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.

A better mechanistic understanding of schizophrenia spectrum disorders is crucial to developing efficient treatment approaches. Therefore, this study investigated longitudinal interrelations between clinical outcomes, brain structure, and somatic health in post-acute individuals from the schizophrenia spectrum.

A sample of 63 post-acute patients from two independent physical exercise studies was included in the final analyses. Demographic, clinical, cognitive, and somatic data were acquired at baseline and follow-up, as were structural magnetic resonance imaging scans. Multivariate cross-lagged panel modeling including mediators was used to study the mutual interrelations over time between the clinical, neural, and somatic levels.

A higher baseline global gray matter volume and larger regional gray matter volumes of the hippocampal formation, precuneus, and posterior cingulate predicted improved clinical outcomes, such as daily-life functioning, negative symptoms, and cognition. Increases in white matter volume from baseline to follow-up resulted in significantly reduced positive symptoms and higher daily-life functioning.

Our findings suggest that stimulating neuroplasticity, especially in the hippocampal formation, precuneus, and posterior cingulate gyrus, may represent a promising treatment target in post-acute schizophrenia spectrum disorders. Physical exercise therapies and other lifestyle interventions, and brain stimulation approaches reflect potential treatment candidates. Given the exploratory character of the statistical analysis performed, these findings need to be replicated in independent longitudinal imaging cohorts of patients with schizophrenia spectrum disorders.

The hippocampal formation represents a key region in the pathophysiology of schizophrenia. Aerobic exercise poses a promising add-on treatment to potentially counteract structural impairments of the hippocampal formation and associated symptomatic burden. However, current evidence regarding exercise effects on the hippocampal formation in schizophrenia is largely heterogeneous. Therefore, we conducted a systematic review and meta-analysis to assess the impact of aerobic exercise on total hippocampal formation volume. Additionally, we used data from a recent multicenter randomized-controlled trial to examine the effects of aerobic exercise on hippocampal formation subfield volumes and their respective clinical implications.

The meta-analysis comprised six studies that investigated the influence of aerobic exercise on total hippocampal formation volume compared to a control condition with a total of 186 people with schizophrenia (100 male, 86 female), while original data from 29 patients (20 male, 9 female) was considered to explore effects of six months of aerobic exercise on hippocampal formation subfield volumes.

Our meta-analysis did not demonstrate a significant effect of aerobic exercise on total hippocampal formation volume in people with schizophrenia (g = 0.33 [−0.12 to 0.77]), p = 0.15), but our original data suggested significant volume increases in certain hippocampal subfields, namely the cornu ammonis and dentate gyrus.

Driven by the necessity of better understanding the pathophysiology of schizophrenia, the present work underlines the importance to focus on hippocampal formation subfields and to characterize subgroups of patients that show neuroplastic responses to aerobic exercise accompanied by corresponding clinical improvements.