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

NCT ID: NCT05777070

Last Updated: 2025-07-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-11-07
• 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 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 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.

Conditions

Unilateral Cerebral Palsy

Study Design

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

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 1-7.

Group Type: EXPERIMENTAL

Bimanual Cup Stacking Training

Intervention Type: BEHAVIORAL

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

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 1-7.

Group Type: SHAM_COMPARATOR

Bimanual Cup Stacking Training

Intervention Type: BEHAVIORAL

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

Interventions

Bimanual Cup Stacking Training

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

Intervention Type: BEHAVIORAL

Other Intervention Names

Remote limb ischemic conditioning; Sham conditioning

Eligibility Criteria

Inclusion Criteria

1. Children diagnosed with unilateral cerebral palsy (UCP)

2. Manual Ability Classification System (MACS) levels I-III

3. Ability to complete a stack of 3 cups in 1 minute

4. Mainstream in school

Exclusion Criteria

1. Children with other developmental disabilities such as autism, attention deficit hyperactivity disorder, developmental coordination disorders, etc.

2. Children with absent active motor threshold

3. Children with known cardiorespiratory, vascular, and metabolic disorders

4. Children with neoplasm and hydrocephalus

5. Children who are currently receiving or received other adjunct therapies such as rTMS and tDCS in the past 6 months

6. Children with seizures within last 2 years and on anti-seizure medications

7. Children with metal implants and incompatible medical devices

• Minimum Eligible Age: 8 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

Locations

Dept. of Physical Therapy, East Carolina University

Greenville, North Carolina, United States

Countries

United States

References

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)

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: RESULT

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: RESULT

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: RESULT

PMID: 24389580 (View on PubMed)

Mattlage AE, Sutter EN, Bland MD, Surkar SM, Gidday JM, Lee JM, Hershey T, Chen L, Lang CE. Dose of remote limb ischemic conditioning for enhancing learning in healthy young adults. Exp Brain Res. 2019 Jun;237(6):1493-1502. doi: 10.1007/s00221-019-05519-w. Epub 2019 Mar 26.

Reference Type: RESULT

PMID: 30915491 (View on PubMed)

Sutter EN, Mattlage AE, Bland MD, Cherry-Allen KM, Harrison E, Surkar SM, Gidday JM, Chen L, Hershey T, Lee JM, Lang CE. Remote Limb Ischemic Conditioning and Motor Learning: Evaluation of Factors Influencing Response in Older Adults. Transl Stroke Res. 2019 Aug;10(4):362-371. doi: 10.1007/s12975-018-0653-8. Epub 2018 Aug 7.

Reference Type: RESULT

PMID: 30088217 (View on PubMed)

Surkar SM, Bland MD, Mattlage AE, Chen L, Gidday JM, Lee JM, Hershey T, Lang CE. Effects of remote limb ischemic conditioning on muscle strength in healthy young adults: A randomized controlled trial. PLoS One. 2020 Feb 4;15(2):e0227263. doi: 10.1371/journal.pone.0227263. eCollection 2020.

Reference Type: RESULT

PMID: 32017777 (View on PubMed)

Surkar SM, Willson JD, Cassidy JM, Kantak S, Patterson CG. Remote ischaemic conditioning combined with bimanual task training to enhance bimanual skill learning and corticospinal excitability in children with unilateral cerebral palsy: a study protocol of a single centre, phase II randomised controlled trial. BMJ Open. 2023 Sep 28;13(9):e076881. doi: 10.1136/bmjopen-2023-076881.

Reference Type: DERIVED

PMID: 37770277 (View on PubMed)

Other Identifiers

MS4_UMCIRB 21-001913

Identifier Type: -

Identifier Source: org_study_id