REMOTE ISCHEMIC CONDITIONING AS A THERAPEUTIC PRIMING APPROACH: FROM MECHANISTIC FOUNDATIONS TO CLINICAL TRANSLATION

Abstract

The primary purpose of this dissertation was to investigate the potential of remote ischemic conditioning (RIC) combined with motor training to enhance functional outcomes, and explore the neuroplastic mechanisms underlying these benefits – spinal reflex modulations, and role of brain-derived neurotrophic factor polymorphism in children with CP. Three specific studies were conducted. The first study examined the effects of RIC combined with Hand-Arm Bimanual Intensive Therapy (HABIT) on real-world bimanual performance in children with unilateral cerebral palsy (UCP), using wrist-worn accelerometers, standardized clinical assessments, and grip strength measures. Children receiving RIC + HABIT showed greater improvements in accelerometry-derived measures (use ratio, magnitude ratio, and median acceleration), accompanied by enhanced fine motor dexterity and grip strength in the affected upper extremity. These findings suggest additive benefits of RIC in augmenting the effects of HABIT, likely through multifactorial neuroprotective and neuroplastic mechanisms. Our second purpose was to understand whether the response (UE outcomes) of the children with UCP who completed the first study varied based on their brain-derived neurotrophic factor (BDNF) genotype. The findings revealed that children with the BDNF Val66Met polymorphism exhibited lower baseline UE performance and capacity but demonstrated the largest post-training improvements when receiving RIC + HABIT. These results suggest that RIC may mitigate genotype-related constraints on neuroplasticity, potentially through enhanced BDNF signaling and systemic genomic reprogramming. The third study explored whether pairing RIC with balance training modulates spinal reflex excitability and balance performance in healthy young adults. In healthy adults, RIC paired with balance training led to greater reductions in maximal Hoffman’s (H) reflex amplitude (H max), H max/ maximal M-wave amplitude (H max/ M max) and H slope/ M slope (Hslp/ Mslp) ratios compared to sham conditioning, indicating modulation of spinal reflex excitability. These neurophysiological changes were associated with close to meaningful improvements in balance performance, supporting the role of RIC as a priming intervention that modulates spinal neural circuits and adaptive motor control. Building on these findings, a follow-up case study was conducted in two children with cerebral palsy to assess the feasibility, challenges, and trends in H-reflex measures using the same experimental protocol. Similar to healthy adults, the child receiving RIC combined with balance training showed a decreasing trend in H-reflex measures relative to the child receiving sham conditioning. Altogether, these findings provide novel mechanistic and translational evidence potentially supporting RIC as a feasible, cost-effective, and non-invasive adjunct to pediatric neurorehabilitation. These studies lay the groundwork for future larger clinical trials examining long-term effects, dose optimization, and genotype-guided precision approaches to maximize functional recovery in children with cerebral palsy.