Remote Ischemic Conditioning, Bimanual Skill Learning, and Corticospinal Excitability

NCT ID: NCT05355883

Last Updated: 2025-07-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-18
• Study Completion Date: 2025-05-30

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.

Conditions

Unilateral Cerebral Palsy; Hemiplegic Cerebral Palsy; Remote Ischemic Conditioning

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

Group Type: EXPERIMENTAL

Remote Ischemic Conditioning (RIC)

Intervention Type: 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.

Hand Arm Bimanual Intensive Therapy (HABIT)

Intervention Type: 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 Training

Intervention Type: BEHAVIORAL

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

Balance training

Intervention Type: BEHAVIORAL

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.

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

Group Type: SHAM_COMPARATOR

Sham conditioning

Intervention Type: BEHAVIORAL

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)

Intervention Type: 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 Training

Intervention Type: BEHAVIORAL

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

Balance training

Intervention Type: BEHAVIORAL

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.

Interventions

Remote Ischemic Conditioning (RIC)

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.

Intervention Type: BEHAVIORAL

Sham conditioning

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.

Intervention Type: BEHAVIORAL

Hand Arm Bimanual Intensive Therapy (HABIT)

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.

Intervention Type: BEHAVIORAL

Bimanual Cup Stacking Training

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

Intervention Type: BEHAVIORAL

Balance training

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.

Intervention Type: BEHAVIORAL

Other Intervention Names

Remote limb ischemic conditioning; Sham; Bimanual skill training; Cup stacking task

Eligibility Criteria

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

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

East Carolina University

OTHER

Sponsor Role: lead

Responsible Party

Swati Manoharrao Surkar

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Swati Surkar

Role: PRINCIPAL_INVESTIGATOR

East Carolina University

Locations

Dept. of Physical Therapy, East Carolina University

Greenville, North Carolina, United States

Countries

United States

References

Surkar SM, Hoffman RM, Willett S, Flegle J, Harbourne R, Kurz MJ. Hand-Arm Bimanual Intensive Therapy Improves Prefrontal Cortex Activation in Children With Hemiplegic Cerebral Palsy. Pediatr Phys Ther. 2018 Apr;30(2):93-100. doi: 10.1097/PEP.0000000000000486.

Reference Type: BACKGROUND

PMID: 29578992 (View on PubMed)

Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 2009 Apr;8(4):398-412. doi: 10.1016/S1474-4422(09)70054-7.

Reference Type: BACKGROUND

PMID: 19296922 (View on PubMed)

Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006 Jun;7(6):437-48. doi: 10.1038/nrn1927.

Reference Type: BACKGROUND

PMID: 16715053 (View on PubMed)

Stetler RA, Leak RK, Gan Y, Li P, Zhang F, Hu X, Jing Z, Chen J, Zigmond MJ, Gao Y. Preconditioning provides neuroprotection in models of CNS disease: paradigms and clinical significance. Prog Neurobiol. 2014 Mar;114:58-83. doi: 10.1016/j.pneurobio.2013.11.005. Epub 2014 Jan 2.

Reference Type: BACKGROUND

PMID: 24389580 (View on PubMed)

Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009 Oct 31;374(9700):1557-65. doi: 10.1016/S0140-6736(09)61421-5.

Reference Type: BACKGROUND

PMID: 19880021 (View on PubMed)

Study Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

21-001913

Identifier Type: -

Identifier Source: org_study_id