Altered ability to access a clinically relevant control network in patients remitted from major depressive disorder

Neurobiological models to explain vulnerability of major depressive disorder (MDD) are scarce and previous functional magnetic resonance imaging studies mostly examined “static” functional connectivity (FC). Knowing that FC constantly evolves over time, it becomes important to assess how FC dynamically differs in remitted‐MDD patients vulnerable for new depressive episodes. Using a recently developed method to examine dynamic FC, we characterized re‐emerging FC states during rest in 51 antidepressant‐free MDD patients at high risk of recurrence (≥2 previous episodes), and 35 healthy controls. We examined differences in occurrence, duration, and switching profiles of FC states after neutral and sad mood induction. Remitted MDD patients showed a decreased probability of an FC state (p < 0.005) consisting of an extensive network connecting frontal areas—important for cognitive control—with default mode network, striatum, and salience areas, involved in emotional and self‐referential processing. Even when this FC state was observed in patients, it lasted shorter (p < 0.005) and was less likely to switch to a smaller prefrontal–striatum network (p < 0.005). Differences between patients and controls decreased after sad mood induction. Further, the duration of this FC state increased in remitted patients after sad mood induction but not in controls (p < 0.05). Our findings suggest reduced ability of remitted‐MDD patients, in neutral mood, to access a clinically relevant control network involved in the interplay between externally and internally oriented attention. When recovering from sad mood, remitted recurrent MDD appears to employ a compensatory mechanism to access this FC state. This study provides a novel neurobiological profile of MDD vulnerability.This study is supported by unrestricted personal grants from the Academic Medical Centre to C.A.F. (AMC MD‐PhD Scholarship) and Dr. R.J.M. (AMC PhD Scholarship) and a dedicated grant from the Dutch Brain Foundation (Hersenstichting The Netherlands: 2009(2)‐72). Dr. J.C. was supported under the project NORTE‐01‐0145‐FEDER‐000023, by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). Dr. G.D. is supported by the Spanish Research Project PSI2016‐75688‐P (AEI/FEDER) and by the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 785907 (Human Brain Project SGA2). Dr. M.L.K. is supported by the ERC Consolidator Grant: CAREGIVING (no. 615539) and Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117). Dr. H.G.R. is supported by a NWO/ZonMW VENI‐Grant #016.126.059. Dr. PE acknowledges support from the EPSRC award EP/N014529/1 funding the EPSRC Centre for Mathematics of Precision Healthcare at Imperial