Brain Age Gap Reduction Following Physical Exercise Mirrors Negative Symptom Improvement in Schizophrenia Spectrum Disorders
Authors: Yilmaz Deniz , Papiol Sergi , Keeser Daniel , Cole James H , Malchow Berend , Schmitt Andrea , Falkai Peter , Maurus Isabel , Roell Lukas 
Published: January 2025

AbstractSchizophrenia spectrum disorders (SSD) are associated with accelerated brain aging, reflected in an increased brain age gap. This gap serves as a biomarker, indicating poorer brain health, cognitive deficits, and greater severity in specific symptom domains. Physical exercise holds promise as an adjunct therapy to mitigate these deficits by potentially promoting brain recovery. However, the extent of overall improvements in brain health following exercise, along with their predictors and relationships to symptom clusters, are yet to be determined. This study examined the brain age gap metric as a quantitative indicator of brain recovery in response to physical exercise. To achieve this, we aggregated data from two randomized controlled trials, analyzing baseline (n= 134) and 3- or 6-month post-exercise (n= 46) data from individuals with SSD. Our findings revealed that patients with a higher baseline BMI demonstrated greater brain recovery, as evidenced by a reduced brain age gap post-exercise. Furthermore, changes in the brain age gap were associated with improvements in negative symptoms and cognition, suggesting that reductions in brain-predicted age may reflect symptom relief, particularly in domains beyond positive symptoms. These results underscore the importance of BMI in brain health, support using the brain age gap as a surrogate marker for tracking clinically relevant brain recovery, and highlight the need for stratified interventions and combined lifestyle modifications to enhance outcomes in SSD.GlossarySchizophrenia spectrum disorders (SSD):Mental health conditions characterized by psychosis, an alteration of the perception of reality. Cardinal symptoms include hallucinations (sensory perception not mirroring reality) and delusions (persistent beliefs that are not rooted in reality).Positive symptoms:A symptom cluster of SSD including complaints that are distinctively present in the patiens: hallucinations, delusions, and thought disorder (disorganized thinking and speech).Negative symptoms:A symptom cluster of SSD including complaints that are distinctively absent in the patiens: loss of interest, motivation, enjoyment, and social interactions, flattened affect.Cognitive symptoms:Another cluster of symptoms in SSD including deficits in attention, executive function, and memory.Biomarker:Objective, quantifiable indicators of biological states or processes used to predict, diagnose, and treat illnesses.Brain age gap:A biomarker of brain health and aging. Brain-predicted age is the age predicted by a machine learning algorithm based on brain imaging data. Subtracting chronological age from the brain-predicted age results in the brain age gap, where positive values indicate an accelerated aging of the brain.Neuroplasticity:The brain’s ability reorganize itself through new synaptic connections following learning, treatment, or injury.Randomized Controlled Trials (RCTs):A study design that randomly assigns participants to an experimental group or a control group to test the efficacy of an intervention.