Remote Ischemic Conditioning to Enhance Motor Learning and Corticospinal Excitability in Children with Unilateral Cerebral Palsy

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PROJECT SUMMARY/ABSTRACT Unilateral cerebral palsy (UCP) is a leading cause of childhood disability. An early brain injury impairs the upper extremity function, bimanual coordination, and impacts the child's independence. The effectiveness of existing rehabilitation approaches to improve the paretic arm function is limited due to higher training doses, modest effect sizes, and poor retention of training effects. Thus, there is a critical need to find an effective priming agent that, when paired with motor (bimanual) skill training, will facilitate neurobiological processes to enhance the magnitude of training effects and improve functional capabilities of children with UCP. This proposal aims to determine the effects of a novel priming agent, remote ischemic conditioning (RIC), when paired with bimanual skill training to enhance bimanual skill learning and to augment skill dependent plasticity in children with UCP. Ischemic conditioning (IC) is a phenomenon of protecting the target organ from ischemia by directly exposing it to brief episodes of sublethal ischemia. RIC is a clinically feasible way of performing IC where episodes of ischemia and reperfusion are delivered with cyclic inflation and deflation of a blood pressure cuff on the arm or leg. Pre-clinical and preliminary clinical trials in humans show neuroprotective effects of RIC. Our prior work has shown that when paired with motor training, RIC enhances motor learning in healthy individuals. Based on these diversified benefits of RIC, our central hypothesis is that the multifactorial mechanisms of RIC can be harnessed as a priming agent to enhance motor learning and augment neuroplasticity in children with UCP. Our Specific Aims are: 1) to determine the effects of RIC + training on bimanual skill performance, and 2) to determine the effects of RIC + training on corticospinal randomized controlled trial, 30 children with UCP will first upper conditioning excitability undergo bimanual speed stack performance, functional extremity, and Transcranial Magnetic Stimulation assessments. Children will then undergo RIC/Sham plus training. in children with UCP. In this triple blind, We will deliver RIC/sham conditioning via cyclic inflation and deflation of a pressure cuff on the paretic arm using a standard protocol. Training will involve 5 days (15 trials/day) of bimanual speed stack training. Thechildren will perform the same baseline assessmentspost-intervention. We hypothesize that compared to sham conditioning + training, RIC + training will significantly enhance: 1) bimanual skill performance (decrease in movement time (sec) to complete bimanual speed stack task), 2) bimanual function (increase in the Assisting Hand Assessment scores), 3) cortical excitability in the ipsilesional primary motor cortex (M1) (larger amplitude of motor evoked potentials and lower resting or active motor thresholds), and 4) reduce motor cortex inhibition (reduced short-interval intracortical inhibition and increase in intracortical facilitation in ipsilesional M1). Our long-term goal is to develop effective interventions to improve function of children with UCP. Outcomes of this project will provide critical ingredients for designing Phase II trials that will determine the effects of RIC combined with intensive behavioral interventions to improve functional outcomes in children with UCP.