifying response predictors, and enhancing DBS treatment with adjunctive therapies.