Impact of physical activity and exercise interventions on white matter integrity in overweight and obese populations: A systematic review and meta-analysis.

Background: Obesity is associated with alterations in white matter microstructure, including reduced fractional anisotropy (FA) and elevated mean diffusivity (MD) and radial diffusivity (RD), which may contribute to cognitive decline. Physical activity interventions may offer neuroprotective benefits, but comprehensive evidence in overweight and obese populations remains limited. Objectives: To systematically evaluate the impact of physical activity interventions and cardiorespiratory fitness on white matter integrity, as measured by diffusion tensor imaging (DTI), in individuals with overweight and obesity. Methods: We searched PubMed, Embase, Scopus, Web of Science, and Ovid MEDLINE from inception to 19 August 2025. We included RCTs and observational studies examining physical activity interventions, cardiorespiratory fitness, or habitual physical activity in relation to DTI-derived white matter metrics in overweight or obese populations. Two reviewers independently conducted screening, data extraction, and risk-of-bias assessment using the RoB 2 and ROBINS-E tools. Meta-analyses were conducted in R using a multivariate multilevel model with Restricted Maximum Likelihood (REML) estimation to account for the non-independence of multiple effect sizes nested within studies. Results: Eight studies comprising an estimated 301 unique participants were included (5 RCTs and 3 cross-sectional studies). Seven studies focused on children and adolescents aged 7-11 years, and one examined older adults. The meta-analyses, conducted exclusively in pediatric RCTs, revealed no statistically significant effects of physical activity interventions on FA (SMD = 0.388, 95% CI: -0.123 to 0.900, p = 0.136), MD (SMD = -0.090, 95% CI: -0.245 to 0.065, p = 0.256), or RD (SMD = 0.454, 95% CI: -0.029 to 0.936, p = 0.065), though a non-significant trend toward reduced RD was observed. All three cross-sectional studies were derived from a single research cohort (ActiveBrains project) and showed largely inconsistent associations between physical fitness and white matter integrity, with most findings not surviving correction for multiple comparisons. Conclusions: Following re-analysis using a methodologically appropriate multilevel model, physical activity interventions did not demonstrate statistically significant effects on any DTI metric in children with overweight or obesity. A non-significant trend toward reduced RD suggests a possible beneficial effect on myelin integrity warranting investigation in future adequately powered studies. The cross-sectional evidence is limited by its derivation from a single research cohort. Large-scale RCTs in adult and older adult populations with obesity, employing harmonised neuroimaging protocols and longer intervention durations, are needed to establish the effects of physical activity on white matter microstructure across the lifespan.