Cortical morphometric inverse divergence alterations in first-episode, treatment-naïve COVID-19 secondary depression correlate with transcriptional signatures.

BACKGROUND

Theneurobiological mechanisms underlying COVID-19 secondary depression(CSD) remain poorly understood, particularly regardingmacrostructural brain alterations and their transcriptionalcorrelations. This study aimed to investigate regional morphometricinverse divergence (MIND) alterations and their molecularassociations with cortical transcriptional signatures in CSDpatients.

METHODS

80 first-episode, treatment-naïve CSD patients and 40 matched healthycontrols underwent high-resolution structural MRI. MIND networks wereconstructed across 308 cortical regions using five morphometricfeatures. Case-control differences were assessed using general linearmodels adjusting for age, sex, and intracranial volume. Partial leastsquares (PLS) regression was employed to link regional MINDalterations with cortical gene expression profiles, meta-analyticcognitive domains, and transcriptomic features includingcross-disorder similarity, functional pathways, cell-typespecificity, cortical layer distribution, and developmental timing.

RESULTS

CSDpatients exhibited significantly elevated MIND values in cingulateand supramarginal regions associated with emotional, memory, andlanguage processing. These changes correlated with stress andcognitive symptoms, independent of infection frequency. PLS4-weightedgenes explained 17.7% of MIND variance and were enriched inneurodevelopmental and metabolic (PLS4+), as well as immune-related(PLS4-) pathways. PLS4- genes were linked to microglia, astrocytes,and cortical layer-I, while PLS4+ genes localized to layer-V.Developmental enrichment indicated disruptions during early (fetal,infant) and late (adult) stages.

CONCLUSIONS

This study reveals that regional MIND alterations in CSD are underpinned by distinct transcriptional signatures, highlighting neurodevelopmental and immune-related mechanisms. These findings offer a multiscale framework connecting brain morphometry with transcriptional architecture in post-COVID depression. CLINICAL TRIALS: Not applicable.