All roads lead to the default-mode network-global source of DMN abnormalities in major depressive disorder.

Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state functional connectivity (rsFC) in various neural networks and especially in default-mode network (DMN). However, inconsistent findings, i.e., increased and decreased DMN rsFC, have been reported, which raise the question for the source of DMN changes in MDD. Testing whether the DMN abnormalities in MDD can be traced to either a local, i.e., intra-network, or a global, i.e., inter-network, source, we conducted a novel sequence of rsFC analyses, i.e., global FC, intra-network FC, and inter-network FC. Moreover, all analyses were conducted without global signal regression (non-GSR) and with GSR in order to identify the impact of specifically the global component of functional connectivity on within-network functional connectivity within specifically the DMN. In MDD our findings demonstrate (i) increased representation of global signal correlation (GSCORR) in DMN regions, as confirmed independently by degree of centrality (DC) and by an independent DMN template, (ii) increased within-network DMN rsFC, (iii) highly increased inter-network rsFC of both lower- and higher order non-DMN networks with DMN, (iv) high accuracy in classifying MDD vs. healthy subjects by using GSCORR as predictor. Further supporting the global, i.e., non-DMN source of within-network rsFC of the DMN, all results were obtained only when including the global signal, i.e., non-GSR, but not when conducting GSR. Together, we show for the first time increased global signal representation within rsFC of DMN as stemming from inter-network sources as distinguished from local sources, i.e., within- or intra-DMN.