Advances in Exercise-Induced Neurogenesis, Neuronal and Functional Adaptations in Neurorehabilitation

Ferroptosis is an iron-dependent form of regulated cell death characterized by iron dyshomeostasis, glutathione depletion, glutathione peroxidase 4 dysfunction, and excessive lipid peroxidation. Exercise is a safe and accessible non-pharmacological intervention with broad neuroprotective potential, but the evidentiary basis linking exercise specifically to ferroptosis is uneven. Only a limited subset of studies directly combines an exercise intervention with ferroptosis-related outcomes in neurodegenerative models; much of the proposed pathway architecture is inferred from pharmacological, cellular, observational, or acute neurological injury studies. This review therefore separates direct exercise evidence from exercise-related supporting evidence and non-exercise mechanistic evidence. The most directly relevant findings, concentrated largely in aerobic exercise models, show exercise-associated changes in brain iron handling, the cystine/glutamate antiporter–glutathione peroxidase 4 antioxidant system, and lipoxygenase-dependent lipid peroxidation. Supporting studies suggest additional peripheral-to-central mechanisms involving muscle-derived exosomes, exercise-associated changes in systemic and cerebral iron handling, and inflammatory regulation. Bone marrow hematopoiesis, adult neurogenesis, synaptic plasticity, and astrocyte-controlled iron traffic are incorporated as biologically plausible but incompletely tested links. Evidence for resistance training, high-intensity interval training, mind–body exercise, and human disease remains insufficient. The central limitation is therefore not pathway plausibility but the scarcity of exercise-specific causal experiments demonstrating that ferroptosis suppression is required for neuroprotection. Full article

Background/Objectives: Serum brain-derived neurotrophic factor (BDNF) is linked to post-stroke neuroplasticity, but its temporal dynamics and clinical relevance during early rehabilitation remain unclear. We investigated changes in serum mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) during the early subacute phase of stroke and their associations with functional improvement under standardized inpatient rehabilitation. Methods: In this prospective observational study at a tertiary inpatient rehabilitation unit, 100 stroke patients were enrolled and 84 were analyzed. Serum biomarkers and clinical assessments—including the National Institutes of Health Stroke Scale (NIHSS), Korean Mini-Mental State Examination, Fugl-Meyer Assessment, and Berg Balance Scale—were obtained at baseline (T0) and after two weeks of rehabilitation (T1). Correlation and multivariable regression analyses examined relationships between biomarker changes and functional outcomes, adjusting for age, sex, time from onset, and BDNF genotype. Results: An increase in serum mature BDNF from T0 to T1 was significantly associated with NIHSS improvement (r = −0.273, p = 0.014), which persisted after multivariable adjustment (β = −0.737, p = 0.009). Changes in proBDNF and MMP-9 showed no significant associations. Conclusions: Greater individual increases in serum mature BDNF during early subacute rehabilitation were independently associated with greater reductions in stroke severity, whereas the group-level mean did not increase over time. Serum mature BDNF may serve as a time-sensitive, objective biomarker of neurobiological recovery, potentially supporting individualized rehabilitation strategies. Full article

Background/Objective: Playing-related musculoskeletal disorders are highly prevalent among bowed string musicians and may impair performance and career longevity. This study aimed to evaluate the effects of motor control-based interventions on pain, functional outcomes, range of motion, and neuromuscular parameters in musicians playing bowed string instruments. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed, Scopus, Web of Science Core Collection, and Cochrane CENTRAL were searched from inception to October 2025, and the search was updated before resubmission to identify any newly published eligible studies. Eligibility screening, full-text assessment, data extraction, and risk-of-bias assessment were independently verified by a second reviewer. Risk of bias was assessed according to study design using RoB 2 for the randomized controlled trial and ROBINS-I for non-randomized interventional studies. Results: Four interventional studies met the inclusion criteria. Three studies reported improvements in pain-related outcomes or PRMD severity, and three reported improvements in functional outcomes. One study demonstrated improved cervical range of motion, whereas one study reported altered shoulder girdle muscle activation patterns with reduced playing comfort. Overall, the certainty of the available evidence was limited by small sample sizes, non-randomized designs, and risk of bias. Conclusions: Limited evidence suggests that motor control-based interventions may be associated with improvements in pain and playing-related function in bowed string musicians; however, the evidence base remains small and methodologically heterogeneous, and conclusions should be interpreted with caution. Full article

Background: Irisin, an exercise-induced myokine, has emerged as a potent neuroprotective factor, though a systematic synthesis of its role across neurological disorders is lacking. This review systematically evaluates clinical and preclinical evidence on irisin’s association with neurological diseases and its underlying mechanisms. Methods: Following PRISMA 2020 guidelines, a systematic search of PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane Library was conducted. The review protocol was prospectively registered in PROSPERO. Twenty-one studies were included, comprising predominantly preclinical evidence (n = 14), alongside clinical observational studies (n = 6), and a single randomized controlled trial (RCT) investigating irisin in cerebrovascular diseases, Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurological conditions. Eligible studies were original English-language research on irisin or FNDC5 and their neuroprotective effects, excluding reviews and studies without direct neuronal outcomes. Risk of bias was independently assessed using SYRCLE, the Newcastle–Ottawa Scale, and RoB 2, where disagreements between reviewers were resolved through discussion and consensus. Results were synthesized narratively, integrating mechanistic, pre-clinical, and clinical evidence to highlight consistent neuroprotective patterns of irisin across disease categories. Results: Clinical studies consistently demonstrated that reduced circulating irisin levels predict poorer outcomes. Lower serum irisin was associated with worse functional recovery and post-stroke depression after ischemic stroke, while decreased plasma irisin in PD correlated with greater motor severity, higher α-synuclein, and reduced dopamine uptake. In AD, cerebrospinal fluid irisin levels were significantly correlated with global cognitive efficiency and specific domain performance, and correlation analyses within studies suggested a closer association with amyloid-β pathology than with markers of general neurodegeneration. However, diagnostic accuracy metrics (e.g., AUC, sensitivity, specificity) for irisin as a standalone biomarker are not yet established. Preclinical findings revealed that irisin exerts neuroprotection through multiple mechanisms: modulating microglial polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, suppressing NLRP3 inflammasome activation, enhancing autophagy, activating integrin αVβ5/AMPK/SIRT1 signaling, improving mitochondrial function, and reducing neuronal apoptosis. Irisin administration improved outcomes across models of stroke, PD, AD, postoperative cognitive dysfunction, and epilepsy. Conclusions: Irisin represents a critical mediator linking exercise to brain health, with consistent neuroprotective effects across diverse neurological conditions. Its dual ability to combat neuroinflammation and directly protect neurons, demonstrated in preclinical models, positions it as a promising therapeutic candidate for future investigation. Future research must prioritize the resolution of fundamental methodological challenges in irisin measurement, alongside investigating pharmacokinetics and sex-specific effects, to advance irisin toward rigorous clinical evaluation. Full article

Background/Objectives: In consideration of the significance of the pursuit of training-induced neuroplastic changes in the stroke population, who are reliant on neurorehabilitation treatment for the restoration of neuronal function, the objectives of this trial were to investigate fMRI paradigms for acute stroke patients with ataxic symptoms, to follow up on changes in motor function and balance due to recovery and rehabilitation, and to investigate the different effects of two treatment methods on neuronal plasticity. Methods: Therefore, fMRI-paradigms foot tapping and the motor imagery (MI) of a balancing task (tandem walking) were employed. Results: The paradigms investigated were suitable for ataxic stroke patients to monitor changes in neuroplasticity while revealing increased activity in the primary motor cortex (M1) and the cerebellum over 3 months of treatment. Furthermore, analysis of the more complex balance task revealed augmented activation of association areas due to training. Coordination exercises, constituting a specific treatment of ataxic symptoms, indicate more consolidated brain activations, corresponding to a faster motor learning process. Activation within Brodmann Area 7 has been prominent among all paradigms, indicating a special importance of this region for coordinative functions. Conclusions: Further studies are needed to confirm our results in larger patient groups. Clinical Trial Registration: German Clinical Trials Registry (drks.de). Identifier: DRKS00020825. Registered 16.07.2020. Full article

Background and Objectives: Whole-body vibration (WBV) therapy presents controversial evidence regarding its effectiveness in improving lower limb functional capacity in children with cerebral palsy (CP), particularly when applied continuously as an adjunct to a physiotherapy program with demonstrated efficacy. This study aimed to evaluate the effectiveness of adding WBV to an intensive therapeutic exercise and functional training program in improving lower limb functional capacity in children with spastic CP. Materials and Methods: Thirty children with spastic CP were randomly assigned to a control or experimental group. Both groups completed a 4-week intensive therapeutic exercise and functional training program (4 sessions/week). The experimental group additionally received daily WBV. Results: Both groups showed significant improvements in all analysed variables at 1, 2, and 6 months post-treatment (p < 0.001). However, no significant between-group differences were found for primary (GMFM-88 D: p = 0.80; GMFM-88 E: p = 0.91) or secondary outcomes in relation to muscle tone and strength, and balance. A trend toward greater improvement was observed in the experimental group but without statistical significance. Conclusions: The addition of WBV to an intensive program of therapeutic exercise and functional training does not yield additional benefits in motor function, spasticity, gait capacity, lower limb muscle strength, or balance compared to intensive physiotherapy and functional training alone in children with spastic CP. The significant within-group improvements can be attributed to the intensive physiotherapy intervention, comprising therapeutic exercises and functional training. Full article

Background and Objectives: Although the growing literature is now focusing on the long-term effects of Deep Brain Stimulation (DBS) in Parkinson’s disease (PD), there is still a large gap of knowledge about its long-term implications in rehabilitation. Therefore, this study aimed at investigating the effects of rehabilitation in PD patients years after DBS implantation. Materials and Methods: This retrospective case–control study analyzed records from Moriggia-Pelascini Hospital, Italy from September 2022 to January 2024. Data of PD patients (n = 47) with (DBS group, n = 22) and without (control group, n = 25) DBS were considered. All study participants underwent a daily rehabilitation program lasting four weeks, including warm-up, aerobic exercises, strength training, postural exercises, and proprioceptive activities. The outcomes assessed were the Unified Parkinson’s Disease Rating Scale (UPDRS), Berg Balance Scale (BBS), Timed Up and Go (TUG), 6 Min Walk Test (6MWT), and Self-Assessment Parkinson Disease Scale (SPDDS). Results: DBS group showed significant improvements in terms of all outcome measures after the rehabilitation intervention (UPDRS III: −7.0 (−11.5 to −1.0); p = 0.001; UPDRS I II IV: −12.0 (−19.0 to −4.5); p = 0.001; BBS: 7.0 (3.8 to 10.3); p < 0.001; TUG (s): −2.8 (−5.7 to −1.1); p < 0.001; SPDDS: −8 (−13.0 to −4.0); p < 0.001; 6MWT (m): 81 (37.3 to 132.3); p < 0.001). No differences were reported in the between-group analysis (p: NS). Conclusions: This study emphasizes positive rehabilitation effects on PD patients irrespective of DBS status. Further research is essential to elucidate long-term effects of DBS on rehabilitation outcomes of PD patients. Full article

Background: Exercise has shown beneficial effects on neuronal neuroplasticity; therefore, we want to analyze the influence of high-intensity interval training (HIIT) on neuroplasticity markers in post-stroke patients. Methods: A systematic review of RCTs including studies with stroke participants was conducted using the following databases (PubMed, LILACS, ProQuest, PEDro, Web of Science). Searches lasted till (20/11/2023). Studies that used a HIIT protocol as the main treatment or as a coadjutant treatment whose outcomes were neural plasticity markers were used and compared with other exercise protocols, controls or other kinds of treatment. Studies that included other neurological illnesses, comorbidities that interfere with stroke or patients unable to complete a HIIT protocol were excluded. HIIT protocol, methods to assess intensity, neuroplasticity markers (plasmatic and neurophysiological) and other types of assessments such as cognitive scales were extracted to make a narrative synthesis. Jadad and PEDro scales were used to assess bias. Results: Eight articles were included, one included lacunar stroke (less than 3 weeks) and the rest had chronic stroke. The results found here indicate that HIIT facilitates neuronal recovery in response to an ischemic injury. This type of training increases the plasma concentrations of lactate, BDNF and VEGF, which are neurotrophic and growth factors involved in neuroplasticity. HIIT also positively regulates other neurophysiological measurements that are directly associated with a better outcome in motor learning tasks. Conclusions: We conclude that HIIT improves post-stroke recovery by increasing neuroplasticity markers. However, a limited number of studies have been found indicating that future studies are needed that assess this effect and include the analysis of the number of intervals and their duration in order to maximize this effect. Full article