Reducing Functional Dysconnectivity in Schizophrenia Spectrum Disorders

ABSTRACT Background As a condition of dysconnectivity, schizophrenia spectrum disorders (SSD) are characterized by positive, negative, and cognitive symptoms. To improve these symptoms in SSD, physical exercise interventions show promise. We examined if reductions of functional dysconnectivity following exercise therapy are associated with clinical improvements in SSD and explored potential genetic underpinnings. Methods The study utilized data from the ESPRIT C3 trial, investigating the effects of aerobic exercise versus flexibility, strengthening, and balance training on different health outcomes in individuals with SSD. Functional dysconnectivity in 23 patients relative to a healthy reference sample, was assessed both pre- and post-intervention. Changes of functional dysconnectivity after exercise and their clinical relevance were evaluated. An imaging transcriptomics approach was used to study the link between changes in functional dysconnectivity and gene expression profiles. Results We observed substantial reductions of functional dysconnectivity on the whole-brain level linked to enhanced gene expression mainly in oligodendrocytes. With regard to the clinical implications, decreases of dysconnectivity in the default-mode network were associated with improvements in global functioning. Reductions of dysconnectivity within the salience network were linked to improvements in symptom severity. Lastly, reductions of functional dysconnectivity in language regions such as Broca’s area were related to cognitive benefits. Conclusions Our study supports a recent theory of oligodendrocyte pathology in SSD and suggests that reducing functional dysconnectivity in the default-mode, salience, and language network reflect a potential therapeutic target to improve global functioning, total symptom severity, and cognitive impairments in post-acute SSD. Trial name: ESPRIT C3 Registry: International Clinical Trials Database, ClinicalTrials.gov Registration number: NCT03466112 URL: https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1