Middle Cerebral Artery Occlusion-induced Deficits in Fine Skilled Motor Movement and Its Recovery Following Combined Treatment with Sodium Valproate and CIMT.

Background: Preclinical studies have shown that sodium valproic acid (VPA) has neuroprotective properties following ischaemic injury. However, its compatibility as an adjuvant therapy with physical rehabilitation in ischaemic stroke recovery, with underlying neurophysiological mechanisms, has not been explored yet. Purpose: The present study has investigated the advantage of combination therapy over monotherapy in ameliorating ischaemic stroke-induced deficits in skilled fine motor movements with associated changes in local and interhemispheric neural connectivity. Methods: Cerebral ischaemic stroke was induced by 60 min of middle cerebral artery occlusion in adult male Sprague-Dawley rats. VPA (300 mg/kg, subcutaneously, twice daily) was administered within 3 h after reperfusion and continued for 7 days, followed by constraint-induced movement therapy (CIMT) for another week (6 h/day). The ischaemic stroke phenotype was assessed based on neurological deficits, gait, forelimb use, rotarod stay time, reach success and infarct volume. Functional recovery, with associated changes in neural activities, was carried out by analysing the local field potential signals from the first reach success during the reach-to-grasp task on day 8 and day 15 post-stroke. Cortical oscillations were analysed at delta (0-4 Hz), theta (4-8 and 8-12 Hz) and beta (12-20 Hz) during the first reach success. Results: Combination therapy after ischaemic stroke significantly improved motor and neurological functions compared to monotherapy and vehicle controls. The neural oscillations revealed a significant increase in theta power in the injured motor cortex after combination therapy when compared to that with monotherapy and control groups. The significant increase in the cross-correlation between hemispheres in the combination therapy group over monotherapy indicating an increased synchronised functional connectivity between the injured (left) and uninjured motor (right) cortices. Interestingly, VPA as monotherapy did not significantly reduce infarct volume compared to the vehicle controls. Furthermore, the therapeutic efficacy of monotherapies with VPA and early-onset CIMT (initiated immediately post-stroke) showed limited efficacy in promoting motor and neurological recovery. Conclusion: In conclusion, the study demonstrates that VPA combined with physical rehabilitative training (CIMT) enhances functional recovery by enhancing inter-hemispheric functional connectivity and represents a promising therapeutic strategy to alleviate persistent post-stroke motor deficits.