Physical Training in Parkinson's Disease: A Systematic Review of Neurobiological Mechanisms, Brain-Muscle Adaptations, and Implications for Personalized Rehabilitation.

BACKGROUND: Physical Training (PT), defined a planned, structured, and long-term exercise intervention, is recognized as an important non-pharmacological therapy in Parkinson's disease (PD). Beyond its symptomatic benefits, experimental evidence suggests that PT may also modulate pathological mechanisms involved in dopaminergic neurodegeneration. This systematic review summarizes the neurobiological and neurophysiological adaptations induced by PT in animal models of PD and in patients with PD, and proposes mechanistically driven recommendations for personalized exercise prescription. SUMMARY: MEDLINE and Web of Science were searched from January 1, 1974, to April 3, 2026. The PRISMA 2020 guidelines were followed, and two reviewers independently screened titles and abstracts to identify studies that reporting neurobiological or neurophysiological effects of PT performed for at least 4 weeks, in both animal models of PD or in patients with PD. Risk of bias were assessed using validated tools for animal studies (SYRCLE), and for randomized (RoB 2) or non-randomized controlled trials (ROBINS-I) in humans. A total of 78 studies were included, comprising 55 animal studies and 23 studies in patients with PD. In parkinsonian animals, PT consisted mainly of forced treadmill training, performed 20-60 min/day, 5 days/week, typically for 4 weeks. PT reduced oxidative stress and mitochondrial dysfunction, enhanced antioxidant defences, and regulated mitochondrial dynamics. Exercise also decreased α-synuclein accumulation, attenuated neuroinflammation, and increased neurotrophic factor expression. These adaptations promoted synaptic plasticity, neurogenesis, and preservation of nigrostriatal dopaminergic neurons. In patients with PD, aerobic training (AT), resistance training (RT) and balance training (BT) have been tested, and multimodal interventions have been investigated, most commonly involving 120-150 min/week for 6-12 weeks, sometimes combined with virtual reality or exergaming. PT induced structural and functional adaptations across the brain-muscle axis, including modulation of dopaminergic signalling, reorganization of cortico-striatal and cerebellar connectivity, improved cortical inhibitory control, enhanced corticospinal drive, and neuromuscular remodelling. AT mainly improved fatigability and cardiorespiratory fitness, whereas RT and BT appear to preferentially enhance muscle strength, rate of force development, gait automaticity, and balance control. KEY MESSAGES: Current evidence indicates that PT acts as a multimodal intervention capable of inducing adaptations ranging from molecular pathways to large-scale motor networks in PD. These findings support the implementation of personalized multimodal programmes combining AT, RT and BT, with progressive intensity and long-term adherence. Future studies should better define dose-response relationships, identify biomarkers of responsiveness, and determine whether exercise may exert disease-modifying effects on PD.