Virtual histology of morphometric similarity network after risperidone monotherapy and imaging-epigenetic biomarkers for treatment response in first-episode schizophrenia

Background: Antipsychotic treatment has been conceived to alter brain connectivity, but it is unclear how the changes of network phenotypes relate to the underlying transcriptomics. Given DNA methylation (DNAm) may alter transcriptional levels, we further integrated an imaging-transcriptomic-epigenetic analysis to explore multiomics treatment response biomarkers. Methods: Forty-two treatment-naive first-episode schizophrenia patients were scanned by TI weighted (T1W) imaging and DTI before and after 8-week risperidone monotherapy, and their peripheral blood genomic DNAm values were examined in parallel with MRI scanning. Morphometric similarity network (MSN) quantified with DTI and T1W data were used as a marker of treatment-related alterations in interareal cortical connectivity. We utilized partial least squares (PLS) to examine spatial associations between treatment-related MSN variations and cortical transcriptomic data obtained from the Allen Human Brain Atlas. Results: Longitudinal MSN alterations were related to treatment response on cognitive function and general psychopathology symptoms, while DNAm values of 59 PLS1 genes were on negative and positive symptoms. Virtual-histology transcriptomic analysis linked the MSN alterations with the neurobiological, cellular and metabolic pathways or processes, and assigned MSN-related genes to multiple cell types, specifying neurons and glial cells as contributing most to the transcriptomic associations of longitudinal changes in MSN. Conclusions: We firstly reveal how brain-wide transcriptional levels and cell classes capture molecularly validated cortical connectivity alterations after antipsychotic treatment. Our findings represent a vital step towards the exploration of treatment response biomarkers on the basis of multiple omics rather than a single omics type as a strategy for advancing precise care.