A working model linking the psychopathology and pathophysiology of major depressive disorder - an umbrella review of neuroimaging studies and a conceptual framework

Background: Major depressive disorder (MDD) is a severe affective disorder with largely unknown neurobiology—partly due to the heterogeneity and often contradictory nature of existing findings. Methods: To address this challenge, we conducted a systematic umbrella review of neuroimaging meta-analyses to identify the most consistent brain alterations associated with prototypical MDD. Data on intrinsic activity, task-based activation, and grey/white matter structure were organized by mapping alterations onto large-scale brain networks and categorizing them by early and chronic illness stages. Results: A core pattern of brain alterations emerged. Functionally, MDD shows decreased intrinsic activity in the somatomotor-visual networks (SMN-VN) and increased activity in the ventral attention/salience network (VAN), both stable across stages; and altered activity in the default-mode network (DMN), with early decreases and chronic increases. Structurally, MDD shows decreased grey matter in the VAN across stages; early increases in SMN-VN and DMN grey matter, and widespread reductions in the chronic stage; and white matter disruption, localized early and widespread chronically. Discussion: Based on these findings, we propose a conceptual framework linking psychopathology and pathophysiology of MDD. In this model, immune dysregulation and chronic inflammation act as central drivers, warping functional brain architecture—activating the insula/VAN and inhibiting SMN-VN and DMN—and triggering early structural homeostatic remodeling followed by chronic widespread deficits. This persistent network imbalance, marked by sensorimotor/SMN-VN deficits and insula/VAN hyperfunctioning, may lead to perception and psychomotor deficits along with polarization toward disembodied interoceptive imagery and related affective states, detuning brain activity and phenomenal-behavioral patterns from the environment as the core of depression.