Linked structural and functional brain network findings on the biological vulnerability to depression.

: Background: Patients in remission/recovery following episodes of Major Depressive Disorder (MDD) remain highly vulnerable to future relapse/recurrence. Whilst psychological determinants of this risk are well established, little is known about associated biological mechanisms. Recent work has implicated the Default Mode Network (DMN) in this vulnerability but specific hypotheses remain untested within the high-risk, recovered-state of MDD. Aims: 1) To test the hypothesis that there is excessive Default Mode Network (DMN) functional connectivity (FC) during task performance within recovered-state MDD; 2) To test for connected DMN cortical gyrification abnormalities. Method : A multimodal fMRI/MRI study, including task-based FC and cortical folding analysis, comparing 20 recovered-state MDD patients with 20 matched healthy controls. Results: Recovered-state MDD patients showed significant task-based DMN hyperconnectivity, associated with hypogyrification of key DMN regions (bilateral precuneus). Conclusions: This is the first evidence of connected structural and functional DMN abnormalities in recovered-state MDD, supporting recent hypotheses on biological-level vulnerability. investigated the effect of continuing maintenance-phase antidepressant medication (detailed in subsidiary material S1) on FC. ANOVA of left precuneus seed FC showed significant main effect of group within a right dmPFC cluster (peak at 30, 36, 39 F 2-75 =17.44, P FWE-corr =0.042). Follow-up t-tests, inclusively masked for main effect of group at p<0.001, were significant for Unmedicated patients > Controls at whole-brain level (cluster extent 28 voxels, cluster-level P FDR-corr =0.021, peak T=5.85 at 30, 36, 39). ANOVA of right precuneus seed FC showed main effect that approached significance in the same right dmPFC region (peak at 30, 36, 39 F 2-75 =16.60, P FWE-corr =0.075) and given the importance of exploring potential bias through medication follow-up t-tests were performed, masked for main effect of group at p<0.001, showing whole-brain significance for Unmedicated patients > Controls (cluster 33 voxels, cluster-level P FDR-corr =0.006, peak T=5.76 at 30, 36, 39). Figure 3 depicts these main between-group findings, using extracted data from 12mm radius spheres centered on the peak voxel for main effect within the 3-group ANOVAs. Implications: Within apparent clinical recovery from MDD there are significant and apparently linked abnormalities in DMN structure (identified through hypogyrification of key hubs) and function (identified through task-based DMN hyperconnectivity). These new findings strengthen our knowledge of the biological-level vulnerability to MDD by confirming and extending an important hypothesis (10) based on previous research (9, 11). When assessed alongside event-related fMRI evidence (5), it seems possible that the identified task-based DMN hyperconnectivity may interfere with switching of important dmPFC areas to more appropriate task-positive activity, in line with earlier theories (35). Further research is needed to confirm the more limited findings that DMN functional hyperconnectivity is greatest in MDD patients who have discontinued maintenance-phase medication; and the theory that this networked brain activity may represent a more dynamic indicator of MDD vulnerability linked to relatively stable cortical gyrification abnormalities.