The dysconnection hypothesis of schizophrenia posits that widespread synaptic inefficiencies lead to altered macroscale brain connectivity, contributing to symptom severity and cognitive deficits in individuals with schizophrenia spectrum disorders (SSD). Emerging evidence suggests that physical exercise may help to ameliorate these connectivity abnormalities and associated clinical impairments.

This study investigated whether reductions in functional dysconnectivity following exercise therapy were associated with clinical improvements in individuals with SSD. In addition, it explored the genetic underpinnings of these changes using imaging transcriptomics.

Using data from the ESPRIT C3 trial, we analysed 23 SSD patients (seven female) undergoing aerobic exercise or flexibility, strengthening and balance training over 6 months. Functional dysconnectivity, assessed at baseline and post-intervention relative to a healthy reference sample (n = 200), was evaluated at the whole-brain, network and regional levels. Linear mixed effect models and voxel-wise Pearson’s correlations were used to assess exercise-induced changes and clinical relevance.

Functional dysconnectivity significantly decreased (d = −2.73, P < 0.001), and this decrease was primarily linked to enhanced oligodendrocyte-related gene expression. Reductions in the default-mode network were correlated with improved global functioning, whereas changes in insular regions were associated with symptom severity and functioning. Dysconnectivity reductions in somatomotor and frontoparietal networks were correlated with total symptom improvements, and changes in language-related regions (e.g. Broca’s area) were linked to cognitive benefits.

Our findings support the role of oligodendrocyte pathology in SSD and suggest that targeting dysconnectivity in the default-mode, salience and language networks may enhance global functioning, symptom severity and cognitive impairments.