Clinical trial NCT05355883: Remote Ischemic Conditioning, Bimanual Skill Learning, and Corticospinal Excitability
Official title: Effects of Remote Ischemic Conditioning on Bimanual Skill Learning, Bimanual Coordination, and Corticospinal Excitability in Children With Unilateral Cerebral Palsy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Unilateral Cerebral Palsy
Hemiplegic Cerebral Palsy
Remote Ischemic Conditioning
Keywords: Cerebral palsy
Bimanual coordination
Corticospinal excitability
Lead sponsor: East Carolina University
Sponsor class: OTHER
First posted: 2022-05-02
Enrollment: 30
Sex: ALL
Minimum age (years): 6
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double blinded, randomized controlled trial
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Assisting Hand Assessment
timeFrame: Baseline and 1 week
measure: Change in Bimanual Task Performance
timeFrame: Baseline and 1 week
measure: Change in Resting and Active Motor Thresholds
timeFrame: Baseline and 1 week
measure: Change in Stimulus-response curves
timeFrame: Baseline and 1 week
Secondary outcomes:
measure: Change in Box and Blocks Test (BBT)
timeFrame: Baseline and 1 week
measure: Change in Nine Hole Peg Test (NHPT)
timeFrame: Baseline and 1 week
measure: Change in Jebsen Hand Function Test (JHFT)
timeFrame: Baseline and 1 week
measure: Change in Balance performance
timeFrame: Baseline and 1 week
measure: Change in Hand grip and pinch strength
timeFrame: Baseline and 1 week
measure: Change in Short-Interval Intracortical Inhibition (SICI)
timeFrame: Baseline and 1 week
measure: Change in Intracortical Facilitation (ICF)
timeFrame: Baseline and 1 week
measure: Change in accelerometry derived variables
timeFrame: Baseline and 1 week
Other outcomes:
Locations:
city: Greenville
country: United States
facility: Dept. of Physical Therapy, East Carolina University
state: North Carolina
Study officials:
affiliation: East Carolina University
name: Swati Surkar
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006 Jun;7(6):437-48. doi: 10.1038/nrn1927.
citation: 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.
citation: 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.