Effects of Remote Ischemic Conditioning on Bimanual Skill Learning and Corticospinal Excitability in Children With Unilateral Cerebral Palsy (RIC)

Effects of Remote Ischemic Conditioning on Bimanual Skill Learning and Corticospinal Excitability in Children With Unilateral Cerebral Palsy

Remote Ischemic Conditioning Combined With Bimanual Task Training to Enhance Bimanual Skill Learning and Corticospinal Excitability in Children With Unilateral Cerebral Palsy

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 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 learning and bimanual coordination, and 2) to determine the effects of RIC + training on corticospinal excitability in children with UCP. In this triple blind, randomized controlled trial, 46 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 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 coordination and bimanual function (improvement in kinematic variables and 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.

Participants are masked to group assignments, investigators are masked to assessments, and outcomes assessors are masked to intervention groups

RIC is achieved via blood pressure cuff inflation to at least 20 mmHg above systolic blood pressure to 250 mmHg on the more involved arm. RIC involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation and requires 45 minutes. RIC is performed on visits 1-7.

Sham conditioning is achieved via blood pressure cuff inflation to 25 mmHg on the more involved arm. RIC involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation and requires 45 minutes. RIC is performed on visits 1-7.

The time (seconds) to complete each trial of cup stack, which will be averaged across nine trials. This will be measured at visit 1 (pre-) and visit 7 (post-intervention).

Symmetric performance is characterized as a time-lag between the affected and less affected arm during movement onset and task completion.

The rMT is the stimulator output required to produce a motor evoked potential (MEP) of > 50 μV in at least 5/10 trials in FDI muscle.

The aMT is the stimulator output required to produce a motor evoked potential (MEP) of > 200 μV in FDI muscle during 30% of MVIC of FDI muscle using a pinch grip. aMT is a measure of motor cortex excitability.

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.

Hand trajectory is defined as the resultant 3D path length between the starting position and task completion.

Normalized movement overlap time is calculated as the percentage of total task completion time that both hands are participating in the stacking sequence during bimanual coordination task

Total participation time is calculated as the total amount of time the affected and the less affected hand participate in bimanual coordination task. A hand will be considered as participating in the task any time the wrist marker tangential velocity remains over 2.0 cm/s for at least 100 ms.

Goal synchronization is defined as a time lag between the initiation of the affected compared to the unaffected arm

Total task duration is defined as the duration from movement onset until the criteria for task completion is reached with both hands.

stimulus-response curves will be constructed for the ipsilesional as well as contralesional M1 at intensities of 90%, 100%, 110%, 120%, 130%, 140%, and 150% of rMT (10 stimuli per intensity in random order). The peak-to-peak amplitude of MEPs and area under the curve of resultant MEPs to these intensities will be calculated.

The peak-to-peak amplitude of the EMG response from the affected as well as unaffected FDI muscle while stimulating the ipsilesional as well as contralesional motor cortex will be recorded at 100% rMT and averaged across 10 single-pulse trials. MEP amplitude indicates the strength of motor response to TMS.

SICI and ICF will be obtained by applying a conditioning stimulus at 80% rMT intensity or AMT intensity followed by a test stimulus at 120% rMT intensity over the hot spot. The interstimulus interval between the conditioning and test stimulus will be 3 ms for obtaining measures of SICI and 15 ms for obtaining ICF.

Inclusion Criteria: Children diagnosed with unilateral cerebral palsy (UCP) Manual Ability Classification System (MACS) levels I-III Ability to complete a stack of 3 cups in 1 minute Mainstream in school Exclusion Criteria: Children with other developmental disabilities such as autism, attention deficit hyperactivity disorder, developmental coordination disorders, etc. Children with absent active motor threshold Children with known cardiorespiratory, vascular, and metabolic disorders Children with neoplasm and hydrocephalus Children who are currently receiving or received other adjunct therapies such as rTMS and tDCS in the past 6 months Children with seizures within last 2 years and on anti-seizure medications Children with metal implants and incompatible medical devices

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