Brain energetic landscapes shape state dysregulation in major depressive disorder: a morphological network controllability perspective

Aberrant dynamic shifts in brain states are a hallmark of cognitive and behavioral dysfunctions in major depressive disorder (MDD), yet the underlying mechanisms of these disturbances remain elusive. Leveraging network control theory of morphological networks, we characterized aberrant brain dynamics and energy deficits of MDD patients in two independent cohorts. MDD patients exhibited reduced dynamic stability, characterized by elevated intra-state transitions and diminished inter-state transitions, which were associated with impaired control energy. Region-specific deficits of energy regulation capacity were observed in key nodes of the default mode and limbic networks, including the posterior cingulate cortex and temporal pole, which correlated with cognition and clinical symptoms in MDD patients. MDD-related energy inefficiency was related to multiscale energy architectures at cellular, molecular, and biological levels, including mitochondrial morphologies and functions, energy metabolism pathways, and brain metabolic patterns. Additionally, we demonstrated an association between energy demands and cortical dynamics, indicating a disrupted energy-dependent neurophysiological activity in MDD patients. Together, these results identified the energetic fundamentals underlying pathological brain-state transitions in MDD patients. Identifying energy-vulnerable nodes from a controllability perspective may therefore provide valuable targets for restoring normative neural dynamics in MDD.