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. 2025 Jun 1;82(6):582-590.
doi: 10.1001/jamapsychiatry.2025.0192.

Functional vs Structural Cortical Deficit Pattern Biomarkers for Major Depressive Disorder

Peter Kochunov  1 , Bhim M Adhikari  1 , David Keator  2   3   4 , Daniel Amen  2   4 , Si Gao  1 , Nicole R Karcher  5 , Demetrio Labate  6 , Robert Azencott  6 , Yewen Huang  6 , Hussain Syed  6 , Hongjie Ke  7 , Paul M Thompson  8 , Danny J J Wang  9 , Braxton D Mitchell  10   11 , Jessica A Turner  12 , Theo G M van Erp  13   14 , Neda Jahanshad  8 , Yizhou Ma  1 , Xiaoming Du  1 , William Burroughs  1 , Shuo Chen  15 , Tianzhou Ma  7 , Jair C Soares  1 , L Elliot Hong  1
Affiliations

Functional vs Structural Cortical Deficit Pattern Biomarkers for Major Depressive Disorder

Peter Kochunov et al. JAMA Psychiatry. .

Abstract

Importance: 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.

Objective: 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.

Design, settings, and participants: 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.

Exposures: ReHo and structural measurements.

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Keator reported receiving a salary for clinical neuroimaging support from Amen Clinics Inc and neuroimaging research support from Change Your Brain Foundation outside the submitted work. Dr Karcher reported receiving grants from the National Institute of Mental Health (NIMH) during the conduct of the study. Dr Turner reported receiving grants from NIMH during the conduct of the study. Dr Jahanshad reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Y. Ma reported receiving grants from NIMH and National Institute on Drug Abuse (NIDA) during the conduct of the study. Dr Soares reported receiving grants from Compass Pathways, Mind Med, Sunovion, and advisory board fees from Alkermes and J&J outside the submitted work. Dr Hong reported receiving grants from the NIH and research funding or consulting fees on research projects from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho, Heptares, Pfizer, Luye Pharma, Sound Pharma, Takeda, IGC Pharma, Alto Neuroscience, and Regeneron outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Representative Maps
Typical regional homogeneity (ReHo), arterial spin labeling (ASL), and single-photon emission computed tomography (SPECT) single-participant images. Despite entirely different acquisition techniques, resolutions, and scales, there are appreciable similarities between the gross ReHo signal distribution pattern and the ASL-derived cerebral blood flow (CBF) and SPECT-derived CBF patterns.
Figure 2.
Figure 2.. Cortical Thickness Regional Effect Sizes (ESs) Maps
Maps of the regional ESs that major depressive disorder (MDD) exerted on cortical thickness in the UK Biobank (UKBB) (A), Amish Connectome Project (ACP) (B), and these reported by the Neuroimaging Genetics Through Meta-Analysis (ENIGMA)–MDD group (C). We observed significant (P < .001) correlation between regional ESs of MDD on cortical thickness in the UKBB (D), ACP (E), and these reported by the ENIGMA (right panel D and E).
Figure 3.
Figure 3.. Regional Effect Sizes (ESs) Maps Based on Regional Homogeneity (ReHo) and Cerebral Blood Flow (CBF)
Maps of the regional effect sizes (major depressive disorder [MDD]–healthy control [HC]) for ReHo and regional CBF (RCBF) from the UK Biobank (UKBB) (A), Amish Connectome Project (ACP)–ReHo (B), ACP-CBF (C) and ACI-CBF (D) cohorts. We observed significant (all P < .001) correlations between regional ESs (MDD-HC) for ReHo in the UKBB and other cohorts (right panel E-G). Note the stronger effect sizes (sign is reversed, A-D) were negative and represented by warmer (eg, red) color, for visualization purposes.
See this image and copyright information in PMC

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