Functional vs Structural Cortical Deficit Pattern Biomarkers for Major Depressive Disorder
Authors: Peter Kochunov, Bhim M. Adhikari, David Keator, Daniel Amen, Si Gao, Nicole R. Karcher, Demetrio Labate, Robert Azencott, Yewen Huang, Hussain Syed, Hongjie Ke, Paul M. Thompson, Danny J. J. Wang, Braxton D. Mitchell, Jessica A. Turner, Theo G.M. van Erp, Neda Jahanshad, Yizhou Ma, Xiaoming Du, William Burroughs, Shuo Chen, Tianzhou Ma, Jair C. Soares, L. Elliot Hong
Journal: JAMA Psychiatry (2025)

Major depressive disorder (MDD) is a severe mental illness characterized more by functional rather than structural brain abnormalities. The pattern of regional homogeneity (ReHo) deficits in MDD may relate to underlying regional hypoperfusion. Capturing this functional deficit pattern provides a brain pattern-based biomarker for MDD that is linked to the underlying pathophysiology. To examine whether cortical ReHo patterns provide a replicable biomarker for MDD that is more sensitive than reduced cortical thickness and evaluate whether the ReHo MDD deficit pattern reflects regional cerebral blood flow (RCBF) deficit patterns in MDD and whether a regional vulnerability index (RVI) thus constructed may provide a concise brain pattern-based biomarker for MDD. The UK Biobank (UKBB) participants had ReHo and structural measurements. Participants from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) Consortium were included for measuring the MDD structural cortical deficit pattern. The UKBB ReHo and ENIGMA cortical thickness effect sizes for MDD were used to test the deficit patterns in the Amish Connectome Project (ACP) with ReHo, structural, and RCBF data. Finally, the Ament Clinic Inc (ACI) sample had RCBF data measured using single-photon emission computed tomography. Data were analyzed from August 2021 to September 2024. ReHo and structural measurements. Included in this analysis were 4 datasets: (1) UKBB (N = 4810 participants; 2220 with recurrent MDD and 2590 controls; mean [SD] age, 63.0 [7.5] years; 1121 female [50%]), (2) ENIGMA (N = 10 115 participants; 2148 with MDD and 7957 healthy controls; mean [SD] age, 39.9 [10.0] years; 5927 female [59%]), (3) ACP (N = 204 participants; 68 with a lifetime diagnosis of MDD and 136 controls; mean [SD] age, 41.0 [14.5] years; 104 female [51%]), and (4) ACI (N = 372 participants; 296 with recurrent MDD and 76 controls; mean [SD] age, 45.3 [17.2] years; 189 female [51%]). MDD participants had lower cortical ReHo in the cingulum, superior temporal lobe, frontal lobe, and several other areas, with no significant differences in cortical thickness. The regional pattern of ReHo MDD effect sizes was significantly correlated with that of RCBF obtained from 2 independent datasets (Pearson r = 0.52 and Pearson r = 0.46; P < 10-4). ReHo and RCBF functional RVIs showed numerically stronger effect sizes (Cohen d = 0.33-0.90) compared with structural RVIs (Cohen d = 0.09-0.20). Elevated ReHo-based RVI-MDD values in individuals with MDD were associated with higher depression symptom severity across cohorts. Results of this case-control study suggest that the ReHo MDD deficit pattern reflected cortical hypoperfusion and was regionally specific in MDD. ReHo-based RVI may serve as a sensitive functional biomarker for MDD.