Dose-Response Effects of Exercise Training on Circulating Brain-Derived Neurotrophic Factor (BDNF): A Systematic Review and Meta-analysis of Randomised Controlled Trials

Brain-derived neurotrophic factor (BDNF) is involved in neuroplasticity, but circulating BDNF is not a validated surrogate for brain BDNF. We synthesised randomised controlled trials comparing chronic exercise with a non-exercising control. Change-score standardised mean differences (Hedges' g) were pooled using restricted maximum likelihood and Hartung-Knapp inference. The analysis included 48 trials, 56 exercise-versus-control comparisons and 2361 unique participants. Shared control sample sizes were apportioned across comparisons, with trial-cluster robust sensitivity analyses. Exercise increased circulating BDNF on average (g = 0.41, 95% CI 0.25 to 0.57; p < 0.001), with substantial heterogeneity (I2 = 67.0%; 95% prediction interval - 0.54 to 1.36). Serum-based comparisons yielded g = 0.27 (95% CI 0.10 to 0.44) and plasma-based comparisons g = 0.69 (0.37 to 1.00); the matrix moderator was significant in the primary analysis (p = 0.017) but not under trial-cluster robust inference (p = 0.065). Population, modality and intervention duration were not significant primary moderators. In the joint dose model (33 comparisons from 29 trials), neither total prescribed exercise volume (β = 0.037 per 1000 min, p = 0.614) nor vigorous versus moderate intensity (β =  - 0.190, p = 0.361) was associated with the BDNF effect. Weekly-volume and quadratic analyses did not establish a dose-response relationship. The overall effect remained positive after restricting sampling to approximately ≥ 24 h after exercise (g = 0.35, 95% CI 0.12 to 0.58). Egger's test indicated small-study effects (p = 0.011). The certainty of evidence was very low. Chronic exercise is associated with an average increase in circulating BDNF, but heterogeneity, methodological limitations and uncertain moderator effects prevent a biomarker-specific exercise prescription or an inference of increased central BDNF. PROSPERO registration: CRD420261448624.