3T MRI of rapid brain activity changes driven by subcallosal cingulate deep brain stimulation

Deep brain stimulation targeting the subcallosal cingulate area (SCC-DBS), a hub with multiple axonal projections, has shown therapeutic potential for treatment-resistant mood disorders. While SCC-DBS drives long-term metabolic changes in corticolimbic circuits, the brain areas that are directly modulated by electrical stimulation of this region are not known. We used 3.0 Tesla functional MRI to map the topography of acute brain changes produced by stimulation in an initial cohort of twelve patients with fully implanted SCC-DBS devices. Four additional SCC-DBS patients were also scanned and employed as a validation cohort. Participants underwent resting state scans (n=78 acquisitions overall) during i) inactive DBS; ii) clinically optimal active DBS; iii) suboptimal active DBS. All scans were acquired within a single MRI session, each separated by a 5-minute washout period. Analysis of the amplitude of low frequency fluctuations (ALFF) in each sequence indicated that clinically optimal SCC-DBS reduced spontaneous brain activity in several areas, including bilateral dorsal anterior cingulate cortex (dACC), posterior cingulate cortex (PCC), precuneus, and left inferior parietal lobule (pBonferroni<0.0001). Stimulation-induced dACC signal reduction correlated with immediate within-session mood fluctuations, was greater at optimal versus suboptimal settings, and related to local cingulum bundle engagement. Moreover, linear modelling showed that immediate changes in dACC, PCC, and precuneus activity could predict individual long-term antidepressant improvement. A model derived from the primary cohort that incorporated ALFF changes in these three areas (along with pre-operative symptom severity) explained 55% of the variance in clinical improvement in that cohort. The same model also explained 93% of the variance in the out-of-sample validation cohort. Additionally all three brain areas exhibited significant changes in functional connectivity between active and inactive DBS states (pBonferroni<0.01). These results provide insight into the network-level mechanisms of SCC-DBS and point towards potential acute biomarkers of clinical response that could help to optimize and personalize this therapy.