Remote Ischemic Conditioning, Bimanual Skill Learning, and Corticospinal Excitability

East Carolina University51 enrolled

Overview

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 existing therapeutic interventions have higher training doses and modest effect sizes. Thus, there is a critical need to find an effective priming agent to enhance bimanual skill learning in children with UCP. This study aims to determine the effects of a novel priming agent, remote ischemic conditioning (RIC), when paired with intensive 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. Investigators prior work has shown that when paired with motor training, RIC enhances motor learning in healthy individuals. Based on these diversified benefits of RIC, the 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. The 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 excitability in children with UCP. In this triple blind, randomized controlled trial, 30 children with UCP, ages 6-16 years will first undergo bimanual speed stack performance, functional upper extremity, and Transcranial Magnetic Stimulation assessments. Children will then undergo RIC/Sham conditioning plus training. Investigators 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 and intensive bimanual training using hand arm bimanual intensive therapy (HABIT) with a standard dose of 6 hours/day for 5 days. The children will perform the same baseline assessments post-intervention. Investigators 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). The 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 different dose of intensive behavioral interventions to improve functional outcomes in children with UCP.

Interventions

Remote Ischemic Conditioning (RIC)BEHAVIORAL

See descriptions under arm/group descriptions. RIC is delivered for 5 intervention visits. Visits 1 is the pre-training assessment visit, visits 2-6 are RIC plus training visits, visit 7 is a post-training assessment visit.

Sham conditioningBEHAVIORAL

See descriptions under arm/group descriptions. Sham conditioning is delivered for 5 intervention visits. Visits 1 is the pre-training assessment visit, visits 2-6 are RIC plus training visits, visit 7 is a post-training assessment visit.

Hand Arm Bimanual Intensive Therapy (HABIT)BEHAVIORAL

HABIT is a child-friendly, intensive intervention directed at improving bimanual coordination and function of the affected arm. The intervention employed in this study includes various age-appropriate fine and gross motor bimanual activities that will be delivered in a play context. Children practice bimanual activities for 6 hours per day, 5 days per week, for 1 week.

Bimanual Cup Stacking TrainingBEHAVIORAL

Children practices bimanual cup stacking, 15 trials/day for 5 consecutive day.

Balance trainingBEHAVIORAL

All children undergo training on a balance board, learning to hold the board level with equal weight on each leg and using various bilateral upper extremity strategies. Participants perform the balance task for 15, 30-second trials per day at visits 2-6.

Eligibility

Sex: ALLMin age: 6 YearsMax age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: Children diagnosed with unilateral cerebral palsy, ages 6-16 years * Manual Ability Classification System (MACS) levels I-III * Ability to complete a stack of 3 cups in 2 minutes * Mainstream in school and has sufficient cognition to follow the experiment instructions Exclusion Criteria: * Children with other developmental disabilities such as autism, developmental coordination disorders, etc. * Children with absent active motor threshold * Children with cognitive deficits or communication problem * Children with known cardiorespiratory and vascular dysfunctions * Children with metabolic disorders, neoplasm, hydrocephalus * Children who are receiving other adjunct therapies such as rTMS and tDCS * Children with seizures and on anti-seizure medications * Children with metal implants and incompatible medical devices for MRI scans

Outcomes

Primary Outcomes

Change in Assisting Hand Assessment

Assisting Hand Assessment assesses bimanual coordination and affected hand function. A 5-point change from pre- to post-intervention is considered a clinically meaningful improvement.