The first brain-wide voxel-level resting state functional-connectivity neuroimaging analysis of depression is reported, with 421 patients with major depressive disorder and 488 controls. Resting state functional connectivity between different voxels reflects correlations of activity between those voxels and is a fundamental tool in helping to understand the brain regions with altered connectivity and function in depression.udOne major circuit with altered functional connectivity involved the medial orbitofrontal cortex BA 13, which is implicated in reward, and which had reduced functional connectivity in depression with memory systems in the parahippocampal gyrus and medial temporal lobe, especially involving the perirhinal cortex BA 36 and entorhinal cortex BA 28. The Hamilton Depression Rating Scale scores were correlated with weakened functional connectivity of the medial orbitofrontal cortex BA 13. Thus in depression there is decreased reward-related and memory system functional connectivity, and this is related to the depressed symptoms. The lateral orbitofrontal cortex BA 47/12, involved in non-reward and punishing events, did not have this reduced functional connectivity with memory systems.udSecond, the lateral orbitofrontal cortex BA 47/12 had increased functional connectivity with the precuneus, the angular gyrus, and the temporal visual cortex BA 21. This enhanced functional connectivity of the non-reward/punishment system (BA 47/12) with the precuneus (involved in the sense of self and agency), and the angular gyrus (involved in language) is thus related to the explicit affectively negative sense of the self, and of self-esteem, in depression. A comparison of the functional connectivity in 185 depressed patients not receiving medication and 182 patients receiving medication showed that the functional connectivity of the lateral orbitofrontal cortex BA 47/12 with these three brain areas was lower in the medicated than the unmedicated patients. This is consistent with the hypothesis that the increased functional connectivity of the lateral orbitofrontal cortex BA 47/12 is related to depression. udRelating the changes in cortical connectivity to our understanding of the functions of different parts of the orbitofrontal cortex in emotion helps to provide new insight into the brain changes related to depression, which are considered in the Discussion.ud
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