Hyperconnectivity and network inflexibility in large‐scale brain networks: Linking childhood neglect to depression via task and resting‐state fMRI

BACKGROUND: Childhood neglect is a potent risk factor for major depressive disorder (MDD), yet its underlying neural mechanisms linking neglect to depression remain poorly understood. This study aimed to investigate brain network alterations and task-rest functional connectivity (FC) similarity associated with childhood neglect and to clarify their mechanistic roles in depression. METHODS: Participants included MDD patients with childhood neglect (n = 42), MDD patients without childhood trauma (n = 23), and healthy controls without childhood trauma (n = 66). All participants completed clinical scales and underwent both resting-state and task-based fMRI during a Go/No-Go response inhibition task. RESULTS: (1) A distinct subnetwork comprising 207 edges across 170 nodes (P < 0.05) exhibited hyperconnectivity in the MDD-Neglect group compared to both the MDD-No Trauma group (P < 0.001) and healthy controls (P < 0.001), with prominent involvement of the default mode network and dorsal attention network. (2) The connectivity strength of the significant subnetwork positively predicted depressive symptom severity (β = 0.438, P < 0.001) and significantly mediated the relationship between childhood neglect and depressive symptoms. (3) The task-rest FC similarity of the significant subnetwork also positively predicted depressive symptom severity (β = 0.328, P < 0.001) and mediated the relationship between childhood neglect and depressive symptoms. CONCLUSION: Childhood neglect may exacerbate depression through two complementary neurofunctional mechanisms: heightened static connectivity within a cognitive control subnetwork and diminished dynamic flexibility in brain network reconfiguration. These complementary network-level features advance a network-based understanding of how early adversity confers lasting depression risk. SIGNIFICANT OUTCOMES: Patients with major depressive disorder and a history of childhood neglect exhibited a distinct pattern of hyperconnectivity within a large-scale brain subnetwork (primarily involving the DMN, DAN, and SAN) during response inhibition. Both increased functional connectivity strength and higher task-rest FC similarity within the network independently mediated the relationship between childhood neglect and depressive symptom severity. LIMITATIONS: The cross-sectional design of this study limits causal inferences about the directional relationships among childhood neglect, brain network alterations, and depressive symptoms. Childhood neglect was assessed retrospectively via self-report, which may be subject to recall bias. The study is specific to the domain of response inhibition and functional connectivity measures, limiting generalization to other cognitive or emotional processes and to multimodal neural mechanisms.