Remote Ischemic Conditioning, Bimanual Skill Learning, and Corticospinal Excitability

Not Applicable

Recruiting

• Conditions: Unilateral Cerebral Palsy; Hemiplegic Cerebral Palsy; Remote Ischemic Conditioning
• Interventions: Behavioral: Remote Ischemic Conditioning (RIC); Behavioral: Sham conditioning; Behavioral: Hand Arm Bimanual Intensive Therapy (HABIT); Behavioral: Bimanual Cup Stacking Training; Behavioral: Balance training

• Registration Number: NCT05355883
• Lead Sponsor: East Carolina University

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2021-12-18
• Study First Submitted: 2022-01-15
• Study First Submitted QC: 2022-04-26
• Study First Posted: 2022-05-02
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-08
• Last Update Posted: 2024-08-12
• Primary Completion: 2024-12-31
• Study Completion: 2025-07-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Remote Ischemic Conditioning (RIC)	Remote Ischemic Conditioning (RIC)	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training
Remote Ischemic Conditioning (RIC)	Balance training	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training
Remote Ischemic Conditioning (RIC)	Bimanual Cup Stacking Training	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training
Remote Ischemic Conditioning (RIC)	Hand Arm Bimanual Intensive Therapy (HABIT)	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training
Sham Conditioning	Sham conditioning	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training
Sham Conditioning	Hand Arm Bimanual Intensive Therapy (HABIT)	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training
Sham Conditioning	Bimanual Cup Stacking Training	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training
Sham Conditioning	Balance training	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 2-6. Intervention * Hand Arm Bimanual Intensive Therapy (HABIT) * Bimanual cup stacking training * Balance training

Primary Outcome Measures

Name	Time	Method
Change in Resting and Active Motor Thresholds	Baseline and 1 week	The minimum intensity of the stimulator output required to produce an MEP of \> 50 μV will be determined using maximum-likelihood parameter estimation by a sequential testing (ML-PEST) algorithm from the lesioned and non-lesioned cortex. Greater reduction in resting and active motor threshold from pre- to post-intervention indicates greater corticospinal excitability.
Change in Stimulus-response curves	Baseline and 1 week	Suprathreshold intensities of 110%, 120%, 130%, 140%, and 150% of resting motor threshold will be administered randomly on the lesioned and non-lesioned cortex. Greater motor evoked potential response at each of these intensities indicate greater corticospinal excitability.
Change in Assisting Hand Assessment	Baseline and 1 week	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.
Change in Bimanual Task Performance	Baseline and 1 week	The time (seconds) to complete each trial of cup stack, which will be averaged across three trials. This will be measured at visit 1 (pre-) and visit 7 (post-intervention). Smaller time to complete the task indicates better performance.

Secondary Outcome Measures

Name	Time	Method
Change in Balance performance	Baseline and 1 week	The average amount of time in seconds that a participant maintains the stability platform within ±5° of horizontal position during 15 trials of 30 seconds each. The total score will range between 0-30 seconds. Higher balance score indicates better balance performance. Greater average balance time indicates better balance performance.
Change in Intracortical Facilitation (ICF)	Baseline and 1 week	For ICF, the interstimulus interval will increase to 12 milliseconds. Greater ICF indicates greater intracortical facilitation.
Change in accelerometry derived variables	Baseline and 1 week	Number of movements, use ratio, magnitude ratio, bilateral magnitude, and acceleration variability will be quantified using wrist worn accelerometers. Greater values indicate better bimanual performance.
Change in Jebsen Hand Function Test (JHFT)	Baseline and 1 week	JHFT assesses fine and gross hand and arm movements. Smaller time to complete JHFT indicates better hand function.
Change in Box and Blocks Test (BBT)	Baseline and 1 week	BBT is a standard test to assess manual speed. Greater number of blocks transferred indicates greater manual speed.
Change in Nine Hole Peg Test (NHPT)	Baseline and 1 week	NHPT is a standard test to assess manual speed and dexterity. Smaller time to complete NHPT indicates greater speed and dexterity.
Change in Hand grip and pinch strength	Baseline and 1 week	Hand grip and pinch strength assesses hand muscle strength. Greater hand and pinch strength indicates greater strength of hand muscles.
Change in Short-Interval Intracortical Inhibition (SICI)	Baseline and 1 week	For SICI, a subthreshold (80% RMT) conditioning pulse to the motor hotspot will be applied followed by a suprathreshold (120% RMT) test pulse 3 milliseconds later. Reduction in SICI indicates intracortical facilitation.

Trial Locations

Locations (1)

Dept. of Physical Therapy, East Carolina University; 🇺🇸 Greenville, North Carolina, United States