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Background: Motor-learning interventions may improve hand function in children with unilateral cerebral palsy (UCP) but with inconsistent outcomes across participants. Objective: To examine if pre-intervention brain imaging predicts benefit from bimanual intervention. Method: Twenty children with UCP with Manual Ability Classification System levels I to III, aged 7-16 years, participated in an intensive bimanual intervention. Assessments included the Assisting Hand Assessment (AHA), Jebsen Taylor Test of Hand Function (JTTHF) and Children's Hand Experience Questionnaire (CHEQ) at baseline (T1), completion (T2) and 8-10 weeks post-intervention (T3). Imaging at baseline included conventional structural (radiological score), functional (fMRI) and diffusion tensor imaging (DTI). Results: Improvements were seen across assessments; AHA (P = 0.04), JTTHF (P < .001) and CHEQ (P < 0.001). Radiological score significantly correlated with improvement at T2; AHA (r = .475) and CHEQ (r = .632), but negatively with improvement on unimanual measures at T3 (JTTFH r = -.514). fMRI showed negative correlations between contralesional brain activation when moving the affected hand and AHA improvements (T2: r = -.562, T3: r = -0.479). Fractional Anisotropy in the affected posterior limb of the internal capsule correlated negatively with increased bimanual use on CHEQ at T2 (r = -547) and AHA at T3 (r = -.656). Conclusions: Children with greater structural, functional and connective brain damage showed enhanced responses to bimanual intervention. Baseline imaging may identify parameters predicting response to intervention in children with UCP.
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Neurorehabilitation and
Neural Repair
1 –14
© The Author(s) 2015
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DOI: 10.1177/1545968315613446
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Original Research Articles
Introduction
Unilateral cerebral palsy (UCP) is characterized by motor
impairment predominantly lateralized to one side of the
body. This results in unimanual and often bimanual move-
ment difficulties when performing 2-handed actions needed
for independence in many daily activities.1 UCP affects
approximately 1 in 1500 births.2,3 It typically occurs as a
result of unilateral brain abnormality such as brain malfor-
mation, periventricular white matter lesions, corticosubcor-
tical lesions, or postnatal injury.4
The pathophysiology of UCP is, however, complex and
not limited to unilateral distribution, with, more typically,
some influence also on less-affected hand function.5 The type,
extent, and timing of cerebral insult influences brain develop-
ment and reorganization particularly affecting sensorimotor
areas and the white matter tracts that arise from them, such as
the corticospinal tract (CST).6-9 Large variability is demon-
strated in brain imaging findings9 and degree of hand function
impairment.10,11
Classification of children with CP has tended to focus on
topography of distribution of motor impairment (eg, UCP),
movement type (eg, spastic), or severity of motor function
(eg, Gross Motor Function Classification System), albeit
with variations in the measures used to identify particular
movement problems and subsequent quantification.12
These classification models have been used to consider
longitudinal outcomes in CP but have been less useful in
613446NNRXXX10.1177/1545968315613446Neurorehabilitation and Neural RepairSchertz et al
research-article2015
1Child Development and Pediatric Neurology Service, Meuhedet-
Northern Region, Haifa, Israel
2Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
3Bar Ilan University, Ramat Gan, Israel
4Tel Aviv University, Tel Aviv, Israel
5Columbia University, New York, USA
6Oxford Brookes University, Oxford, UK
Corresponding Author:
Mitchell Schertz, MD, Child Development & Pediatric Neurology
Service, Meuhedet-Northern Region, Simtat Atlit 6 Haifa, 33501 Israel.
Email: mitchell.schertz@gmail.com
Imaging Predictors of Improvement From
a Motor Learning–Based Intervention for
Children With Unilateral Cerebral Palsy
Mitchell Schertz, MD1,2, Shelly I. Shiran, MD2, Vicki Myers, MSc2,
Maya Weinstein, PhD2,3, Aviva Fattal-Valevski, MD2, Moran Artzi, PhD2,
Dafna Ben Bashat, PhD2,4, Andrew M. Gordon, PhD5, and Dido Green, PhD4,6
Abstract
Background. Motor-learning interventions may improve hand function in children with unilateral cerebral palsy (UCP) but
with inconsistent outcomes across participants. Objective. To examine if pre-intervention brain imaging predicts benefit
from bimanual intervention. Method. Twenty children with UCP with Manual Ability Classification System levels I to III, aged
7-16 years, participated in an intensive bimanual intervention. Assessments included the Assisting Hand Assessment (AHA),
Jebsen Taylor Test of Hand Function (JTTHF) and Children’s Hand Experience Questionnaire (CHEQ) at baseline (T1),
completion (T2) and 8-10 weeks post-intervention (T3). Imaging at baseline included conventional structural (radiological
score), functional (fMRI) and diffusion tensor imaging (DTI). Results. Improvements were seen across assessments;
AHA (P = 0.04), JTTHF (P < .001) and CHEQ (P < 0.001). Radiological score significantly correlated with improvement
at T2; AHA (r = .475) and CHEQ (r = .632), but negatively with improvement on unimanual measures at T3 (JTTFH
r = –.514). fMRI showed negative correlations between contralesional brain activation when moving the affected hand
and AHA improvements (T2: r = –.562, T3: r = –0.479). Fractional Anisotropy in the affected posterior limb of the
internal capsule correlated negatively with increased bimanual use on CHEQ at T2 (r = –547) and AHA at T3 (r = –.656).
Conclusions. Children with greater structural, functional and connective brain damage showed enhanced responses to
bimanual intervention. Baseline imaging may identify parameters predicting response to intervention in children with UCP.
Keywords
unilateral cerebral palsy, fMRI, DTI, prediction, treatment
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2 Neurorehabilitation and Neural Repair
predicting treatment response.13,14 The development of neu-
roimaging has enabled improved understanding of the
pathophysiology in these children along with the under-
standing that children with UCP with similar unilateral
clinical presentations demonstrate wide variations of find-
ings on neuroimaging.9 Yet many questions regarding etiol-
ogy persist regarding the impact of etiology on function and
development.15
Advances in neuroimaging and electrophysiological
methods have allowed further progress in the field of pedi-
atric neurodisability, with appreciation of abnormalities on
microstructural neuroanatomy as seen in diffusion tensor
imaging (DTI),8 on measures of real-time brain function as
seen in functional MRI (fMRI),7 and on cortical mapping
and excitability as measured with transcranial magnetic
stimulation (TMS).16 fMRI signals are an indirect measure
of neural activity. The BOLD (blood-oxygen-level depen-
dent) contrast mechanism reflects changes in cerebral blood
volume, cerebral blood flow, and oxygen consumption and
relies on the fact that cerebral blood flow and neuronal acti-
vation are coupled.17 In typically developed individuals,
unilateral activation is expected in the primary motor cortex
of the contralateral hemisphere to the hand engaged in
movement (henceforth referred to in this article as typical
activation). However fMRI and TMS have shown atypical
activation patterns, including bilateral activation and acti-
vation in the ipsilateral hemisphere to the hand engaged in
movement in UCP.18-22
Parallel to advances in neuroimaging of UCP have been
developments of effective motor learning–based interven-
tions, including unimanual and bimanual training such as
constraint-induced motor therapy (CIMT) and hand arm
bimanual training (HABIT).14,23-28 However, results are
inconsistent across studies with respect to the extent of
change and including some participants not demonstrating
improvement.29 There is a need to determine what treatment
and regimen is best for whom.3
The advances in neuroimaging, along with lack of uni-
form improvement in those with UCP who underwent motor
learning–based interventions, have led investigators to try to
identify predictors of treatment response in order to deter-
mine which children with which type of imaging findings
may benefit most. Studies to date have been preliminary,
with small sample sizes and limited, almost exclusively, to
children undergoing CIMT.
Islam et al,6 reporting results for children with UCP
who underwent CIMT, found improved motor outcomes to
be independent of the baseline corticomotor projection
pattern (contralateral, mixed, ipsilateral) and structural
MRI lesion characteristics. Rickards et al31 reported on 2
studies in children with CP and adults after stroke who
underwent CIMT. They found that neither integrity (frac-
tional anisotropy [FA]) nor distorted or disrupted path of
the CST predicted response to outcome; nor did it prevent
participants from benefiting maximally from intervention.
Friel et al32 reported that peduncle asymmetry, an estimate
of CST dysgenesis, was a poor predictor of training effi-
cacy in children with hemiplegic CP who underwent a
bimanual intervention.
Reports by Kuhnke et al30 and Rocca et al33 and, most
recently, Manning et al,34 identified more definitive imag-
ing predictors for children with UCP undergoing motor
interventions. For example, Kuhnke et al30 found that chil-
dren with UCP undergoing a CIMT intervention progressed
differently; those whose paretic hand was controlled by pre-
served crossed projections made progress accompanied by
a significant gain in speed, whereas patients with the paretic
hand controlled by ipsilateral projections tended to show
speed reduction.
The aim of our study was to examine whether structural,
functional, and microstructural MR imaging may predict
response to treatment in children with UCP undergoing a
themed variation of HABIT. Specifically, we examined
whether the degree of overall brain injury, the functional
motor activation at the sensorimotor cortex, or the white
matter (WM) integrity of CSTs and the corpus callosum
(CC) may predict response to treatment in children with
UCP undergoing a themed variation of HABIT. A better
understanding of the differences in baseline imaging param-
eters between these children might improve our ability to
target treatment protocols effectively. Our hypothesis was
that both structural (MR), functional (fMRI), and micro-
structural (DTI) imaging biomarkers of the affected hemi-
sphere and connecting neural pathways would predict
which children with UCP would make progress following a
bimanual intervention. Response to treatment was consid-
ered within the framework of the International Classification
of Functioning, Disability and Health–Children and Youth
Version (ICF-CY) to consider impact of movement disorder
on body function and activity performance.35
Materials and Methods
Participants
Children identified with UCP and determined to be eligi-
ble by pediatric neurologists and pediatricians were
recruited from regional hospitals and/or child develop-
mental centers in Israel and the United Kingdom. Baseline
preintervention imaging data (including standard MR,
fMRI, and DTI studies as noted later in the “Imaging
Assessments” section) were available for 20 children with
UCP (11 boys; mean age = 10 years, 11 months ± 1 year, 9
months; range = 7 years, 9 months to 16 years, 3 months)
with manual capacity measured via the Manual Ability
Classification System (MACS)36 at levels I to III, who
subsequently participated in one of three 2-week summer
camps that used a “magic” theme-based variation of the
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Schertz et al 3
HABIT program for improving activity performance.14
Diagnosis, MACS level, and any coexisting conditions
were documented at baseline assessment and verified via
medical records. Three children were known to have
attention-deficit hyperactivity disorder (participants 4, 6,
and 11), 2 of whom had received pharmacological inter-
vention (methylphenidate) for this but not during the
period of intervention. Two other children were known to
have some mild learning difficulties (participants 5 and
17). Participant characteristics are presented in Table 1.
Inclusion/Exclusion Criteria
Children were invited if they received age appropriate
educational services and showed clinical signs of predom-
inant spastic unilateral motor impairment caused by UCP.
Based on clinical history and subsequent radiology, in the
majority of cases, injury had occurred in utero or during
the perinatal period; with 1 child the infarct occurred at
age 2.5 years, and in 1 case the time of injury was unknown.
Exclusion criteria were overt seizure activity and/or
administration of motor therapy/medical/surgical treat-
ment aimed at improving upper-extremity movements (eg,
botulinum toxin injections or intensive motor learning
intervention) in the previous 6 months and any contraindi-
cations to MRI. There was 1 child in the UK cohort who
had participated in a 2-week intensive motor learning
intervention 2 years previously (participant 19). Notably,
children with severe movement limitations to active range
of movement of wrist extension (<20°) or fingers (<10°
flexion) or limited active grasp capacity of the affected
hand were included.
Hand function and imaging assessments were under-
taken in the week prior to participation in the camp (base-
line-T1), in the week after the camp (postintervention, T2),
and 8 to 10 weeks following the intervention (T3). The
Table 1. Participant Characteristics: Clinical.
Participant Camp Gender
GA at Birth
(weeks)
Age at MRI
(years,
months)
Hemiparetic
Side Type of InjuryaGMFCS MACS MM
1 Israel M Term 8, 6 R IVH 2 3 0b
2 Israel F Preterm, 31 13 R IVH 2 2 1
3 Israel F Preterm, 26 14, 3 R IVH 2 2 1
4 Israel M Term 9, 2 R Infarct 2 2 3
5 Israel M Term 7, 2 R Infarct 2 3 0b
6 Israel M Preterm, 27 10, 2 L PVL 1 1 0-1
7 Israel F Preterm, 26 14 R IVH 2 3 0-1b
8 Israel M Preterm, 29 7, 2 L PVL + Focal
infarct
1 1 0
9 Israel F Term 7, 3 R Infarct 1 2 0-1
10 Israel M Term 13.0 R Infarct at 2.5 years 2 3 1
11 Israel F Unknown 16.0 R Infarct 1 1 No data
12 Israel F Term 10, 2 R Infarct 1 1 0-1b
13 Israel M Preterm, 32 9, 2 R IVH 2 2 0
14 Israel M Term 7, 2 R Infarct 2 3 0-1
15 UK F Term 9, 11 L Congenital
malformation
2 2 1
16 UK M Term 7, 10 R Infarct 2 4 2
17 UK M Term 15, 9 L Congenital
malformation
1 2 2
18 UK F Term 10, 9 R PVL + Focal
infarct
1 1 No data
19 UK F Term 13, 2 L Congenital
malformation
2 2 0
20 UK M Term 8, 3 R PVL + Multifocal
white matter
changes
2 3 1
Abbreviations: F, female; GMFCS, gross motor functional classification system; IVH, intraventricular hemorrhage; L, left; M, male; MACS, manual ability
classification system; MM mirror movements; PVL, periventricular leukomalacia; R, right.
aIf time of injury not stated, injury was presumed to be prenatal or perinatal.
bSpasticity high and very little movement observed; MMs possibly reflected in increased fisting and/or elbow flexion.
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4 Neurorehabilitation and Neural Repair
results presented here refer to baseline imaging and change
in hand function assessments over the 3 time points.
Assessments of Hand Function
The Assisting Hand Assessment (AHA; version 4.3), a stan-
dardized test of spontaneous use and performance of the
affected hand across 22 predefined items, uses a 4-point rat-
ing scale, during bimanual interactions in functional/play-
based tasks37 and not bimanual function per se. The AHA is
scored from video recordings, with good reliability and
validity reported.13 Raw scores are transformed into logits
via Rasch analysis and converted to a 0 to 100 AHA unit
scale, with higher scores representing better bimanual
skills.38 The AHA unit scale is used here as recommended
by the authors of the AHA.39 Evaluations from video were
made by a trained therapist blinded to treatment status and
the other test results.
Unimanual skill was measured via the Jebsen Taylor Test
of Hand Function (JTTHF),40 a standardized test of speed of
unimanual grasp and release (modified by eliminating the
writing task because of difficulties of scoring legibility in
children), with reliability and normative data reported for
children.41 Maximum time allowable to complete each task
successfully was capped at 3 minutes; thus, the maximum
time for all 6 items for each hand was 1080 seconds. Scores
were obtained for the affected and less-affected hands.
The Children’s Hand Experience Questionnaire (CHEQ),
a 29-item questionnaire, was administered to record the inde-
pendent performance and skilled use of the affected/hemiple-
gic hand in daily bimanual activities.42 Incorporating the
CHEQ also allowed us to link outcomes to broader aspects of
independence and participation of the ICF, reported as impor-
tant to children and families.42,43 Children 13 years and older,
or parents, completed the English version if they were fluent
in English or the Hebrew translation. Scores are provided for
the total number of independent activities and the number of
independent activities performed using 2 hands. The percent-
age of independent activities performed bimanually was cal-
culated (CHEQ percentage use).
Mirror movements (MMs) were assessed using the
Woods and Teuber Scale44 to obtain estimated measures of
presence/extent of MMs (0 = no clear imitative movement
to 4 = movement equal to that expected for the intended
hand). Ratings were made from videos of the motor task in
the MRI (Israeli group) or estimated from simultaneous
movement actions recorded by sphygmometers placed in
both hands during the fMRI tasks (UK group). Ratings cor-
responding to the Woods and Teuber Scale were calculated,
in which 0% to 5% change in pressure (squeezing) from the
resting state indicated no clear imitative movement (score =
0) and >5% to 25% (score = 1), >25% to 50% (score = 2),
and >50% to 75% (score = 3) to changes consistent with
those recorded in the “active” hand (score = 4).
Imaging Assessments
MRI scans were performed at baseline on a 3-T gradient
echo (GE) according to our previously published protocol.22
Structural images included sagittal T1-weighted spin echo
sequence; T2-weighted fast spin echo; FLAIR; high-resolu-
tion anatomical 3D fast spoiled gradient echo sequence, and
DTI, which was acquired along 19 diffusion gradient direc-
tions for the Israeli group and 16 diffusion directions for the
UK group (b = 1000 s/mm2), and one was acquired without
an applied diffusion gradient. To control for possible effect
of different DTI parameters (number of diffusion gradients),
we performed a t test between the DTI parameters of the CC,
posterior limb of the internal capsule (PLIC), and CST
between the UK and Israeli groups. No significant differ-
ences in DTI values were found. The 2 MR scanners used at
the 2 sites (Israel and UK) were both GE scanners. An iden-
tical detailed protocol was used at both locations to ensure
that the MRI parameters of the scans were identical.
A pediatric radiologist, blinded to medical history and
hand function assessments, scored conventional MRI using
a quantitative scoring method for brain injury based on
topographical MR imaging patterns of the brain. The score,
which ranges from 0 for a normal scan to a maximum of 18
for each hemisphere, covers 7 aspects across 4 domains:
(1) number of affected lobes, (2) volume and type of white
matter injury, (3) extent of gray matter damage, and (4)
major white matter tract injury, per our published protocol.
This scoring will be referred to as the radiological score
and is consistent with classification recommended by the
Surveillance of Cerebral Palsy Europe (SCPE) consensus.9
Scores have been demonstrated to correlate with clinical
function.45
fMRI was performed with T2*-weighted GE-echo planar
imaging sequence: slice thickness/gap = 3.5/0.3 mm; field of
view/matrix = 240 mm/128 × 128; repetition time/echo time/
flip angle = 2250/29 ms/79°. The fMRI motor task was a
block design involving clenching and extending all fingers of
1 hand in synchrony with 2-Hz paced tones, alternating
between affected and less-affected hands.46-48 Children were
asked to do their best to move only 1 hand without moving
the opposite hand. Range of movement was limited by an
inflated sphygmometer (UK) or a soft sponge ball (Israel)
placed in children’s hands, depending on the research site.
This allowed for movement with minimal effort but control-
ling/limiting large variations in range of movement.
The choice of fMRI task was intentionally kept simple
with auditory cues to minimize difficulties of analyses
from more complex motor planning tasks or motion arti-
facts caused by eye movements, respectively. Although
generalized activation patterns through attentional net-
works may influence results, we aimed to minimize the
impact of these by replication of the tasks in the active and
passive conditions.
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Schertz et al 5
fMRI analysis was performed using BrainVoyager
QX2 software package (http://www.brainvoyager.com).
Preprocessing and fMRI analysis were previously
described.22 Two contrasts were studied: (1) activation
when moving the affected hand versus baseline activation
and (2) activation when moving the less-affected hand
versus baseline activation. A false discovery rate proce-
dure was used for the selection of thresholds, and the
false discovery rate (q value) of 0.005 was chosen. The
number of voxels in sensorimotor areas around the central
sulcus within left and right hemispheres in each condition
was quantified separately. The sensorimotor activations
that were measured consisted of the numbers of voxels
activated around the central sulcus, which anatomically
consist of primary motor and sensory areas. This defini-
tion was intentionally broad to account for possible brain
plasticity, including significant shifts in brain structures
that have been shown to occur following brain injury
early in life. Because of the variability in the brains
caused by the lesions, we did not coregister the brains to
a standard space; therefore, we did not use a predefined
region of interest (ROI) but rather manually traced the
ROI on each individual brain.
A laterality index (LI)20,49 was determined for each par-
ticipant to take into account relative contralateral and ipsi-
lateral activation when moving 1 hand. The LI was
calculated according to the formula LI = (Contralateral
Ipsilateral)/(Contralateral + Ipsilateral), where contralat-
eral and ipsilateral equal the total number of voxels
activated above threshold in areas around the central sulcus
contralateral or ipsilateral to the moving hand. LI values
closer to 1 indicate a more typical unilateral pattern of acti-
vation; values closer to 0 indicate a more bilateral pattern
of activation; and values closer to 1 indicate more atypi-
cal ipsilateral activation.
DTI analysis was performed using DTIStudio software
(Johns Hopkins University, Baltimore, MD). Preprocessing
of diffusion data and DTI tractography analysis were previ-
ously described.22 Briefly, the CC and CST were recon-
structed with streamline fiber tracking using the Fiber
Assignment by Continuous Tracking (FACT) algorithm.50
The CC was further segmented into the genu, midbody, and
splenium based on an adaptation of the Witelson segmenta-
tion scheme.51 Because of the relatively small sample size
and the large brain lesions in our cohort, we combined areas
of the original 7 subdivisions of the Witelson protocol to
create 3 simplified regions as previously performed by
Wilde et al.52 Based on findings from our previous study,22
we excluded the genu from further analysis. ROI analysis
was performed for the left and right PLIC using ROIEditor
software (Johns Hopkins University, Baltimore, MD).
Mean values of axial diffusivity (Da), radial diffusivity
(Dr), mean diffusivity (MD), and FA were calculated from
these fiber tracts and ROIs. Higher Da, Dr, and MD and
lower FA values reflect reduced tract integrity and, thus,
more abnormality or damage.
The PLIC region is part of the CST fiber tract. However,
when performing tractography, we measured the diffusivity
indices within the entire CST and obtained mean values
across the entire tract. Because this may have masked dif-
ferences in specific areas within the CST and because the
PLIC is in an area known to be sensitive for detection of
injury within the CST,53,54 we also included it as a separate
ROI in this study.
Intervention Procedures
Children attended one of three 2-week camps, 6 hours daily
for 10 days over 2 weeks during the summer holidays.
Additional homework tasks were set and reviewed each
morning with practice and demonstration of previously
learnt activities.
The camp program followed the procedures summarized
by Charles and Gordon,55 using the HABIT principles to
promote intensive practice and repetition in part and whole
task movements. A magical theme was incorporated into the
program such that children learned specifically selected/
modified magic hand tricks in collaboration with profes-
sional magicians and prepared costumes and props for a
magic show performed at the end of the camp. Details of the
protocol are outlined in Green et al.14 Magic tricks were
scaled to challenge increasingly complex bimanual skills
either in timing, accuracy, or fine manipulation. Staffing
numbers were equitable across camps (3 staff; 4 partici-
pants) and consisted of undergraduate and graduate students
of physiotherapy and occupational therapy.
Statistical Analysis
This analysis sought to determine the relationship between
the degree of improvement (Δ) on hand function measures
postintervention at time points T2 and T3 and imaging
characteristics at baseline. Improvement was calculated as
the percentage of change between precamp and postcamp
(T1 T2) and precamp and follow-up (T1 T3) to enable
similar comparisons across hand function measures. In
cases where prescores on the CHEQ were 0 (eg, no activity
performed independently), these were transformed to 0.5,
and 0.5 accordingly added to postscores to enable a per-
centage change score to be calculated. For ease of compre-
hension, percentage increase (performance scores) was
used for AHA and CHEQ and percentage decrease (time)
for JTTHF, so that all Δs represented improvement. CHEQ
analyses were based on CHEQ percentage use, with Δs cal-
culated as the difference between scores, which were
already in percentage form.
Pearson’s correlation was assessed between Δ on hand
function measures and the following baseline imaging
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6 Neurorehabilitation and Neural Repair
variables: radiological score, fMRI (number of voxels in
ipsilateral and contralateral hemispheres when moving the
affected and less-affected hands), and DTI (FA, MD, Da,
and Dr) in the midbody and splenium of the CC and in the
affected and less-affected PLIC and distal CST. In view of
the mix of ordinal and interval scales, the Spearman ρ was
calculated with similar results, and therefore, Pearson cor-
relations are reported. Because of differences in measure-
ment of MM, correlation analyses of fMRI results were run
with and without children identified with MM rather than
running partial correlations.
Statistical analysis was performed using SPSS software
(SPSS 17.0, Chicago, IL). The study was approved by the
institutional review board of Tel Aviv Sourasky Medical
Center (0204-10-TLV and 0239-11-TLV) and the UK
National Research Ethics Committee (H-10/H080/40/
AM01), conforming to the Helsinki Declaration of research
sites, and fully informed consent was obtained from parents
and assent from children.
Results
Whereas 28 children participated in the 3 camps, imaging
data were available for 20 children with UCP (11 boys;
mean age = 10 years, 11 months ± 1 year, 9 months; range
= 7 years, 9 months to 16 years, 3 months) with Manual
Ability Classification System level I to III (see Table 1).
Imaging data were not obtained for 4 children: 1 who had
dental braces at the time of imaging; 1 who had a peritoneal
shunt and, therefore, did not go in the 3T scanner; and 2
who were unavailable for logistical purposes. Unclear scan-
ning sequences were obtained in 4 cases because of excess
movements; therefore, these children were excluded, leav-
ing 20 children with usable imaging data.
Of the 20 children, all with clinical diagnosis of UCP, 2
children were found to have some form of bilateral brain
injury on structural MR imaging. Child 7 had both clinical
and imaging findings involving both lower extremities and
the right upper extremity. Child 20 had bilateral damage
across nonmotor areas of the frontal lobe without clinical
indication of involvement of the less-affected hand.
All 3 children (4, 16, and 17) with significant MM had
evidence of bilateral activation on fMRI in the sensorimotor
areas. However, there were 3 additional children with LI, sug-
gesting bilateral activation, of whom 2 (6, 19) did not have
significant MM and 1 (18) had no MM data available. Further
details regarding bilateral activation are noted in Table 2.
Hand Function Measures
Tables 3 and 4 provide details of individual and group data
changes across time points. It should be noted that our
cohort contains data from 7 children that were reported on
previously.14 Analysis of the data shows that as a group,
children made overall progress immediately after the
intervention for all measures used: bimanual (AHA),
F(2, 36) = 3.58, P = .04, η2 = 0.166; bimanual independence
(CHEQ), percentage use, F(1.50, 24.00) = 14.96, P < .001,
η2 = 0.483; and unimanual (JTTHF), F(1.27, 22.89) = 11.43,
P = .001, η2 = 0.388. Improvement was maintained at
follow-up except for performance on the AHA (Table 3).
Considerable interindividual variation was noted between
the children along the different time points as well as on the
different measures (unimanual vs bimanual). Given the sig-
nificant change criteria of >4 logits on the AHA or >20% on
the JTTHF, observation of Table 3 shows that one group,
consisting of 8 children (2, 3, 6, 8, 11, 12, 13, and 19), made
progress on both the AHA and the JTTHF after the interven-
tion, though only 3 of these maintained that improvement at
follow-up. A second group, consisting of 11 children (1, 4,
5, 7, 10, 14, 15, 16, 17, 18, and 20), made progress on either
AHA or JTTHF after the intervention, though this included
3 (4, 17, and 20) who actually showed poorer scores on the
AHA. A third group, consisted of 1 child (9), who showed
no progress on either the AHA or JTTHF but did show
improvement on the CHEQ.
Radiological Score
Figures 1A to 1C show the correlations between radiological
score at T1 (preintervention) and changes on hand function
measures at T2 and T3. Radiological score positively corre-
lated with improvement on the AHA (r = 0.475; P = .034)
and CHEQ percentage use (r = 0.632; P = .003) at T2 (ie,
immediate posttest) but negatively correlated with improve-
ment on the JTTHF (affected hand: r = 0.514; P = .024) at
T3 (ie, 3-month follow-up). No relationship was found for
the AHA or CHEQ at T3.
fMRI Measures
Figures 1D to 1F show the significant relationships between
baseline fMRI measures and changes on hand function
measures. A negative correlation was noted between activa-
tion of the ipsilesional hemisphere when moving the
affected hand and progress on the AHA at T3 (r = .613, P
= .009; Figure 1D) but not at T2. A negative correlation was
also noted between activation of the contralesional hemi-
sphere when moving the affected hand and progress on the
AHA at T2 (r = .562, P = .015; Figure 1E) and at T3 (r =
.479, P = .052; Figure 1F). We note that there was an out-
lier on the AHA outcomes (Table 3, participant 20) at T3;
removing this score from the analysis resulted in a reduc-
tion in the significance between the activation of the ipsile-
sional hemisphere and progress on the AHA (r = 0.361; P =
.17) but did not affect the significance of other findings. No
relationships were found for the CHEQ or JTTHF at either
T2 or T3.
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Schertz et al 7
In a post hoc analysis, we checked the extent to which
atypical activation of the ipsilateral (contralesional) hemi-
sphere when moving the affected hand may have been a
result of MM. As noted earlier, our cohort included 3 chil-
dren with significant MM (see Table 1; children 4, 16, and
17). One of these children was seen to be a significant outlier
for activation of the ipsilesional hemisphere and was visibly
seen to have significant and functionally impairing MM of
both hands. When running the correlations without these 3
children, correlations between ipsilesional activation and
AHA were no longer significant, whereas the correlation
between activation in the contralesional hemisphere and
AHA at T2 maintained the same trend (r = .482; P = .069).
Of interest, correlations emerged between the number of
voxels in the ipsilesional hemisphere during movement of
the affected hand and progress in unimanual function on the
JTTHF, both postintervention and at follow-up (T2: r = 0.54,
P = .04; T3: r = 0.63, P = .02, respectively).
Table 2. Participant Characteristics: Imaging.a
Participant Type of Injury
Structural Functional DTI Parameters in CST and PLIC
Radiological
Score fMRI LI
Aff_
CST
Aff_
CST
Lessaff_
CST
Lessaff_
CST
Aff_
PLIC
Aff_
PLIC
Lessaff_
PLIC
Lessaff_
PLIC
MD FA MD FA MD FA MD FA
1 IVH 18 1.00 — 0.76 0.59 — — 0.75 0.66
2 IVH 9 0.49 0.86 0.56 0.75 0.65 0.91 0.6 0.52 0.68
3 IVH 5 0.51 0.81 0.66 0.77 0.67 0.75 0.64 0.73 0.68
4 Infarct 10 0.01b0.83 0.62 0.71 0.64 0.81 0.58 0.71 0.67
5 Infarct 15 —c0.9 0.58 0.79 0.6 0.79 0.56 0.94 0.56
6 PVL 7 0.39 0.86 0.56 0.83 0.63 0.87 0.53 0.8 0.66
7 IVH 18 1.00 0.78 0.61 0.79 0.68 — 0.72 0.68
8 PVL + Focal
infarct
7 1.00 0.79 0.59 0.77 0.61 0.8 0.68 0.78 0.73
9 Infarct 17 0.55 — 0.8 0.56 — — 0.71 0.65
10 Infarct at 2.5 years 13 c0.8 0.55 0.8 0.54 1.51 0.31 0.77 0.54
11 Infarct 13 0.77 0.79 0.58 0.88 0.62 0.84 0.49 0.76 0.61
12 Infarct 7 0.78 0.73 0.61 0.72 0.6 0.73 0.64 0.71 0.7
13 IVH 13 1.00 0.84 0.6 0.74 0.62 0.95 0.43 0.73 0.72
14 Infarct 13 —c0.89 0.56 0.73 0.62 0.79 0.51 0.72 0.68
15 Congenital
malformation
7 —c0.82 0.54 0.78 0.58 0.8 0.6 0.74 0.7
16 Infarct 17 0.12b 0.76 0.6 — 0.76 0.69
17 Congenital
malformation
70.21b0.87 0.61 0.86 0.71 0.79 0.7 0.78 0.68
18 PVL + Focal
infarct
4 0.34 1.25 0.56 0.79 0.6 0.83 0.59 0.77 0.63
19 Congenital
malformation
90.02 0.9 0.6 0.85 0.64 0.84 0.5 0.8 0.58
20 PVL + Multifocal
white matter
changes
12 0.55 0.9 0.64 0.85 0.62 0.85 0.63 0.83 0.61
Abbreviations: Aff, affected; CST, corticospinal tract; DTI, diffusion tensor imaging; FA, fractional anisotropy (arbitrary units); fMRI, functional MRI; IVH,
intraventricular hemorrhage; Lessaff, less affected; LI, lateralization index; MD, mean diffusivity (×10-3 mm2/s); PLIC, posterior limb of internal capsule;
PVL, periventricular leukomalacia.
aRadiological score: scored conventional MRI using a quantitative scoring method for brain injury based on topographical MR imaging patterns of the brain.
The score noted here is the total score and represents the sum of 7 subscores from 4 domains: (1) number of affected lobes, (2) volume and type of white
matter injury, (3) extent of gray matter damage, and (4) major white matter tract injury, per our published protocol.41 LI = (Contralateral Ipsilateral)/
(Contralateral + Ipsilateral), where contralateral and ipsilateral equal the total number of voxels activated above threshold in areas around the central
sulcus contralateral or ipsilateral to the moving hand. An LI closer to 1 indicates a more unilateral pattern of activation, whereas an LI closer to 0 indicates
a more bilateral pattern of activation; a negative LI indicates more ipsilateral activation. Missing values are a result of large lesions in these regions, which
impeded measurement in these areas.
bSignificant mirror movements evident.
cMissing LI data: children 5, 14, no fMRI data because of head movements; child 10, no fMRI data because of dental braces; child 15, no activation on
affected/ipsilesional hemisphere.
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8 Neurorehabilitation and Neural Repair
Diffusion Tensor Imaging
Figure 2 shows the significant correlations between changes
on hand function measures and the FA values in the affected
and less-affected CST and in the PLIC. DTI measures of the
CC did not correlate with change on the AHA, CHEQ, or
JTTHF at T2 or T3. DTI measures of the CST were mixed
with no correlation for any of the hand function assessments
at T2. However, at T3, FA in both the affected and less-
affected CST demonstrated a negative correlation with
Table 3. Motor Function Data at 3 Time Points Over the Study Period.
Participant
AHA
CHEQ No. of Independent Activities
(No. Performed 2-Handed) JTTHF
T1 T2 T3 T1 T2 T3 T1 T2 T3
1 30 39a35a18 (10) 18 (17)a24a (13) 1080 1080 1080
2 48 53a46 22 (11) 21 (19)a21 (20)a293.4 131.6b 144b
3 50 58a46 25 (22) 24 (22) 23 (18)c770.7 446b391.5b
4 63 55c62 22 (20) 24 (23) 25 (22) 343.2 151b238.8a
5 30 47b 12 (8) 19a (19)a 863.2 847.4
6 58 66a74 21 (21) 24 (24) 24 (24) 86.3 86.7 61.2a
7 32 45b33 13 (1) 16a (9)a15 (7)a1080 1080 1080
8 77 80 82a25 (25) 27 (27) 28 (28) 152.3 38.2b 29b
9 42 41 15 (6) 23b (17)b 1080 1080
10 27 32a37b16 (5) 20a (15)b20a (15)b1080 1080 1080
11 63 72a63 29 (26) 29 (26) 28 (22) 462.5 48.6b 50b
12 71 76a76a21 (20) 24 (23) 26a (25)a68.6 52.8a43.2a
13 55 63a58 1 (0) 19b (18)b14b (12)b612.5 365a442.5a
14 32 43b38a1 (0) 19b (18)b14b (12)b1080 1080 1080
15 72 71 71 15 (14) 25b (21) 24b (21)b735.2 242.9b263.9b
16 32 37a35 17 (8) 15 (10) 17 (7) 1080 922.8a 918a
17 70 64c69 20 (17) 23 (21)a16c (15) 596.9 571.1 301.5b
18 66 69 73a20 (18) 25a (23)a26a (26)b63.9 57.7 54.5
19a55 71a64a20 (17) 23 (23)a23 (23)a270.9 283.3 164a
20 68 64 53d16 (15) 22a (22)b23a (22)b301.7 285.5 199.2a
Abbreviations: AHA, Assisting Hand Assessment; CHEQ, Children’s Hand Experience Questionnaire (performed with 2 hands to total number of
CHEQ activities performed); JTTHF, Jebsen Taylor Test of Hand Function (affected hand); T1, baseline/preintervention; T2, postintervention; T3,
3-month follow-up.
aSignificant progress 1 least detectable difference or >20% from T1.
bSignificant progress 2 least detectable difference or >40% from T1.
cPoorer scores 1 least detectable difference or <20% from T1.
dPoorer scores 2 least detectable difference or <40% from T1.
Table 4. Performance on Each Outcome Measure at Precamp, Postcamp, and 3-MFU.
Camp
AHA Logic Scale Score, Mean (SD)
CHEQ Independent Activities Using
2 Hands, Mean (SD) JTTHF Raw Score (s), Mean (SD)
Precamp Postcamp 3-MFU Precamp Postcamp 3-MFU Precamp Postcamp 3-MFU
Israel 48.4 (16.7) 55.0 (14.8) 51.6 (17.4) 13.5 (9.9) 20.1 (5.1) 18.2 (6.4) 646.6 (406.3) 540.5 (467.9) 546.8 (465.2)
UK 60.5 (15.2) 62.7 (13.0) 60.8 (14.5) 14.8 (3.7) 20.0 (5.0) 19.0 (6.9) 508.1 (369.5) 393.9 (306.9) 316.9 (306.7)
All 52.1 (16.8) 57.3 (14.4) 54.4 (16.8) 13.2 (8.2) 19.9 (4.7) 18.4 (6.4) 605.1 (391.3) 496.5 (423.5) 477.8 (429.6)
FF(2, 36) = 3.58; P = .04; η2 = 0.166 F(1.50, 24.00) = 14.96; P < .001;
η2 = 0.483
F(1.27, 22.89) = 11.43; P = .001; η2 = 0.39
Mean
difference
T1 T2: 4.37; P = .04
(CI = 8.6 to 0.97)
T1 T2: 5.88; P = .001
(CI = 9.29 to 2.47)
T1 T2: 110.2; P = .01
(CI = 29.4 to 190.9)
P, CI T1 T3: 1.76; P = .81
(CI = 5.8 to 2.3)
T1 T3: 4.42; P = .009
(CI = 7.78 to 1.06)
T1 T3: 145.5; P = .001
(CI = 70.0 to 221.1)
Abbreviations: 3-MFU, 3-month follow-up; AHA, Assisting Hand Assessment; CHEQ, Children’s Hand Experience Questionnaire (performed with
2 hands to total number of CHEQ activities performed); CI, confidence intervals; JTTHF, Jebsen Taylor Test of Hand Function (affected hand); SD,
standard deviation; T1, baseline/preintervention; T2, postintervention; T3, 3-month follow-up.
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progress on the AHA (affected: r = 0.594, P = .015; less
affected: r = 0.497, P = .036; Figures 2A and 2B). DTI
measures of the PLIC showed correlations with outcome
measures at both T2 and T3. At T2, FA in the affected PLIC
correlated negatively with progress on CHEQ percentage
use (r = 0.547, P = .038; Figure 2C). At T3, FA in the
affected PLIC correlated negatively with improvement on
the AHA (r = 0.656, P = .008; Figure 2D).
Discussion
In this study, we examined the ability of MR and DTI char-
acteristics of brain injury in children with UCP to predict
hand function following a bimanual intervention. Our find-
ings revealed a varying set of relationships between the
imaging findings and change in hand function. Most clear
was the finding that children with greater overall severity of
brain injury at baseline, as indicated by higher radiological
score and decreased cortical activation of the affected hemi-
sphere on fMRI, showed greater improvement on bilateral
hand function but less improvement on unimanual function.
Consistent with this was the finding that DTI values in the
PLIC and CST, indicating more white matter damage (both
to the affected and less-affected sides), were also associated
with greater improvement on bimanual function but no
improvement on unimanual assessment. These data point to
the overall consistent finding that children with UCP with
greater overall brain damage made greater progress on
bimanual function following a bimanual intervention. Given
that degree of brain damage correlates with the severity of
hand function impairment,45 we may conclude that children
with UCP with greater severity of motor impairment may
make greater progress on bimanual function following a
bimanual intervention. Collinearity between measures of
unimanual and bimanual function prevents a more definitive
statement on this latter point or comparisons between uni-
manual or bimanual intervention. Although a number of
individual studies have attempted to determine best respond-
ers within their limited sample, it remains largely unknown
who is likely to benefit.29 We explored the extent to which
the relative lack of improvement of children with less-severe
motor impairments may have been the result of a ceiling
effect. We did not identify any child who did not have fur-
ther capacity, of at least 1 least-detectable difference (beyond
Figure 1. Scatterplots showing correlations between baseline radiological score and motor improvement postintervention on
the (A) AHA, (B) CHEQ at T2 and (C) JTTHF at T3; and between fMRI parameters in the ipsilesional (D) and contralesional (E, F)
hemispheres and motor improvement on the AHA.
Abbreviations: AHA, Assisting Hand Assessment; CHEQ, Children’s Hand Experience Questionnaire; fMRI, functional MRI; JTTHF, Jebsen Taylor Test
of Hand Function; T2, postintervention; T3, 3-month follow-up.
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10 Neurorehabilitation and Neural Repair
the standard error of measurement), for change across mea-
sures following intervention.
Despite the above initial conclusions, our results also
contained data suggesting that other elements are at play in
the equation of which children with UCP make progress
after intervention. We identified a recurring theme suggest-
ing that severity of impairment and type of connectivity in
both affected (ipsilesional) and less-affected (contrale-
sional) hemispheres predicted degree of improvement after
a bimanual intervention. These findings held true mostly
regarding bimanual function, but there was some sugges-
tion of an effect on unimanual function on the less-affected
side. Arguably, some improvement in bimanual function
(and independence) may in part be a result of improved
skills of the less-affected hand.
We found on post hoc analysis that more typical activa-
tion of the ipsilesional, and not contralesional, hemisphere
during movements of the affected hand corresponded to
better progress in unimanual function when analyses
excluded children with significant MM. This is consistent
with our DTI results corresponding to the integrity of the
CST and PLIC. We further noted that whereas all 3 children
with significant MM had evidence of atypical bilateral acti-
vation, there were 2 other children with atypical bilateral
activation who did not have significant MM and 1 for whom
no MM data were available (see Table 2). These findings
are consistent with the idea that bilateral activation may be
a result of either ipsilateral reorganization and or presence
of MM.56 Clearly, further research is required, with more
robust measures of MM, to determine the extent to which
atypical contralesional activation is caused by MM and the
impact this has on bimanual performance. Indeed, it is not
possible to state at this stage whether children with MM
may benefit more from a combined unimanual and biman-
ual therapy program.57
We had 2 children who at presentation showed inconsis-
tent findings between structural imaging and clinical data.
One made good progress that was not sustained at
Figure 2. Scatterplots showing correlations between baseline DTI parameters in the CST (A, B) and the PLIC (C, D) and motor
improvement postintervention.
Abbreviations: CST, corticospinal tract; DTI, diffusion tensor imaging; PLIC, posterior limb of the internal capsule.
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follow-up. The other made no progress on bilateral function
but good progress on unimanual function. Additionally,
there were 3 children with significant MM who demon-
strated worsening scores on the AHA together with improve-
ment on unilateral function. What remains to be clarified is
the functionality of these findings, including the impact on
learning rates and maintenance of skills in the affected hand
of children with unilateral motor impairments.
As noted earlier, studies examining imaging biomarkers
as predictors for improvement in children with UCP who
underwent intervention for the upper extremity are emerg-
ing in the literature.6,31,32,34,58 Our findings, suggesting that
certain imaging biomarkers predict improvement in chil-
dren with UCP, are in contrast to the studies noted earlier by
Islam et al,6 Rickards et al,31 and Friel et al,32 that did not
identify such biomarkers. Our study is partially consistent
with that of the study by Kuhnke et al,30 in that atypical
activation of the nonlesioned hemisphere when moving the
affected hand corresponded to less progress regarding
speed. This suggests that either ipsilateral reorganization
and/or transcallosal inhibition may be linked to behavioral
factors such as MMs and/or developmental disregard, sub-
sequently impeding acquisition of bimanual function.
However, it should be noted that fMRI findings (as used in
our study) are less definitive for mapping the strength of
corticospinal connectivity than those obtained using TMS.18
Our findings are at odds with those of Rocca et al,33 in
that we found fiber integrity (FA) in the lesion area to be
negatively associated with outcome after an intervention,
although intervention type differed. Manning et al,34 consis-
tent with our findings, recently reported higher MD in the
PLIC of the affected tract corresponding to prediction of
better progress in unimanual skills, following a unimanual
therapy, and a more unilateral (typical) activation pattern
associated with greater improvements in clinical scores.
Our study adds to the previous literature, most notably
by examining predictors of change after a bimanual inter-
vention, which has received little attention. Only 1 study32
used a bimanual intervention, and in contrast to that study,
we identified some imaging biomarkers that predicted
improvement. Previous studies enrolled children with less-
severe hand function, whereas we included those with
MACS levels I to III.
A number of our findings warrant further discussion.
Our results showed that children with greater overall brain
damage, based on a quantitative scoring method of MR
images (radiological score), made the most progress on
bimanual tasks. This is consistent with a report that exam-
ined best responders among children with UCP who
received either a unimanual (CIMT) or a bimanual inter-
vention and found that children with poorer hand function
(suggesting greater brain pathology) made the most prog-
ress on unilateral tasks.29 However, the question remains as
to why this is so? Is this a case of regression to the mean,59
whereby those children with more extreme values at base-
line tend to be less extreme at follow-up? This appears less
likely given that our findings were true across multiple
measures and analyses. Alternatively, those with poorer
hand function may have greater latent function to be acti-
vated/greater capacity for change once they undergo an
effective intervention. Furthermore, our assessments of
hand function focused predominantly on the activity level
of the ICF-CY, whereas outcomes of importance to children
and families are directed more to participation in commu-
nity and social life, emotional well-being, and gaining inde-
pendence.43 Finding discrete indicators that may predict
outcomes of intervention for these broader dimensions of
disability in childhood is outside the scope of this study;
however, the increase in independence documented on the
CHEQ provides a promising indication of the impact of the
therapy. Future studies should extend measures to capture
outcomes of importance to children and families.
Of all the predictors in our study, those of the affected
PLIC appear to be most consistent with previous literature.
For example, a recent study of stroke patients proposed that
FA in the PLIC may be a useful biomarker for prediction of
upper-limb motor recovery.53 This finding should be com-
pared against the recent report by Marumoto et al,54 who, in
a small sample of stroke survivors with hemiplegia who
underwent a unimanual intervention (CIMT), found the
ratio of FA between the affected and less-affected PLIC to
be positively correlated with motor improvement after
intervention. This is also consistent with recent findings of
more typical patterns of activation and more significant
white matter immaturity of the PLIC corresponding with
unimanual progress in children with UCP.34 However, as
noted earlier, others have found that white matter integrity
was not associated with motor outcome or improvement
after intervention, specifically relating to a unimanual inter-
vention in CP and stroke patients.31,60 Given the heterogene-
ity between the studies, these conflicting findings await
clarification by future studies.
We found that children with increased contralesional
(atypical) activation, associated with active movements of
the affected hand, made less progress on bimanual func-
tion, whereas those with increased contralesional activa-
tion during movements of the less-affected hand made
more progress on unimanual function of the affected hand
(eg, more typical activation of the hemispheres during
movements of the affected or less-affected hand). This per-
haps suggests that improvements in bimanual skills may
partly be a result of improved skills of the less-affected
hand.61 Previous work has demonstrated that different
types of reorganization, including intrahemispheric and
interhemispheric connectivity, such as ipsilateral reorgani-
zation identified via TMS, may influence treatment
response to unimanual interventions.62 Lack of TMS data
in our study preclude us from making definitive statements
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12 Neurorehabilitation and Neural Repair
regarding CST reorganization but do suggest a complex
interaction between lesion severity, reorganization, and
brain activation patterns and unimanual and bimanual
function. The issues yet to be unraveled include the func-
tionality of bilateral brain activation and the relative
impedance of ipsilateral reorganization or transcallosal
inhibition in the acquisition of skills in the affected hand of
children with unilateral motor impairments. It is evident
that better means for categorizing neural pathology need to
consider not only the etiology, location, and severity of
brain lesions, but also patterns of functional connectivity
and brain activation.
Limitations
Our study, like others in this field, contains limitations
related to the small sample size and varied lesions causing
UCP in the participants. Our finding of an outlier, possibly
affecting results at time 3 but not consistent with other
findings, is an example of where a large sample size might
have clarified the meaning of this outlier. The develop-
ment of hand function involves a complex interplay
between motor, sensory, cognitive, and motivational
factors, often presenting as coexisting conditions63 that
were beyond the scope of our study to explore. Missing
also are data related to mastery motivation, persistence
and resilience, and quality of life in these children, all of
which may contribute to intervention response. Thus, our
findings should be considered preliminary and hypothesis
generating, leading to studies with larger samples and
well-defined comparison groups. Despite the relatively
small sample size, our study compares favorably to
others6,31,32,34,58 in terms of methodological strength and is
the first to report identification of imaging predictors of
progress using a bimanual intervention.
We also note some limitations to the hand function
assessments used in our study. There were 4 children who
did not show progress on the JTTHF at all time points.
Additionally, there was 1 child who did not show progress
on the JTTHF but for whom data were only available at
time points T1 and T2. This lack of progress may have been
a result of the floor effect, with a maximum response time
achieved if the child failed to perform all the tasks in the
item (eg, turn all 5 cards over). However, some of these
children may have managed to increase the number achieved
but without obtaining an improved time.
Despite using the same scanners and identical protocols
at the 2 sites, there may have been small differences in
results between these sites because of software updates.
Similarly, although MMs were addressed in this study, there
is a report stating that by focusing attention, mirror activity
can be voluntarily suppressed.64 This might have led to an
underestimation of the MM scoring and might have influ-
enced the fMRI results. Similar to other pediatric imaging
studies, the logistical and ethical issues regarding imaging
and neurophysiology assessment need to be considered as a
significant limiting factor in data acquisition. These issues
include the young age of many of the children and frequent
movement artifacts in imaging data.
Conclusions
In conclusion, we found that children with greater brain
damage, as demonstrated on structural, functional, or DTI,
showed enhanced responses to a bimanual intervention.
Thus, baseline imaging may identify parameters that pre-
dict which children with UCP will make progress after a
bimanual intervention. Defining reliable and homogeneous
subgroups is essential to predict future clinical outcomes
and best responders to treatment. Further studies with larger
samples, with unified methods of classifying and quantify-
ing neuropathology, are necessary to better delineate these
findings and inform as to which interventions are most
suited for each individual child.
Acknowledgments
We are extremely grateful to the children and their families, and
magicians and young magicians, who gave so much of their time
to participate in this study, as well as Geoff Charles-Edwards,
Clinical Scientist Guy’s and St Thomas’ NHS Foundation Trust
(GSTFT) and Gareth Barker of the Department of Neuroimaging,
Kings College, London, for providing the data from the UK par-
ticipants. We would also like to thank therapy students from
Oxford Brookes University and Tel Aviv University, staff of Guys
and St Thomas’ NHS Trust and the Tel Aviv Sourasky Medical
Centre, and Becca Krom for their support.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
project was funded by grants from Guy’s and St Thomas’ Charity,
Breathe Arts Health Research, and Marnie Kimelman Trust, and
funding from ILAN, the Israeli Association for Disabled Children
and Beit Issie Shapiro provided a venue and funding for one of the
summer camps. DG was supported by a grant from the Department
of Immigration and Absorption during 2010-2011.
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... 1,7,[13][14][15] Moreover, following bimanual therapy in children with CP, reduced integrity of the corticospinal tract (CST) was associated with greater improvement in bimanual function but not unimanual dexterity. 16 Integrity of sensorimotor connectivity is not the only predictor of UE function. For example, lateralization of the CST may also predict UE function following intensive therapies, although these findings are not always equivocal. ...
... A similar procedure was previously done in children with CP and children with traumatic brain injury. 16,31 The ROIs and the callosal pathways for 1 participant are depicted in Figure 1. ...
... To the best of our knowledge, only 1 study evaluated the associations between DTI measures and changes in UE function following bimanual therapy. 16 Similar to our findings, no significant correlations were observed between bimanual changes and the integrity of the CC following bimanual therapy in children with CP. It is important to note that for the HABIT group, we only found one significant correlation between the FA values of the midbody and bimanual function changes. ...
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Background: The corpus callosum (CC) plays an important role in upper extremity (UE) function. The impact on UE function in children with unilateral spastic cerebral palsy (USCP) and improvements following intensive interventions remain unknown. Objectives: To examine the (1) relationship between UE function and CC integrity and (2) relationship between CC integrity and changes in UE function following intensive interventions. Methods: We retrospectively analyzed clinical and neuroimaging data from a sample of convenience of 44 participants (age 9.40 ± 3.10 years) from 2 larger trials. Participants received 90 hours of Hand-Arm Bimanual Intensive Therapy (HABIT) or Constraint-Induced Movement Therapy (CIMT). Unimanual dexterity (Jebsen-Taylor Test of Hand Function [JTTHF]) and bimanual performance (Assisting Hand Assessment [AHA]) were assessed preintervention and postintervention. CC tractography was reconstructed with diffusion tensor imaging (DTI) and segmented into 3 regions (genu, midbody, splenium). Pearson correlations and regression were used to assess the relationship between outcomes and DTI parameters (ie, fractional anisotropy [FA], number of streamlines, and mean, radial, and axial diffusivity). Results: Both groups improved in bimanual performance (P < .01). The CIMT group improved in unimanual dexterity (P < .01). Baseline unimanual dexterity and bimanual performance correlated with FA and number of streamlines for most CC regions (P < .05). Following CIMT, pre-post changes in JTTHF were negatively correlated with axial and radial diffusivity of the CC, and AHA with splenium and number of streamlines for the CC, midbody, and splenium (all P < .05). Following HABIT, midbody FA was positively correlated with pre-post AHA changes (r = 0.417; P = .042). Conclusions: CC integrity is important for UE function in children with USCP.
... And, it has been used as such elsewhere. Both Lam et al. [19] and Bagienski et al. [20] recently reviewed how magic can be used in a wide spectrum of clinical contexts, ranging from physical rehabilitation [21][22][23] to alleviation of anxiety in the perioperative setting [24]. Further, Dr. Pitt recently explained how magic techniques can be used to improve clinical encounters and communication between pediatricians and child patients [25]. ...
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Background/Objectives: Intensive training of the more affected upper extremity (UE) has been shown to be effective for children with unilateral spastic cerebral palsy (USCP). Two types of UE training have been particularly successful: Constraint-Induced Movement Therapy (CIMT) and Bimanual training. Reorganization of the corticospinal tract (CST) early during development often occurs in USCP. Prior studies have suggested that children with an ipsilateral CST controlling the affected UE may improve less following CIMT than children with a contralateral CST. We tested the hypothesis that improvements in UE function after intensive training depend on CST laterality. Study Participants and Setting: Eighty-two children with USCP, age 5 years 10 months to 17 years, University laboratory setting. Materials/Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to determine each child's CST connectivity pattern. Children were stratified by age, sex, baseline hand function and CST connectivity pattern, and randomized to receive either CIMT or Bimanual training, each of which were provided in a day-camp setting (90 h). Hand function was tested before, immediately and 6 months after the intervention with the Jebsen-Taylor Test of Hand Function, the Assisting Hand Assessment, the Box and Block Test, and ABILHAND-Kids. The Canadian Occupational Performance Measure was used to track goal achievement and the Pediatric Evaluation of Disability Inventory was used to assess functioning in daily living activities at home. Results: In contrast to our hypothesis, participants had statistically similar improvements for both CIMT and Bimanual training for all measures independent of their CST connectivity pattern (contralateral, ipsilateral, or bilateral) (p < 0.05 in all cases). Conclusions/Significance: The efficacy of CIMT and Bimanual training is independent of CST connectivity pattern. Children with an ipsilateral CST, previously thought to be maladaptive, have the capacity to improve as well as children with a contralateral or bilateral CST following intensive CIMT or Bimanual training. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02918890.
... Advances in imaging and stimulation have recently shown promise for linking neurophysiology with upper extremity function for people with CP. By combining diffusion tensor imaging that can elucidate neural connectivity, with functional stimulation techniques like transcranial magnetic stimulation, researchers have been able to demonstrate important differences in neural circuits that impact arm and hand function (Friel et al. 2014;Bleyenheuft et al. 2015;Schertz et al. 2016;Robert et al. 2019). Unfortunately, these methods are much more challenging to apply to the lower extremity. ...
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KEY POINTS • Understanding the pathophysiology of skeletal muscle in cerebral palsy (CP) is paramount to developing and applying interventions that reduce contracture while preserving strength. • The ‘traditional view’ whereby spastic/dynamic muscle contractures lead to fixed contractures and bony deformities, is likely incorrect and needs reconsideration in light of recent studies. • Sarcomeres, the basic contractile unit of skeletal muscle, are long and may contribute to the muscle weakness seen in children with CP. • Fixed muscle contractures are related to increases in connective tissue, possibly an adaptive mechanism in the face of increased in vivo muscle tension. • Titin, a spring-like molecule that supports the sarcomere at its ends, is negatively affected in CP, resulting in highly elastic myofibrils and possibly accounting for decreases in eccentric muscle force. • DNA methylation is abnormal in CP and may be responsible for abnormalities in muscle growth and function. • Botulinum neurotoxin A (BoNT-A) causes muscle atrophy and upregulation of fibrofatty connective tissue in animal models, consistent with the lack of functional improvement seen in recent human studies. • Further study is needed to understand the effect of muscle lengthening surgery on function, but changes in fascicle length and pennation angles have been observed In book: Improving Quality of Life for Individuals with Cerebral Palsy through Treatment of Gait Impairment International Cerebral Palsy Function and Mobility SymposiumPublisher: Mac Keith Press / Clinics in Developmental Medicine
... Advances in imaging and stimulation have recently shown promise for linking neurophysiology with upper extremity function for people with CP. By combining diffusion tensor imaging that can elucidate neural connectivity, with functional stimulation techniques like transcranial magnetic stimulation, researchers have been able to demonstrate important differences in neural circuits that impact arm and hand function (Friel et al. 2014;Bleyenheuft et al. 2015;Schertz et al. 2016;Robert et al. 2019). Unfortunately, these methods are much more challenging to apply to the lower extremity. ...
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KEY POINTS • Historically, much emphasis on the treatment of children with cerebral palsy (CP) has been on spasticity reduction, but the effects of current treatments on daily life functioning are lacking or highly variable. • Botulinum neurotoxin A (BoNT-A) and selective dorsal rhizotomy (SDR) should be applied in well-selected patients only. • Scientific evidence on the treatment of dystonia in ambulatory patients with CP is almost completely lacking. • Better outcome assessment of current treatment options as well as a search for novel treatment modalities is crucial. http://www.mackeith.co.uk/product-tag/clinics-in-developmental-medicine/
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Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain–computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.
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Unilateral cerebral palsy (UCP) usually results in damage to the unilateral pyramidal system. However, the clinical presentation of neuromotor deficits also suggests lesions to the extrapyramidal and cerebellar systems bilaterally. In this study, we developed and tested a behavioral neuromotor examination protocol assessing impairments at three levels of motor integration for children with UCP, also considering impairments of the non-paretic upper limb as well as the influences of the laterality of the lesion. We included 30 children with UCP (10.79 ± 2.61 years) and 60 healthy children (8.27 ± 1.57 years) in the study. All children were assessed on general cognitive ability and classified according to the manual ability classification system (MACS). Our neuromotor examination protocol incorporated specific tasks for each level of motor integration: pyramidal, extrapyramidal and cerebellar. Children with UCP and controls did not differ with respect to general cognitive abilities and sex but children with UCP were significantly older. Controls performed significantly better than children with UCP on neuromotor tasks at all levels of motor integration. Additionally, performance of the non-plegine hand in children with UCP was significantly inferior to controls. With the exception of fine motor skills (pyramidal level), children with right and left UCP did not differ. Our behavioral neuromotor examination was sensitive to reveal impairments at all three levels of motor integration bilaterally in children with UCP—although more subtle for the non-paretic limb.
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Selective voluntary motor control is the ability to move or stabilize the joints of the body in a controlled and isolated way when intending to do so. It includes the need to control speed, fluency, reciprocity, and amplitude of activation of the specific muscles required for a given task. In spastic cerebral palsy, damage to the descending corticospinal system of an immature brain results in reduced selective voluntary motor control, while other, less finely tuned, descending pathways may persist in control of the extremities. Changes in the descending motor pathways can be evaluated in a laboratory with neurophysiological and peripheral measures to quantify the structure and output of the central nervous system. Limitations in selective voluntary motor control can be observed in activities of daily living and assessed using a number of validated outcome measures to systematically evaluate selective voluntary motor control at each joint of the upper and lower extremities. Therapeutic approaches aimed at motor learning in which there is intensive, variable, and specific task practice toward patient-specific goals have been shown to be the most effective in improvement of selective voluntary motor control. Use of neuromodulatory agents and technology to enhance plasticity or motivation represents areas of future study. Evidence is emerging to support the idea that early and targeted intervention during periods of enhanced plasticity may have the greatest likelihood of improving selective control over the course of the life-span to reduce secondary musculoskeletal impacts and facilitate performance of desired activities.
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Cerebral palsy is a childhood-onset, lifelong neurological disorder that primarily impairs motor function. Unilateral cerebral palsy (UCP), which impairs use of one hand and perturbs bimanual co-ordination, is the most common form of the condition. The main contemporary upper limb rehabilitation strategies for UCP are constraint-induced movement therapy and bimanual intensive therapy. In this Review, we outline the factors that are crucial to the success of motor rehabilitation in children with UCP, including the dose of training, the relevance of training to daily life, the suitability of training to the age and goals of the child, and the ability of the child to maintain close attention to the tasks. Emerging evidence suggests that the first 2 years of life are a critical period during which interventions for UCP could be more effective than in later life. Abnormal brain organization in UCP, and the effects of development on rehabilitation, must also be understood to develop new effective interventions. Therefore, we also consider neuroimaging methods that can provide insight into the neurobiology of UCP and how the condition responds to existing therapies. We discuss how these methods could shape future rehabilitative strategies based on the neurobiology of UCP and the therapy-induced changes seen in the brain.
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The aim was to identify neuroimaging predictors of clinical improvements following constraint-induced movement therapy. Resting state functional magnetic resonance and diffusion tensor imaging data was acquired in 7 children with hemiplegic cerebral palsy. Clinical and magnetic resonance imaging (MRI) data were acquired at baseline and 1 month later following a 3-week constraint therapy regimen. A more negative baseline laterality index characterizing an atypical unilateral sensorimotor resting state network significantly correlated with an improvement in the Canadian Occupational Performance Measure score (r = -0.81, P = .03). A more unilateral network with decreased activity in the affected hemisphere was associated with greater improvements in clinical scores. Higher mean diffusivity in the posterior limb of the internal capsule of the affect tract correlated significantly with improvements in the Jebsen-Taylor score (r = -0.83, P = .02). Children with more compromised networks and tracts improved the most following constraint therapy. © The Author(s) 2015.
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Informing the NHS Outcomes Framework: evaluating meaningful health outcomes for children with neurodisability using multiple methods including systematic review, qualitative research, Delphi survey and consensus meeting. Background The identification of suitable outcome measures will improve the evaluation of integrated NHS care for the large number of children affected by neurodisability, and has the potential to encourage the provision of more appropriate and effective health care. This research sought to appraise the potential of patient-reported outcome measures (PROMs) for children and young people with neurodisability. Aim This research aimed (i) to identify key outcomes of health care for children with neurodisability, beyond morbidity and mortality, from the perspectives of children, parents and professionals; (ii) to critically appraise existing generic multidimensional PROMs; and (iii) to examine whether or not the key outcomes might be measured by existing PROMs. We also sought agreement on a definition of neurodisability. Methods Data were gathered in three main ways, (i) a systematic review identified eligible generic multidimensional PROMs and peer-reviewed studies evaluating psychometric performance using English-language questionnaires. Studies were appraised for methodological quality and psychometric performance was appraised using standard criteria. (ii) Focus groups and interviews with children and young people with neurodisability, and separately with parents, sought to identify important outcomes of NHS care, and their feedback on example PROM questionnaires. (iii) An online Delphi survey was conducted with a multidisciplinary sample of health professionals to seek agreement on appropriate NHS outcomes. In addition, we convened a consensus meeting with a small nominal group of young people, parents and professionals; the group sought agreement on a core set of important health outcomes. Results From the systematic review, we identified 126 papers that reported eligible evidence regarding the psychometric performance of 25 PROMs. Evidence of psychometric robustness was more favourable for a small number of PROMs: KIDSCREEN (generic), DISABKIDS (chronic-generic) and Child Health Utility 9D (preference-based measure). The Pediatric Quality of Life Inventory and KINDL offer both self-report and a proxy report version for a range of age bands, but evidence of their psychometric performance was weaker. Evidence was lacking in one or more respects for all candidate PROMs, in both general populations and those with neurodisability. Proxy reporting was found generally to be poorly correlated with self-report. Focus groups and interviews included 54 children and young people, and 53 parents. The more important health outcomes were felt to be communication, emotional well-being, pain, mobility, independence/self-care, worry/mental health, social activities and sleep. In addition, parents of children with intellectual impairment identified behaviour, toileting and safety as important outcomes. Participants suggested problems with the face validity of example PROM questionnaires for measuring NHS care. In the Delphi survey, 276 clinicians from a wide range of professions contributed to at least one of four rounds. Professionals rated pain, hearing, seeing, sleep, toileting, mobility and communication as key goals for the NHS but also identified treating neurological symptoms as important. Professionals in the Delphi survey and parents working with the research team agreed a proposed definition for neurodisability. The consensus meeting confirmed overlap between the outcomes identified as important by young people, parents and professionals, but not complete agreement. Conclusions There was agreement between young people, parents and professionals regarding a core suite of more important health outcomes: communication, emotional well-being, pain, mobility, independence/self-care, worry/mental health, social activities and sleep. In addition, behaviour, toileting and safety were identified as important by parents. This research suggests that it would be appropriate to measure these constructs using PROMs to assess health care. None of the candidate PROMs in the review adequately captures all of the identified constructs, and there is inadequate evidence that candidate PROMs are psychometrically robust for use across children with neurodisability. Further consultation with young people, families and professionals is warranted to support the use of PROMs to measure NHS outcomes. Research to test potential PROMs with different age groups and conditions would be valuable. Funding The National Institute for Health Research Health Services and Delivery Research programme.
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Recovery of upper limb function is important for regaining independence after stroke. To test the effects of priming upper limb physical therapy with intermittent theta burst stimulation (iTBS), a form of noninvasive brain stimulation. Eighteen adults with first-ever chronic monohemispheric subcortical stroke participated in this randomized, controlled, triple-blinded trial. Intervention consisted of priming with real or sham iTBS to the ipsilesional primary motor cortex immediately before 45 minutes of upper limb physical therapy, daily for 10 days. Changes in upper limb function (Action Research Arm Test [ARAT]), upper limb impairment (Fugl-Meyer Scale), and corticomotor excitability, were assessed before, during, and immediately, 1 month and 3 months after the intervention. Functional magnetic resonance images were acquired before and at one month after the intervention. Improvements in ARAT were observed after the intervention period when therapy was primed with real iTBS, but not sham, and were maintained at 1 month. These improvements were not apparent halfway through the intervention, indicating a dose effect. Improvements in ARAT at 1 month were related to balancing of corticomotor excitability and an increase in ipsilesional premotor cortex activation during paretic hand grip. Two weeks of iTBS-primed therapy improves upper limb function at the chronic stage of stroke, for at least 1 month postintervention, whereas therapy alone may not be sufficient to alter function. This indicates a potential role for iTBS as an adjuvant to therapy delivered at the chronic stage. © The Author(s) 2015.