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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Discussion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月28日

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  • Smriti Mavar,
  • Yun-Shan Lee,
  • Elizaveta Baranova,
  • Niall W. Duncan,
  • Paola Magioncalda,
  • Matteo Martino

摘要

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.