Functional vs Structural Cortical Deficit Pattern Biomarkers for Major Depressive Disorder

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With markedly inconsistent previous neuroimaging studies on major depressive disorder (MDD), investigators sought to find an improved biomarker for the disorder by investigating reductions in cerebral blood flow of individuals with MDD. In their recent publication “Functional vs Structural Cortical Deficit Pattern Biomarkers for Major Depressive Disorder,” Kochunov et al explored whether regional homogeneity (ReHo) seen in functional MRI (fMRI) would provide an improved biomarker of MDD and if these patterns relate to decreases in regional cerebral blood flow (RCBF) seen in MDD.

Analysis was performed on previously collected data sourced from 4 different datasets. Data were sourced from different sets because there was no prior study which collected the same RCBF measurements the authors evaluated for both controls and MDD patients. Investigators found that data from those with MDD had lower cortical regional homogeneity in specific regions, and that regional patterns of homogeneity were significantly correlated with a decrease in RCBF. The regions of interest which showed this lower homogeneity were the cingulum, superior temporal lobe, and frontal lobe.

From their results, the authors suggest a consistent, regionally-specific decreased blood flow found in MDD which can be associated with regional homogeneity deficits; this functional approach was found to be more strongly associated with quantitative depression symptom ratings than with a structural approach. Therefore, a more functional and ReHo based regional variability index (RVI) may be a useful novel biomarker for MDD. In the regions in question, there was no significant difference in cortical thickness, providing further evidence against cortical atrophy as the main mechanism occurring with MDD.

The neurological effects of MDD are often seen as reductions in RCBF, and the authors used resting-state fMRI data to gather ReHo values—values which have been linked to RCBF in healthy participants. They posited that effect sizes for ReHo values in those with MDD could be a proximal measurement for RCBF and would show a stronger association to MDD than previously seen in structural MRI. RCBF is closely linked with MDD, and ReHo measurements are connected to these blood flow changes. Using fMRI data, investigators measured the amount of similarity in timing of resting-state BOLD signals in neighboring voxels of specific regions. After identifying differences in blood flow in these regions between participants with MDD and controls, they compared region-specific ReHo effect sizes with structural measurements to evaluate if deficits in ReHo patterns indicated RCBF. ReHo measurements gathered from fMRI were taken to be a proximal measurement for RCBF.

Because regional patterns of deficit were consistent across ReHo and RCBF, ReHo provides evidence for a reproducible pattern of region-specific lack of blood flow in those with MDD. With this functional measurement, the authors found that using a function-based RVI founded on ReHo deficit patterns was significantly correlated with severity of depression symptoms, meaning that larger ReHo deficits came with more severe symptoms. Structural RVIs had much smaller effect sizes and had no significant correlation to symptom ratings, indicating that functional RVIs are stronger indexes of MDD.

Measuring functional deficit patterns provides a pattern-based biomarker for MDD and demonstrates that the ReHo deficits are related to regional decreases in blood flow. These pattern findings indicate that a functional, ReHo-based regional variability index may be an improved marker for MDD. This new index may be useful in further investigation of MDD using markers distinctly connected to patterns in pathophysiology.

References

1. Kochunov P, Adhikari BM, Keator D, et al. Functional vs structural cortical deficit pattern biomarkers for major depressive disorder. JAMA Psychiatry. 2025;82;(6):582-590.

2. Cooper CM, Chin Fatt CR, Liu P, et al. Discovery and replication of cerebral blood flow differences in major depressive disorder. Mol Psychiatry. 2020;25(7):1500-1510.