Intensive Unimanual (CIMT) and Bimanual Training (HABIT) in Children With Hemiplegia
Phase: NA
Conditions: Cerebral Palsy, Hemiplegia, Children
Sponsor: Teachers College, Columbia University

 
 
Study Protocol and Statistical Analysis Plan 
 
 
Title: Improvements in upper extremity function following intensive training are 
independent of corticospinal tract organization in children with unilateral spastic cerebral 
palsy: A clinical randomized trial. 
 
NCT: 02918890 
 
Date: 5/1/2014 
 
 

Study Objectives 
This study aims to test the hypothesis that improvements in upper extremity function 
following either constraint induced movement therapy (CIMT) or bimanual training 
depend on corticospinal tract (CST) laterality and type of training (unimanual vs. 
bimanual) in children with unilateral spastic cerebral palsy (USCP). Specifically, we 
predict that children with a maintained contralateral CST will respond equally to CIMT 
and bimanual training, while children with ipsilateral CST laterality will be less 
responsive to CIMT than bimanual training.  
 
Study Design 
All study procedures will be approved by the Institutional Review Boards of Teachers 
College, Columbia University, where the treatments will be conducted, the Burke 
Medical Research Institute, where TMS evaluations will be performed, and Weill Cornell 
Medicine, where magnetic resonance imaging (MRI) will be performed.  
 
We will recruit participants from clinics in the NYC area, our website 
(http://www.tc.edu/centers/cit/), ClinicalTrials.gov (NCT02918890), and online support 
groups. We will obtain written informed consent and assent from children and their 
caregivers.  
 
We will randomize participants to receive either 90 hours of CIMT or Hand-Arm 
Bimanual Intensive Training (HABIT) after they complete all baseline outcome 
measures. Block randomization will be implemented for each cohort of participants, with 
each cohort stratified by age, sex, baseline hand function and CST connectivity pattern 
as closely as possible. Randomization will occur offsite using concealed allocation to 
receive either CIMT or HABIT. Intervention will be delivered in a day-camp model for 6 
hours/day over 15 days for a total of 90 hours. 
 
The inclusion criteria will be: 1) ages 6 to 17 years, 2) diagnosed with USCP 3) capable 
of participating in a 15 day, 6 hours/day day camp while separated from caregiver(s), 4) 
capable of following directions regarding hand use and testing, 5) capable of 
communicating needs, 6) mainstreamed in age-appropriate school classroom, and 7) 
able to lift the more affected arm 15cm above a table surface and grasp light objects. 
The exclusion criteria will be: 1) unwillingness to comply with instructions or other 
behavioral issues making delivery of an intensive therapy infeasible, 2) health problems 
unassociated with hemiplegia, 3) visual impairment that could interfere with 
participation, 4) orthopedic surgery on the more affected hand within 1 year, 5) 
presence of metallic objects in the body, and 6) botulinum toxin in the more affected 
upper extremity within the past 6 months or intended treatment within the study period, 
7) seizures after the age of 2 years, 8) family history of seizure disorders, 9) current 
medication use to lower the seizure threshold, 10) claustrophobia, or  11) pregnancy.  
 
We aim to recruit 82 participants based on sample size calculations from results of the 
Assisting Hand Assessment (AHA) and Jebsen-Taylor Test of Hand Function (JTTHF) 
outcomes of a prior CIMT/HABIT randomized controlled trial and pilot data.  
 

Methodology 
 
Children will participate in an intensive hand training intervention using either one 
(CIMT) or both (HABIT) hands. During the intervention, children will be paired with a 
trained interventionist, with an interventionist:child ratio of at least 1:1. We will recruit 
and train physical and occupational therapists, graduate students in 
kinesiology/neuroscience, speech pathology, and psychology, and undergraduates to be 
interventionists. Interventionists will be supervised by experienced PT/Ots. Both the 
interventionists and supervisors will be blinded to CST connectivity patterns. Prior to the 
intervention, a training session will be conducted by the supervisors for standardization 
based on the established manual of procedures for CIMT and HABIT. Fidelity will be 
reinforced by supervisors during the day camp and daily post-camp meetings. 
Participants receiving CIMT and HABIT will be located in separate rooms, with each 
room being supervised by experienced PTs/OTs who will model and ensure uniformity of 
treatment. Each day, interventionists will attend team meetings to discuss the progress 
and needs of each child. 
 
Participants will work one-on-one with their interventionist or in groups, and activities will 
be divided into whole and part task practice. Whole task practice involves sequencing 
successive movements within the context of activities (e.g., games, arts and crafts, goal 
training). The activities will be performed continuously for at least 15 to 20 minutes. 
Targeted movements and spatial and temporal coordination will be practiced within the 
context of completing the task. Part task practice will involve breaking down motor skills 
into smaller components and reinforcement of successive approximations of the desired 
behavior (e.g., card turning to promote forearm supination) while increasing repetitions 
and progressing skill requirements. This approach will also serve to increase treatment 
intensity by requiring as many repetitions as possible over repeated 30 second intervals 
(typically a minimum of 5 intervals). 
 
Constraint-Induced Movement Therapy 
CIMT will be modified to be child-focused, using a cotton sling fastened to the child’s 
trunk with the distal end enclosed to prevent using the less affected arm or hand as an 
assist. The sling will be continuously worn throughout the intervention, and breaks of up 
to 30 minutes will be given as requested. To engage the child in the intervention and to 
maintain engagement, we will establish a list of fine motor and manipulative gross motor 
activities that elicit movement behaviors of interest that include a battery of age-
appropriate, unimanual functional and play activities. Interventionists will select tasks 
based on which train the targeted hand impairments and the child’s interest. Task 
difficulty will be progressed as children improved by requiring greater speed, accuracy, 
or movement repetition. 
 
Hand-Arm Bimanual Intensive Therapy 
We will establish a list of age-appropriate fine and gross motor activities that require use 
of both hands. Activities will be chosen by taking into consideration the role of the more 
affected upper extremity (UE) increasing in complexity from passive assist to active 
manipulator. Children will be asked to use the more affected UE in the same manner as 
that of the non-dominant limb of a typically developing child. Directions will be provided 

to the child before the start of each task to avoid use of compensatory strategies, 
specifying how each hand will be used during the activity.  
 
Outcome Measures 
We will use several measures of hand function to capture different aspects of manual 
ability. All measures will be administered immediately before treatment (pre-test), within 
two days after (post-test), and 6 months after treatment (follow-up). Assessments will be 
administered by an experienced physical or occupational therapist who is blinded to the 
treatment allocation and CST connectivity of each child. 
 
The primary outcome measures will be the Assisting Hand Assessment (AHA) and 
Jebsen-Taylor Test of Hand Function (JTTHF). The AHA will measure bimanual hand 
use, while the JTTHF will measure unimanual dexterity of the affected hand.  
 
AHA: The AHA is a validated test for measuring bimanual hand use in children with UE 
impairments. The AHA measures the use of the more affected hand in bimanual 
activities during a play-like testing session. Sessions will be videotaped and scored off-
site by a blinded evaluator. The AHA has excellent validity, reliability (0.97-0.99) and 
responsiveness to change. The AHA units will be used for the analysis. The smallest 
detectable difference (SDD) for AHA is an improvement of at least 5 units. 
 
JTTHF: The JTTHF measures the time taken to complete six unimanual tasks, which 
include flipping cards, moving small objects, and lifting cans. The total score is the 
amount of time taken to complete all tasks. The test will be performed on both the more 
affected and less affected hands. The JTTHF is well-validated and has excellent 
reliability.  
 
Several secondary outcome measures will also be used. The Box and Blocks Test 
(BBT) will measure unimanual dexterity. The Canadian Occupational Performance 
Measure (COPM) will measure caregiver perceptions of a child’s performance of 
functional goals, and satisfaction with how well the child can perform the goal. The 
ABILHAND-Kids is a parent-report of child’s manual ability. The Pediatric Evaluation of 
Disability Inventory (PEDI) will be used to measure functioning in the home 
environment.  
 
BBT: The BBT measures how many blocks (2.5 cm3) an individual can move from one 
box, over a barrier, to an adjacent box in one minute. Both hands will be tested. The 
BBT is valid and reliable for children with CP. 
 
COPM: The COPM is a structured interview in which the individuals are asked to 
identify up to five functional goals. In this study, parents will report their child’s functional 
goals in terms of how they perform each goal (COPM-Performance), and how satisfied 
they are with the child’s performance (COPM-Satisfaction). The same caregiver will be 
interviewed at all time points. A change of 2 or more points in each scale of COPM is 
considered a minimum clinically important difference (MCID). The COPM has been 
validated for parents of children with disabilities.  

 
ABILHAND-Kids: The questionnaire measures the ability of a child to perform specific 
21 daily tasks which require hand use, according to the parent’s perspective. It has 
been validated for children with CP over the age of 6 and it is a reliable test. 
 
PEDI: Caregivers will be interviewed to assess children’s daily functioning using the 
PEDI, a valid/reliable test focusing on child’s functioning in daily living activities at home. 
Children’s functional skills (PEDI-FS) and caregiver assistance (PEDI-CA) in self-care 
will be assessed. 
 
Determination of CST Laterality 
We will determine CST laterality in two ways. 1) TMS (primary approach): We will 
determine which hemisphere evokes muscle activation of the affected hand when TMS 
is applied to the primary motor cortex (M1); 2) DTI (secondary approach): We will use 
DTI to visualize the affected CST only in children whose CST laterality cannot be 
determined with TMS. We have shown that DTI is an accurate surrogate measure of 
CST laterality. 
 
Transcranial Magnetic Stimulation 
Single-pulse transcranial magnetic stimulation (TMS) will be used to determine which 
hemisphere’s M1 controls movement of the child’s more affected hand. We will record 
EMG from the first dorsal interosseous (FDI) muscle in both hands. Skin will be cleaned 
with rubbing alcohol and a mild abrasive (NuPrep, Weaver and Company, Aurora, CO). 
Electrodes will be placed on the FDI muscle belly. Reference electrodes will be placed 
on the muscle tendon, and a ground electrode will be placed on the wrist styloid 
process. EMG will be recorded with Neuroconn hardware and software (Neuroprax, 
Germany). The Neuroconn will receive a trigger input from the TMS stimulator, such that 
the relative timing of an EMG response to a stimulus can be measured and visualized. 
The EMG response to TMS is a motor evoked potential (MEP). 
 
We will identify the spot at which a single TMS pulse evokes the strongest MEP in the 
affected FDI muscle (the motor “hotspot”). To identify the motor hotspot, single TMS 
pulses will be delivered to the child’s scalp, starting approximately 4 cm from midline 
above the ear. The initial TMS stimulus intensity will be 50% stimulator output. If an 
MEP is not found, the coil position will be moved in 1cm increments to stimulate the 
scalp above motor cortex on both hemispheres. Stimulus intensity will be increased in 
2-5% increments until an MEP is found. We will stimulate up to 80% stimulator output, 
because higher stimulation can be painful to participants. If we are unable to find an 
MEP in the motor strip, we will stimulate at 80% stimulator output at 50 points across 
frontal and parietal cortices in one hemisphere. If no MEP is found at any of these sites, 
we will classify that hemisphere as having no direct control of the movement of either 
upper extremity. 
 
After the motor hotspot is found, the resting motor threshold (rMT) will be determined. 
The rMT is defined as the minimum stimulus intensity needed to evoke an MEP in the 
affected FDI in 6 of 10 trials. Stimuli will be delivered at a frequency <0.1Hz. If an MEP 

is found after 6 of 10 pulses, the stimulus intensity will be lowered 2% until an MEP is 
no longer found in 6 of 10 trials. 
 
We will then place a circular grid over the hemisphere, centered over the hotspot, using 
Brainsight. The grid will have a 10cm diameter, with five concentric rings, each gridpoint 
placed 1cm apart. The grid will be centered over the hotspot for that hemisphere. We 
will stimulate each site 1-3 times at 110% the participant’s rMT to thoroughly search for 
all motor cortex representations of the upper extremities. Responses are sites at which 
a TMS stimulus evoked an MEP 50µV or larger. We will calculate the ratio between the 
number of responses in the more affected FDI obtained from the lesioned and 
contralesional hemispheres. This ratio is the laterality index (LI).   
 
Participants will be categorized as having a contralateral CST connectivity pattern if the 
LI is between 0.9 and 1; i.e., 90% to 100% of the responses in the more affected hand 
come from the lesioned hemisphere. Participants will be categorized as having an 
ipsilateral CST connectivity pattern if the LI is between 0 and 0.1; i.e., 0% to 10% of the 
responses in the affected hand come from the lesioned hemisphere. Participants will be 
categorized as having a bilateral CST connectivity pattern if the LI is between 0.1 and 
0.9. 
 
Transcranial Magnetic Stimulation Analysis 
The latency and peak-to-peak amplitude of each TMS pulse will be measured using a 
suite of custom-written MATLAB (Mathworks, Waltham, MA) scripts. If the latency of the 
MEP is longer than 40ms after the TMS pulse, that trial will be excluded from analysis. 
Additionally, if high levels (>100µV) of background EMG activity are seen before the 
MEP, the trial will be excluded from analysis.  
 
Magnetic Resonance Imaging 
Each child will receive a structural MR scan (MP-RAGE, 3D, T1-weighted) and diffusion 
tensor imaging scan, without sedation prior to participation. The structural MRI will be 
used to co-register TMS stimulation targets with specific brain landmarks, using a 
frameless stereotaxic neuronavigation system (Brainsight Frameless, Rogue Research, 
Montreal, QC, Canada). For TMS localization, there is normal variability in brain 
topography relative to scalp landmarks. MR scans will be done on a Siemens Prisma 
MRI Scanner (Malvern, PA) in the Citigroup Biomedical Imaging Center (CBIC). 
Structural scans (165 slices) will be taken at a resolution of 256 x 256 px. The structural 
MRI will be used to identify the lesion type and extent, as well as to localize the TMS 
coil (i.e., neuronavigation). The DTI scan will be done during the same session as the 
structural MRI. For DTI, a 65-direction protocol will be used, 75 slices per direction at a 
resolution of 112 x 112 px each.  
 
Diffusion Tensor Imaging Analysis 
DT images for participants whose CST laterality cannot be determined with TMS due to 
excessively high threshold or safety reasons will be imported into DTI Studio (Johns 
Hopkins University) software for processing and analyses. This has been shown to be a 
reliable surrogate for TMS in determining CST laterality. Image series for each 

participant will be screened for movement artifact, and slices showing artifact will be 
removed. Since images are obtained using 65 gradients, up to 30% of slices may be 
removed without compromising feasibility of tract reconstruction. Using DTI Studio, we 
will place region of interest seeds in the affected motor cortex and cerebral peduncle, 
and later in the unaffected motor cortex and cerebral peduncle. We will use tractography 
to find tracts that pass through both regions of interest.  We will categorize each CST as 
present or absent. If there is a present CST on the affected side, the child will be 
categorized as having a contralateral CST. If there is not a CST present on the affected 
side, and a CST present on the other side, the child will be categorized as having an 
ipsilateral CST.  
 
 
Statistical Analysis Plan 
This will be an intention-to-treat study. If a child misses their 6 month follow-up 
assessment, we will impute their missing data based on the average change data for 
other participants in their subgroup. Statistical analyses will be performed using SPSS 
(IBM). A treatment (CIMT, HABIT) x CST connectivity pattern (contralateral, ipsilateral, 
bilateral) x test session (pre-, post-, 6 month) ANOVA with repeated measures on test 
session will be performed on all measures and Newman-Keuls post hoc tests will be 
performed where appropriate. Regression analyses will be done to determine predictors 
of outcomes. For children with a bilateral CST, correlations will be done between the LI 
and changes in outcome measures. Statistical significance will be considered at the 
p<0.05 level.