Neurophysiological Correlates of Neuroanatomical Dimensions in Major Depressive Disorder: Electroencephalographic Markers of Brain Function and Treatment Outcome

Abstract Major depressive disorder (MDD) is a heterogeneous disorder with variable treatment responses and no established biomarkers for identification or predictors of treatment response. In the COORDINATE-MDD consortium, a data-driven classification identified two neuroanatomic-based dimensions: Dimension 1 (D1), with preserved grey and white matter volumes, and Dimension 2 (D2), with widespread reductions. Here, we investigated whether resting-state electroencephalography (EEG) features differ between these dimensions and whether such features predict treatment response. Participants were 237 MDD (155 women; mean age 37.47 ± 13.36 year) from two clinical trials: CAN-BIND (escitalopram) and EMBARC (randomized to sertraline or placebo). All were medication-free at baseline, in a current depressive episode of at least moderate severity. Resting-state, eyes-closed EEG was recorded at baseline. EEG features included spectral power, frontal alpha asymmetry (FAA), multiscale sample entropy (MSE), and inter-site phase clustering (ISPC). Analyses examined effects of neuroanatomical dimension (D1, D2) and clinical outcome (responder, non-responder), using ANCOVA and threshold-free cluster enhancement (TFCE). D1 participants showed greater absolute and log-transformed theta, alpha, and beta power, and lower relative delta power compared to D2, particularly in frontal and central regions. Among responders, D1 showed higher alpha and theta power and greater MSE at coarse time scales. Individuals with preserved neuroanatomy in D1 exhibit electrophysiological markers of more flexible and integrated brain function, possibly reflecting efficient top-down regulation and adaptive neural dynamics. In contrast, the D2 dimension, marked by lower complexity and elevated delta activity, may reflect disrupted network integrity, reduced cortical arousal, and impaired information processing.