# Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy

Rodrigo Araneda, Daniela Ebner-Karestinos, Julie Paradis, Anne Klöcker, Geoffroy Saussez, Josselin Demas, Rodolphe Bailly, Sandra Bouvier, Astrid Carton de Tournai, Enimie Herman, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Rodrigo Araneda, Daniela Ebner-Karestinos, Julie Paradis, Anne Klöcker, Geoffroy Saussez, et al. Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy. Medicine Archives of Pediatrics & Adolescent - JAMA Pediatrics, 2024, 178 (1), pp.19. 10.1001/jamapediatrics.2023.4809. [https://doi.org/10.1001/jamapediatrics.2023.4809](https://doi.org/10.1001/jamapediatrics.2023.4809).

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# Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy

Rodrigo Araneda, Daniela Ebner-Karestinos, Julie Paradis, Anne Klöcker, Geoffroy Saussez, Josselin Demas, Rodolphe Bailly, Sandra Bouvier, Astrid Carton de Tournai, Enimie Herman, et al.

► To cite this version:

Rodrigo Araneda, Daniela Ebner-Karestinos, Julie Paradis, Anne Klöcker, Geoffroy Saussez, et al. Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy. Medicine Archives of Pediatrics & Adolescent - JAMA Pediatrics, 2024, 178 (1), pp.19. 10.1001/jamapediatrics.2023.4809. [https://doi.org/10.1001/jamapediatrics.2023.4809](https://doi.org/10.1001/jamapediatrics.2023.4809).

HAL Id: hal-04595703

https://univ-angers.hal.science/hal-04595703v1

Submitted on 12 Jun 2024

**HAL** is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
# Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy
## A Randomized Clinical Trial

Rodrigo Araneda, PhD; Daniela Ebner-Karestinos, PhD; Julie Paradis, PhD; Anne Klöcker, PhD; Geoffroy Saussez, PhD; Josselin Demas, PhD; Rodolphe Bailly, PhD; Sandra Bouvier, MSc; Astrid Carton de Tournai, MSc; Enimie Herman, MSc; Aghiles Souki, MSc; Grégoire Le Gal, PhD; Emmanuel Nowak, PhD; Stephane V. Sizonenko, PhD; Christopher J. Newman, PhD; Mickael Dinomais, PhD; Inmaculada Riquelme, PhD; Andrea Guzzetta, PhD; Sylvain Brochard, PhD; Yannick Bleyenheuft, PhD

<figure><img src="image_3.png" /></figure>

Supplemental content

**IMPORTANCE** Intensive interventions are provided to young children with unilateral cerebral palsy (UCP), classically focused on the upper extremity despite the frequent impairment of gross motor function. Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) effectively improves manual dexterity and gross motor function in school-aged children.

**OBJECTIVE** To verify if HABIT-ILE would improve manual abilities in young children with UCP more than usual motor activity.

**DESIGN, SETTING, AND PARTICIPANTS** This prospective randomized clinical trial (November 2018 to December 2021), including 2 parallel groups and a 1:1 allocation, recruitment took place at European university hospitals, cerebral palsy specialized centers, and spontaneous applications at 3 sites: Brussels, Belgium; Brest, France; and Pisa, Italy. Matched (age at inclusion, lesion type, cause of cerebral palsy, and affected side) pairs randomization was performed. Young children were assessed at baseline (TO), 2 weeks after baseline (T1), and 3 months after baseline (T2). Health care professionals and assessors of main outcomes were blinded to group allocation. At least 23 young children (in each group) aged 12 to 59 months with spastic/dyskinetic UCP and able to follow instructions were needed. Exclusion criteria included uncontrolled seizures, scheduled botulinum toxin injections, orthopedic surgery scheduled during the 6 months before or during the study period, severe visual/cognitive impairments, or contraindications to magnetic resonance imaging.

**INTERVENTIONS** Two weeks of usual motor activity including usual rehabilitation (control group) vs 2 weeks (50 hours) of HABIT-ILE (HABIT-ILE group).

**MAIN OUTCOMES AND MEASURES** Primary outcome: Assisting Hand Assessment (AHA); secondary outcomes: Gross Motor Function Measure-66 (GMFM-66), Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and Canadian Occupational Performance Measure (COPM).

**RESULTS** Of 50 recruited young children (26 girls [52%], median age; 35.3 months for HABIT-ILE group; median age, 32.8 months for control group), 49 were included in the final analyses. Change in AHA score from TO to T2 was significantly greater in the HABIT-ILE group (adjusted mean score difference [MD], 5.19; 95% CI, 2.84-7.55; *P* < .001). Changes in GMFM-66 (MD, 4.72; 95% CI, 2.66-6.78), PEDI-CAT daily activities (MD, 1.40; 95% CI, 0.29-2.51), COPM performance (MD, 3.62; 95% CI, 2.91-4.32), and satisfaction (MD, 3.53; 95% CI, 2.70-4.36) scores were greater in the HABIT-ILE group.

**CONCLUSIONS AND RELEVANCE** In this clinical trial, early HABIT-ILE was shown to be an effective treatment to improve motor performance in young children with UCP. Moreover, the improvements had an impact on daily life activities of these children.

**TRIAL REGISTRATION** ClinicalTrials.gov Identifier: NCT04020354

JAMA Pediatr. 2024;178(1):19-28. doi:10.1001/jamapediatrics.2023.4809
Published online November 6, 2023. Corrected on December 18, 2023.

**Author Affiliations:** Author affiliations are listed at the end of this article.

**Corresponding Author:** Yannick Bleyenheuft, PhD, Institute of Neuroscience, Université catholique de Louvain, 53 Avenue Mounier, UCL-B1.53.04, B-1200 Brussels, Belgium (yannick.bleyenheuft@uclouvain.be).
# Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy
A Randomized Clinical Trial

Rodrigo Araneda, PhD; Daniela Ebner-Karestinos, PhD; Julie Paradis, PhD; Anne Klöcker, PhD; Geoffroy Saussez, PhD; Josselin Demas, PhD; Rodolphe Bailly, PhD; Sandra Bouvier, MSc; Astrid Carton de Tournai, MSc; Enimie Herman, MSc; Aghiles Souki, MSc; Grégoire Le Gal, PhD; Emmanuel Nowak, PhD; Stephane V. Sizonenko, PhD; Christopher J. Newman, PhD; Mickael Dinomais, PhD; Inmaculada Riquelme, PhD; Andrea Guzzetta, PhD; Sylvain Brochard, PhD; Yannick Bleyenheuft, PhD

<figure><img src="image_2.png" /></figure>

Supplemental content

**IMPORTANCE** Intensive interventions are provided to young children with unilateral cerebral palsy (UCP), classically focused on the upper extremity despite the frequent impairment of gross motor function. Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) effectively improves manual dexterity and gross motor function in school-aged children.

**OBJECTIVE** To verify if HABIT-ILE would improve manual abilities in young children with UCP more than usual motor activity.

**DESIGN, SETTING, AND PARTICIPANTS** This prospective randomized clinical trial (November 2018 to December 2021), including 2 parallel groups and a 1:1 allocation, recruitment took place at European university hospitals, cerebral palsy specialized centers, and spontaneous applications at 3 sites: Brussels, Belgium; Brest, France; and Pisa, Italy. Matched (age at inclusion, lesion type, cause of cerebral palsy, and affected side) pairs randomization was performed. Young children were assessed at baseline (TO), 2 weeks after baseline (T1), and 3 months after baseline (T2). Health care professionals and assessors of main outcomes were blinded to group allocation. At least 23 young children (in each group) aged 12 to 59 months with spastic/dyskinetic UCP and able to follow instructions were needed. Exclusion criteria included uncontrolled seizures, scheduled botulinum toxin injections, orthopedic surgery scheduled during the 6 months before or during the study period, severe visual/cognitive impairments, or contraindications to magnetic resonance imaging.

**INTERVENTIONS** Two weeks of usual motor activity including usual rehabilitation (control group) vs 2 weeks (50 hours) of HABIT-ILE (HABIT-ILE group).

**MAIN OUTCOMES AND MEASURES** Primary outcome: Assisting Hand Assessment (AHA); secondary outcomes: Gross Motor Function Measure-66 (GMFM-66), Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and Canadian Occupational Performance Measure (COPM).

**RESULTS** Of 50 recruited young children (26 girls [52%], median age; 35.3 months for HABIT-ILE group; median age, 32.8 months for control group), 49 were included in the final analyses. Change in AHA score from TO to T2 was significantly greater in the HABIT-ILE group (adjusted mean score difference [MD], 5.19; 95% CI, 2.84-7.55; *P* < .001). Changes in GMFM-66 (MD, 4.72; 95% CI, 2.66-6.78), PEDI-CAT daily activities (MD, 1.40; 95% CI, 0.29-2.51), COPM performance (MD, 3.62; 95% CI, 2.91-4.32), and satisfaction (MD, 3.53; 95% CI, 2.70-4.36) scores were greater in the HABIT-ILE group.

**CONCLUSIONS AND RELEVANCE** In this clinical trial, early HABIT-ILE was shown to be an effective treatment to improve motor performance in young children with UCP. Moreover, the improvements had an impact on daily life activities of these children.

**TRIAL REGISTRATION** ClinicalTrials.gov Identifier: NCT04020354

**Author Affiliations:** Author affiliations are listed at the end of this article.

**Corresponding Author:** Yannick Bleyenheuft, PhD, Institute of Neuroscience, Université catholique de Louvain, 53 Avenue Mounier, UCL-B1.53.04, B-1200 Brussels, Belgium (yannick.bleyenheuft@uclouvain.be).
Cerebral palsy (CP) is the most common pediatric motor disorder, occurring in 2 to 2.5 per 1000 live births.¹,² The initial lesion or maldevelopment occurs before the age of 2 years and can affect different periods of brain growth. CP is caused by the ensuing atypical brain development, especially if the pathways for the control of skilled movements are compromised.³⁻⁷ The motor impairments caused by CP mostly affect the execution of daily life activities, primarily because of reduced manual abilities and gross motor function.⁸ These limitations may have a detrimental effect on the quality of life and participation of these children throughout their lives.²

Evidence supports the use of intensive goal-directed in-
terventions based on motor skill learning to improve motor
function and daily activities in school-aged children with CP,
as compared with regular care.⁹⁻¹¹ These interventions in-
duce neuroplastic changes that result in improved function.¹²,¹³
However, the main activity-dependent brain reorganization
produced by environmental experience occurs early in life. Pro-
viding interventions to children with CP during this window
of opportunity could potentially maximize functional changes,
positively impact the whole developmental curve, and mini-
mize subsequent complications.¹⁴⁻¹⁷ However, few studies have
evaluated the effectiveness of intensive rehabilitation in
young children.⁹,¹⁵,¹⁷

Most intensive interventions investigated in young chil-
dren with unilateral CP (UCP) involved constraint-induced
movement therapy or bimanual training that only target the
upper extremities, despite the frequent impairment of gross
motor function, including the lower extremities and trunk.¹⁸
Hand-Arm Bimanual Intensive Therapy Including Lower
Extremities (HABIT-ILE) is an intensive intervention that
involves the practice of voluntary movement with many rep-
etitions and progressive shaping in a child-friendly manner.
In addition to stimulating bimanual coordination, HABIT-ILE
includes continuous stimulation of the lower extremities
and trunk.¹⁹ Recently, a single-group, self-controlled pilot
study of the feasibility of HABIT-ILE in 10 preschool children
with UCP found large differences in manual dexterity and
gross motor function after 50 hours of therapy.²⁰ It is now
crucial to confirm these results in an adequately powered
randomized clinical trial (RCT).

We aimed to evaluate the effect of HABIT-ILE against usual (spontaneous and unstructured) motor activity, including usual rehabilitation on bimanual performance at 3 months in children with UCP between 1 and 4 years old. We hypothesized that HABIT-ILE would improve bimanual ability and gross motor function more than usual, unstructured motor activity.

Methods

Full ethical approval was obtained for this RCT in Belgium (B403201316810), France (29BRC19.0050/N2019-A01173-54), and Italy (244/2019). The parents of the young children included provided signed informed consent for their child's participation. This study is part of a large multicenter European project including 2 RCTs: one for children with unilateral cerebral palsy and the second for children with bilateral

Key Points

**Question** What is the effect of early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) intervention on bimanual performance vs usual, unstructured spontaneous motor activity in children between 1 and 4 years old with unilateral cerebral palsy after 3 months?

**Findings** This randomized clinical trial including 50 children found improvements in bimanual hand function scores that were significantly higher in the HABIT-ILE group than in the control group.

**Meaning** Early HABIT-ILE improved bimanual performance more than usual motor activity in young children with unilateral cerebral palsy.

cerebral palsy. This study is reported in accordance with the
Consolidated Standards of Reporting Trials (CONSORT)
reporting guidelines. The study protocol is available in
Supplement 2.

Study Population

Fifty young children (1 to 4 years old) were recruited from Belgian university hospital centers dedicated to the treatment of children with CP, from Brest University Hospital Centre in France, and from the IRCCS Fondazione Stella Maris in Pisa, Italy. Spontaneous applications from the parents of children were also considered. The inclusion criteria were young children with a diagnosis of unilateral spastic or dyskinetic CP, aged between 12 and 59 months (corrected age if preterm birth), and able to follow instructions. Half of the children recruited were aged 12 to 35 months, when descending motor pathways are likely to reorganize,²¹,²² and half were aged 36 to 59 months, when reorganization is less likely. Children were excluded if they had uncontrolled seizures, botulinum toxin injections, orthopedic surgery scheduled less than 6 months previously or scheduled during the study period, had severe visual or cognitive impairments that could interfere with the intervention and/or assessments, or had any contraindications to magnetic resonance imaging. Recruitment occurred across the 3 sites: Belgium (n = 18), France (n = 16), and Italy (n = 16) (Figure 1).

The young children were classified according to their
manual performance using the Manual Ability Classification
System for Children with CP aged 1 to 4 (Mini-MACS),²³ and
their gross motor function using the Gross Motor Function Clas-
sification System-Expanded and Revised (GMFM-66),²⁴ and
the corresponding modified versions for children younger than
2 years and those between 2 and 4 years old. Both systems in-
volve a 5-level classification, with I indicating the highest mo-
tor ability (best performers) and V the lowest motor ability level.

Study Design and Data Collection

This prospective multicenter RCT was a 2 parallel-group
design with a 1:1 allocation ratio performed between Novem-
ber 2018 and December 2021. A matched-pairs randomiza-
tion was performed at each site according to age at inclusion,
lesion type (brain malformation/ periventricular white mat-
ter lesion/ gray matter lesion), and affected side (right/left).
Cerebral palsy (CP) is the most common pediatric motor disorder, occurring in 2 to 2.5 per 1000 live births.¹,² The initial lesion or maldevelopment occurs before the age of 2 years and can affect different periods of brain growth. CP is caused by the ensuing atypical brain development, especially if the pathways for the control of skilled movements are compromised.³⁻⁷ The motor impairments caused by CP mostly affect the execution of daily life activities, primarily because of reduced manual abilities and gross motor function.⁸ These limitations may have a detrimental effect on the quality of life and participation of these children throughout their lives.²

Evidence supports the use of intensive goal-directed interventions based on motor skill learning to improve motor function and daily activities in school-aged children with CP, as compared with regular care.⁹⁻¹¹ These interventions induce neuroplastic changes that result in improved function.¹²,¹³ However, the main activity-dependent brain reorganization produced by environmental experience occurs early in life. Providing interventions to children with CP during this window of opportunity could potentially maximize functional changes, positively impact the whole developmental curve, and minimize subsequent complications.¹⁴⁻¹⁷ However, few studies have evaluated the effectiveness of intensive rehabilitation in young children.⁹,¹⁵,¹⁷

Most intensive interventions investigated in young children with unilateral CP (UCP) involved constraint-induced movement therapy or bimanual training that only target the upper extremities, despite the frequent impairment of gross motor function, including the lower extremities and trunk.¹⁸ Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) is an intensive intervention that involves the practice of voluntary movement with many repetitions and progressive shaping in a child-friendly manner. In addition to stimulating bimanual coordination, HABIT-ILE includes continuous stimulation of the lower extremities and trunk.¹⁹ Recently, a single-group, self-controlled pilot study of the feasibility of HABIT-ILE in 10 preschool children with UCP found large differences in manual dexterity and gross motor function after 50 hours of therapy.²⁰ It is now crucial to confirm these results in an adequately powered randomized clinical trial (RCT).

We aimed to evaluate the effect of HABIT-ILE against usual (spontaneous and unstructured) motor activity, including usual rehabilitation on bimanual performance at 3 months in children with UCP between 1 and 4 years old. We hypothesized that HABIT-ILE would improve bimanual ability and gross motor function more than usual, unstructured motor activity.

## Methods

Full ethical approval was obtained for this RCT in Belgium (B403201316810), France (29BRC19.0050/N2019-A01173-54), and Italy (244/2019). The parents of the young children included provided signed informed consent for their child's participation. This study is part of a large multicenter European project including 2 RCTs: one for children with unilateral cerebral palsy and the second for children with bilateral

## Key Points

**Question** What is the effect of early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) intervention on bimanual performance vs usual, unstructured spontaneous motor activity in children between 1 and 4 years old with unilateral cerebral palsy after 3 months?

**Findings** This randomized clinical trial including 50 children found improvements in bimanual hand function scores that were significantly higher in the HABIT-ILE group than in the control group.

**Meaning** Early HABIT-ILE improved bimanual performance more than usual motor activity in young children with unilateral cerebral palsy.

cerebral palsy. This study is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines. The study protocol is available in Supplement 2.

## Study Population

Fifty young children (1 to 4 years old) were recruited from Belgian university hospital centers dedicated to the treatment of children with CP, from Brest University Hospital Centre in France, and from the IRCCS Fondazione Stella Maris in Pisa, Italy. Spontaneous applications from the parents of children were also considered. The inclusion criteria were young children with a diagnosis of unilateral spastic or dyskinetic CP, aged between 12 and 59 months (corrected age if preterm birth), and able to follow instructions. Half of the children recruited were aged 12 to 35 months, when descending motor pathways are likely to reorganize,²¹,²² and half were aged 36 to 59 months, when reorganization is less likely. Children were excluded if they had uncontrolled seizures, botulinum toxin injections, orthopedic surgery scheduled less than 6 months previously or scheduled during the study period, had severe visual or cognitive impairments that could interfere with the intervention and/or assessments, or had any contraindications to magnetic resonance imaging. Recruitment occurred across the 3 sites: Belgium (n = 18), France (n = 16), and Italy (n = 16) (Figure 1).

The young children were classified according to their manual performance using the Manual Ability Classification System for Children with CP aged 1 to 4 (Mini-MACS),²³ and their gross motor function using the Gross Motor Function Classification System-Expanded and Revised (GMFM-66),²⁴ and the corresponding modified versions for children younger than 2 years and those between 2 and 4 years old. Both systems involve a 5-level classification, with I indicating the highest motor ability (best performers) and V the lowest motor ability level.

## Study Design and Data Collection

This prospective multicenter RCT was a 2 parallel-group design with a 1:1 allocation ratio performed between November 2018 and December 2021. A matched-pairs randomization was performed at each site according to age at inclusion, lesion type (brain malformation/ periventricular white matter lesion/ gray matter lesion), and affected side (right/left).
<figure><img src="image_4.png" /><figcaption>Figure 1. Flow Diagram of Participants</figcaption></figure>

HABIT-ILE indicates Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; TO, first testing session (baseline); T1, second testing session 2 weeks after TO; T2, third testing session 3 months after TO.

The young children were then randomly allocated to either the control or the treatment group using computer generated randomization. Health care professionals, as well as the assessors of the Assisting Hand Assessment (AHA), GMFM-66, and Melbourne Assessment 2 (MA2) were blinded to group allocation. The RCT compared the effect of 50 hours over 2 weeks of early HABIT-ILE with spontaneous, unstructured motor activity with an estimated activity time of around 50 hours over 2 weeks. Assessments were performed at 3 time points: baseline (TO), 2 weeks after baseline (T1), and 3 months after baseline (T2).

## Assessments

### Primary Outcomes

The primary outcome was the between-group difference in score change (T2-TO) at 3 months in the AHA²⁵ (AHA, children older than 18 months) or the version for children younger than 18 months (Mini-AHA²⁶). This tool evaluates how children use their more affected hand to assist the less affected hand in bimanual activities. Scores are transformed into linear measures on a scale from 0 to 100 using a Rasch model (logit based AHA-unit). The session was video recorded for subsequent blind scoring by an AHA certified examiner.

### Secondary Outcomes

The GMFM-66²⁷ was used to evaluate the children's gross motor function. The MA2²⁸,²⁹ was used to evaluate the unimanual performance of the more and less affected upper extremity in terms of movement range, accuracy, dexterity, and

fluency. Each child's MA2 and GMFM-66 test sessions were video recorded for subsequent blind scoring.

The Canadian Occupational Performance Measure (COPM)³⁰ was used to establish and evaluate the children's functional goals (defined by their parents) in terms of the child's performance and parent's satisfaction. The Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT)³¹ was used to evaluate functional skills in the daily activities and mobility domains. All questionnaires were completed by the parents. For the secondary outcomes, P values should be considered as a reference for exploratory purposes.

## Procedures

### Treatment Group: Early HABIT-ILE

Interventionists and physical or occupational therapists oversaw daily by experienced and trained HABIT-ILE supervisors provided the early HABIT-ILE intervention. Additionally, to ensure fidelity to the intervention, therapists participated in 1 to 2 days of training to familiarize themselves with the therapeutic concepts; they were subsequently guided by the supervision team throughout the study. Throughout all the study and sites, the same supervision team ensured the exclusive use of HABIT-ILE, as well as the adaptation of the intervention to the child's age, motor abilities, and functional goals.

The young children participated in day-camp therapy 5 days a week over 2 weeks.¹⁹,³²,³³ At least 1 interventionist was assigned to each child. As described in the pilot study,²⁰ to ac-
<figure><img src="image_3.png" /><figcaption>Figure 1. Flow Diagram of Participants</figcaption></figure>

HABIT-ILE indicates Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; TO, first testing session (baseline); T1, second testing session 2 weeks after TO; T2, third testing session 3 months after TO.

The young children were then randomly allocated to either the control or the treatment group using computer generated randomization. Health care professionals, as well as the assessors of the Assisting Hand Assessment (AHA), GMFM-66, and Melbourne Assessment 2 (MA2) were blinded to group allocation. The RCT compared the effect of 50 hours over 2 weeks of early HABIT-ILE with spontaneous, unstructured motor activity with an estimated activity time of around 50 hours over 2 weeks. Assessments were performed at 3 time points: baseline (TO), 2 weeks after baseline (T1), and 3 months after baseline (T2).

## Assessments

### Primary Outcomes

The primary outcome was the between-group difference in score change (T2-TO) at 3 months in the AHA²⁵ (AHA, children older than 18 months) or the version for children younger than 18 months (Mini-AHA²⁶). This tool evaluates how children use their more affected hand to assist the less affected hand in bimanual activities. Scores are transformed into linear measures on a scale from 0 to 100 using a Rasch model (logit based AHA-unit). The session was video recorded for subsequent blind scoring by an AHA certified examiner.

### Secondary Outcomes

The GMFM-66²⁷ was used to evaluate the children's gross motor function. The MA2²⁸,²⁹ was used to evaluate the unimanual performance of the more and less affected upper extremity in terms of movement range, accuracy, dexterity, and

fluency. Each child's MA2 and GMFM-66 test sessions were video recorded for subsequent blind scoring.

The Canadian Occupational Performance Measure (COPM)³⁰ was used to establish and evaluate the children's functional goals (defined by their parents) in terms of the child's performance and parent's satisfaction. The Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT)³¹ was used to evaluate functional skills in the daily activities and mobility domains. All questionnaires were completed by the parents. For the secondary outcomes, P values should be considered as a reference for exploratory purposes.

## Procedures

### Treatment Group: Early HABIT-ILE

Interventionists and physical or occupational therapists oversaw daily by experienced and trained HABIT-ILE supervisors provided the early HABIT-ILE intervention. Additionally, to ensure fidelity to the intervention, therapists participated in 1 to 2 days of training to familiarize themselves with the therapeutic concepts; they were subsequently guided by the supervision team throughout the study. Throughout all the study and sites, the same supervision team ensured the exclusive use of HABIT-ILE, as well as the adaptation of the intervention to the child's age, motor abilities, and functional goals.

The young children participated in day-camp therapy 5 days a week over 2 weeks.¹⁹,³²,³³ At least 1 interventionist was assigned to each child. As described in the pilot study,²⁰ to ac-
count for the specificity of children younger than 5 years, we
modified the original HABIT-ILE protocol.¹⁹ Daily sessions con-
sisted of 5 hours of HABIT-ILE per day with 3 hours in the
morning, 2.5 hours off (nap/rest time), and 2 hours in the af-
ternoon, for a total of 50 hours. Briefly, therapy activities are
chosen according to the child's baseline upper extremity and
lower extremity capacities and postural control. The activi-
ties are progressed by varying the environmental con-
straints, moving to more challenging activities as perfor-
mance improves.

Control Group: Spontaneous, Unstructured Motor Activity

Young children allocated to the active control group contin-
ued with their usual daily life activities, consisting mainly
of spontaneous unstructured motor activity (at home or
daycare). The estimated usual motor activity time of chil-
dren 1 to 4 years old is around 5 hours per day.³⁴,³⁵ To ensure
that this theoretical amount of hours reported for this
age group in the literature matched the actual amount of
activity performed by the children in our sample (time
spent in movement),³⁶,³⁷ we measured the daily amount of
activity using inertial sensors in both groups between TO
and T1. The children in the control group performed their
usual therapies during this time, including physical, occu-
pational, and psychomotor therapy (mean total, 2 hours
per week).

Sample Size

As reported in the study protocol,³⁸ we calculated the sample
size based on previous studies of children older than 5 years³⁹
and the pilot trial performed in children younger than 5 years.²⁰
Those studies showed an improvement minima of 6 AHA units
in the treatment group and of 2 AHA units in the control group
(effect size, 1.26).³⁹ The AHA improved by 10 (SD, 6.7) AHA units
at the third month of follow-up.²⁰ Consequently, a minimal im-
provement of 1 SD in the treatment group vs the control group
was expected, with an α of .05 and a 1-β of 0.9. Accordingly,
46 participants were required (23 per group) but we planned
to recruit 50 children in case of dropouts.

Statistics

The analyses were performed by an independent group of
statisticians using SAS/STAT software, version 9.4 (SAS Insti-
tute). As planned in the study protocol,³⁸ between-group com-
parisons of the primary outcome were performed using analy-
sis of covariance (ANCOVA) with adjustment for baseline
measurements.⁴⁰ Additionally, the same analyses were per-
formed with consideration of age (older than/younger than 2
years old, ie, up to 35 and from 36 months) and manual abil-
ity limitations (Mini-MACS level) to determine their impact on
the therapy outcomes. ANCOVA was also performed on the
secondary outcomes. If homoscedasticity and normality were
not met, nonparametric analyses (Wilcoxon test) were per-
formed. For exploratory purposes, the paired *t* test (or
Wilcoxon) was performed within groups to compare out-
comes between assessment time points. The Fisher (or χ²) test
was also used to comparing qualitative data. Effects were con-
sidered statistically significant at *P* < .05.

Results

From a total of 140 young children screened, 90 were ex-
cluded: 13 had no CP diagnosis and 15 did not have UCP, 18 were
older than 59 months, 16 had associated problems that could
interfere with assessments/intervention, and 1 had a sched-
uled botulinum toxin injection during the study period.
Twenty-seven children who fulfilled all the inclusion criteria
could not be peer matched. Among the 50 young children in-
cluded and randomized, 1 from the control group dropped-
out at TO due to COVID-19 restrictions. One child from each
group did not perform the last assessment session (eTable 1 in
*Supplement 1*).

The groups did not show imbalances at baseline in terms
of age, lesion type, affected side, GMFM-66 score, or sex
(Table 1). Only the Mini-MACS level showed a slight imbal-
ance between groups. Also, there was no between-group im-
balances in the number of minutes per week of usual rehabili-
tation, including physical therapy, occupational therapy,
and psychomotor therapy (Table 1).

Primary Outcome

Mini-MACS/AHA mean score differences (MD) between TO and T2 were significantly larger in the HABIT-ILE than the control group (MD, 5.19; 95% CI, 2.84-7.55; *P* < .001) (Table 2). Larger differences were also found in the HABIT-ILE group between TO and T1 but not between T1 and T2 (Figure 2 and Table 2). Subgroup analysis revealed greater improvements in children younger than 2 years old (Table 3) with no differences in the extent of the improvement between the different Mini-MACS levels (Table 3).

Secondary Outcomes

The results of the secondary outcomes have been presented
for exploratory purposes. GMFM-66 MDs between TO and T2
were larger for the HABIT-ILE than the control group (MD, 4.72;
95% CI, 2.66-6.78). This was also the case as between TO and
T1 but not between T1 and T2 (Figure 2 and Table 2).

MA2 MDs (more affected upper extremity) between
TO and T2 were larger for the HABIT-ILE than the control
group for movement range (MD, 14.12; 95% CI, 8.26-19.97),
dexterity (MD, 18.18; 95% CI, 12.21-24.16), and fluency
(MD, 8.77; 95% CI, 1.07-16.46) but not accuracy (MD, 4.03;
95% CI, -3.20 to 11.26) (Table 2). The less affected
upper extremity had MDs between TO and T2 and were
larger for the HABIT-ILE than the control group for move-
ment range (MD, 5.98; 95% CI, 1.45-10.50) and dexterity
(MD, 8.93; 95% CI, 4.37-13.49), but not for accuracy (MD,
3.57; 95% CI, -1.37 to 8.50) or fluency (MD, 2.78; 95% CI,
-3.28 to 8.84).

COPM MDs between TO and T2 were larger for the HABIT-
ILE than the control group for children's performance (MD,
3.62; 95% CI, 2.91-4.32) and parents' satisfaction level (MD,
3.53; 95% CI, 2.70-4.36) (Figure 2 and Table 2). Scaled
PEDI-CAT MDs were larger for the HABIT-ILE than the con-
trol group only for the daily activity domain between TO and
T2 (MD, 1.40; 95% CI, 0.29-2.51) (Table 2).
count for the specificity of children younger than 5 years, we
modified the original HABIT-ILE protocol.¹⁹ Daily sessions con-
sisted of 5 hours of HABIT-ILE per day with 3 hours in the
morning, 2.5 hours off (nap/rest time), and 2 hours in the af-
ternoon, for a total of 50 hours. Briefly, therapy activities are
chosen according to the child's baseline upper extremity and
lower extremity capacities and postural control. The activi-
ties are progressed by varying the environmental con-
straints, moving to more challenging activities as perfor-
mance improves.

Control Group: Spontaneous, Unstructured Motor Activity

Young children allocated to the active control group contin-
ued with their usual daily life activities, consisting mainly
of spontaneous unstructured motor activity (at home or
daycare). The estimated usual motor activity time of chil-
dren 1 to 4 years old is around 5 hours per day.³⁴,³⁵ To ensure
that this theoretical amount of hours reported for this
age group in the literature matched the actual amount of
activity performed by the children in our sample (time
spent in movement),³⁶,³⁷ we measured the daily amount of
activity using inertial sensors in both groups between TO
and T1. The children in the control group performed their
usual therapies during this time, including physical, occu-
pational, and psychomotor therapy (mean total, 2 hours
per week).

Sample Size

As reported in the study protocol,³⁸ we calculated the sample
size based on previous studies of children older than 5 years³⁹
and the pilot trial performed in children younger than 5 years.²⁰
Those studies showed an improvement minima of 6 AHA units
in the treatment group and of 2 AHA units in the control group
(effect size, 1.26).³⁹ The AHA improved by 10 (SD, 6.7) AHA units
at the third month of follow-up.²⁰ Consequently, a minimal im-
provement of 1 SD in the treatment group vs the control group
was expected, with an α of .05 and a 1-β of 0.9. Accordingly,
46 participants were required (23 per group) but we planned
to recruit 50 children in case of dropouts.

Statistics

The analyses were performed by an independent group of statisticians using SAS/STAT software, version 9.4 (SAS Institute). As planned in the study protocol,³⁸ between-group comparisons of the primary outcome were performed using analysis of covariance (ANCOVA) with adjustment for baseline measurements.⁴⁰ Additionally, the same analyses were performed with consideration of age (older than/younger than 2 years old, ie, up to 35 and from 36 months) and manual ability limitations (Mini-MACS level) to determine their impact on the therapy outcomes. ANCOVA was also performed on the secondary outcomes. If homoscedasticity and normality were not met, nonparametric analyses (Wilcoxon test) were performed. For exploratory purposes, the paired *t* test (or Wilcoxon) was performed within groups to compare outcomes between assessment time points. The Fisher (or χ²) test was also used to comparing qualitative data. Effects were considered statistically significant at *P* < .05.

Results

From a total of 140 young children screened, 90 were ex-
cluded: 13 had no CP diagnosis and 15 did not have UCP, 18 were
older than 59 months, 16 had associated problems that could
interfere with assessments/intervention, and 1 had a sched-
uled botulinum toxin injection during the study period.
Twenty-seven children who fulfilled all the inclusion criteria
could not be peer matched. Among the 50 young children in-
cluded and randomized, 1 from the control group dropped-
out at TO due to COVID-19 restrictions. One child from each
group did not perform the last assessment session (eTable 1 in
*Supplement 1*).

The groups did not show imbalances at baseline in terms
of age, lesion type, affected side, GMFM-66 score, or sex
(Table 1). Only the Mini-MACS level showed a slight imbal-
ance between groups. Also, there was no between-group im-
balances in the number of minutes per week of usual rehabili-
tation, including physical therapy, occupational therapy,
and psychomotor therapy (Table 1).

Primary Outcome

Mini-MACS/AHA mean score differences (MD) between TO and T2 were significantly larger in the HABIT-ILE than the control group (MD, 5.19; 95% CI, 2.84-7.55; *P* < .001) (Table 2). Larger differences were also found in the HABIT-ILE group between TO and T1 but not between T1 and T2 (Figure 2 and Table 2). Subgroup analysis revealed greater improvements in children younger than 2 years old (Table 3) with no differences in the extent of the improvement between the different Mini-MACS levels (Table 3).

Secondary Outcomes

The results of the secondary outcomes have been presented
for exploratory purposes. GMFM-66 MDs between TO and T2
were larger for the HABIT-ILE than the control group (MD, 4.72;
95% CI, 2.66-6.78). This was also the case as between TO and
T1 but not between T1 and T2 (Figure 2 and Table 2).

MA2 MDs (more affected upper extremity) between
TO and T2 were larger for the HABIT-ILE than the control
group for movement range (MD, 14.12; 95% CI, 8.26-19.97),
dexterity (MD, 18.18; 95% CI, 12.21-24.16), and fluency
(MD, 8.77; 95% CI, 1.07-16.46) but not accuracy (MD, 4.03;
95% CI, -3.20 to 11.26) (Table 2). The less affected
upper extremity had MDs between TO and T2 and were
larger for the HABIT-ILE than the control group for move-
ment range (MD, 5.98; 95% CI, 1.45-10.50) and dexterity
(MD, 8.93; 95% CI, 4.37-13.49), but not for accuracy (MD,
3.57; 95% CI, -1.37 to 8.50) or fluency (MD, 2.78; 95% CI,
-3.28 to 8.84).

COPM MDs between TO and T2 were larger for the HABIT-
ILE than the control group for children's performance (MD,
3.62; 95% CI, 2.91-4.32) and parents' satisfaction level (MD,
3.53; 95% CI, 2.70-4.36) (Figure 2 and Table 2). Scaled
PEDI-CAT MDs were larger for the HABIT-ILE than the con-
trol group only for the daily activity domain between TO and
T2 (MD, 1.40; 95% CI, 0.29-2.51) (Table 2).
The activity count did not differ between the HABIT-ILE (n = 22) and the control group (n = 16) for the less affected upper extremity (HABIT-ILE: mean, 43.4 [SD, 8.43] activity count per second; control: mean, 39.7 [SD, 5.15] activity count per second; P = .28). In contrast, mean activity count was higher for the more-affected upper extremity in the HABIT-ILE (mean, 27.7 [SD, 5.3] activity count per second) than the control group (mean, 23.2 [SD, 2.61] activity count per second; P = .002) (eTable 2 in Supplement 1).

Discussion

This multicenter RCT confirmed our hypothesis that 50 hours of early HABIT-ILE would improve bimanual performance more than usual unstructured motor activity in young children with UCP aged 1 and 4 years old. Moreover, improvements in the main outcome occurred in children who were younger than 2 years old. In addition, greater improvements in gross motor function, functional goals, and daily life activities occurred with HABIT-ILE than spontaneous unstructured motor activity.

The magnitude of change in bimanual performance measured by the AHA (5.17 AHA units) after 50 hours of therapy exceeded the smallest detectable difference (5.0 AHA units)⁴¹ and was similar to that observed in older children after 90 hours of HABIT-ILE (6 AHA units).³² Furthermore, the effect of the therapy was greater in the younger children than the older children included, although this needs to be confirmed by further studies. This large change in children younger than 2 years, despite the lower dose of HABIT-ILE than that provided to school-aged children (6 years old and older), suggests that this early intervention had a positive impact on neural structures, particularly the corticospinal tract, since intense structured activity has a large impact on the corticospinal tract during the early stages of development, as demonstrated in an animal model.⁴² The smaller effect in the older children in the present study suggests that more than 50 hours of intervention are required for children older than 2 years to achieve a clinically meaningful change. Such a change occurred in school-aged children who underwent 90 hours of HABIT-ILE. The secondary analyses of the AHA regarding the manual ability limitations through the Mini-MACS showed a larger improvement in children with greater limitations. These results are in line with reports indicating that children with greater limitations have lower AHA scores and their performance stabilizes at an older age.⁴³,⁴⁴ Therefore, the window of opportunity for progression of performance may be wider in this group.

Between-group differences were also found in gross motor function and unimanual performance. Previous studies in young children with UCP mainly focused on the more affected upper extremity.⁴⁵,⁴⁶ The results for unimanual performance and gross motor function in the present study suggest that the less affected hand and the lower extremities/trunk can be successfully trained concomitantly to the more affected upper extremity in these young children, with no loss of effectiveness on the more affected upper extremity. This is supported by a previous report⁴⁷ of intensive interventions in school-aged children with UCP that found that the addition of

<table><caption>Table 1. Baseline Participant Characteristics</caption><thead><tr><th>Characteristic</th><th>Control group (n = 24)</th><th>HABIT-ILE group (n = 25)</th></tr></thead><tbody><tr><td>Sex, No. (%)</td><td></td><td></td></tr><tr><td>Male</td><td>9 (38)</td><td>14 (56)</td></tr><tr><td>Female</td><td>15 (63)</td><td>11 (44)</td></tr><tr><td>Age, mo</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>33.16 (12.16)</td><td>35.51 (11.99)</td></tr><tr><td>Median (Q1-Q3)</td><td>32.8 (25.4-44.3)</td><td>35.3 (24.7-45.5)</td></tr><tr><td>Range</td><td>14-52</td><td>16-54</td></tr><tr><td>Lesion type, No. (%)</td><td></td><td></td></tr><tr><td>Premature</td><td>2 (8)</td><td>4 (16)</td></tr><tr><td>Perinatal asphyxia</td><td>1 (4)</td><td>1 (4)</td></tr><tr><td>Cerebrovascular accident</td><td>22 (92)</td><td>23 (92)</td></tr><tr><td>Other</td><td>2 (8)</td><td>3 (12)</td></tr><tr><td>Affected side, No. (%)</td><td></td><td></td></tr><tr><td>Right</td><td>19 (79)</td><td>20 (80)</td></tr><tr><td>Left</td><td>5 (21)</td><td>5 (20)</td></tr><tr><td>GMFM-66, No. (%)</td><td></td><td></td></tr><tr><td>I</td><td>16 (67)</td><td>17 (68)</td></tr><tr><td>II</td><td>5 (21)</td><td>5 (20)</td></tr><tr><td>III</td><td>2 (8)</td><td>1 (4)</td></tr><tr><td>IV</td><td>1 (4)</td><td>2 (8)</td></tr><tr><td>Mini-MACS, No. (%)</td><td></td><td></td></tr><tr><td>I</td><td>1 (4)</td><td>7 (28)</td></tr><tr><td>II</td><td>16 (67)</td><td>16 (64)</td></tr><tr><td>III</td><td>5 (21)</td><td>1 (4)</td></tr><tr><td>IV</td><td>1 (4)</td><td>1 (4)</td></tr><tr><td>V</td><td>1 (4)</td><td>0</td></tr><tr><td>Physiotherapy, min per wk</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>40.45 (11.84)</td><td>40.77 (9.25)</td></tr><tr><td>Median (IQR)</td><td>37.5 (30.0-45.0)</td><td>45.0 (30.0-45.0)</td></tr><tr><td>Range</td><td>30-60</td><td>30-60</td></tr><tr><td>Occupational therapy, min per wk</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>44.58 (8.91)</td><td>45.00 (9.49)</td></tr><tr><td>Median (IQR)</td><td>45.0 (45.0-45.0)</td><td>45.0 (45.0-45.0)</td></tr><tr><td>Range</td><td>30-65</td><td>30-60</td></tr><tr><td>Psychomotor therapy, min per wk</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>44.62 (13.76)</td><td>43.75 (8.66)</td></tr><tr><td>Median (IQR)</td><td>45.0 (40.0-60.0)</td><td>45.0 (42.5-45.0)</td></tr><tr><td>Range</td><td>15-60</td><td>30-60</td></tr></tbody></table>

Abbreviations: GMFM-66, Gross Motor Function Measure; HABIT-ILE, Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; min, minutes; Mini-MACS, Manual Ability.

the lower extremities/trunk component did not affect upper extremity performance. The larger activity count for the more affected upper extremity in the HABIT-ILE than the control group highlights the importance of intensity, in terms of amount of active movement, on performance. However, although the activity count for the less affected upper extremity did not differ between groups, the unimanual performance of this upper extremity also improved more in the HABIT-ILE group, suggesting that the structured motor activities also contribute to the effectiveness of this intervention.
The activity count did not differ between the HABIT-ILE (n = 22) and the control group (n = 16) for the less affected upper extremity (HABIT-ILE: mean, 43.4 [SD, 8.43] activity count per second; control: mean, 39.7 [SD, 5.15] activity count per second; P = .28). In contrast, mean activity count was higher for the more-affected upper extremity in the HABIT-ILE (mean, 27.7 [SD, 5.3] activity count per second) than the control group (mean, 23.2 [SD, 2.61] activity count per second; P = .002) (eTable 2 in Supplement 1).

Discussion

This multicenter RCT confirmed our hypothesis that 50 hours of early HABIT-ILE would improve bimanual performance more than usual unstructured motor activity in young children with UCP aged 1 and 4 years old. Moreover, improvements in the main outcome occurred in children who were younger than 2 years old. In addition, greater improvements in gross motor function, functional goals, and daily life activities occurred with HABIT-ILE than spontaneous unstructured motor activity.

The magnitude of change in bimanual performance measured by the AHA (5.17 AHA units) after 50 hours of therapy exceeded the smallest detectable difference (5.0 AHA units)⁴¹ and was similar to that observed in older children after 90 hours of HABIT-ILE (6 AHA units).³² Furthermore, the effect of the therapy was greater in the younger children than the older children included, although this needs to be confirmed by further studies. This large change in children younger than 2 years, despite the lower dose of HABIT-ILE than that provided to school-aged children (6 years old and older), suggests that this early intervention had a positive impact on neural structures, particularly the corticospinal tract, since intense structured activity has a large impact on the corticospinal tract during the early stages of development, as demonstrated in an animal model.⁴² The smaller effect in the older children in the present study suggests that more than 50 hours of intervention are required for children older than 2 years to achieve a clinically meaningful change. Such a change occurred in school-aged children who underwent 90 hours of HABIT-ILE. The secondary analyses of the AHA regarding the manual ability limitations through the Mini-MACS showed a larger improvement in children with greater limitations. These results are in line with reports indicating that children with greater limitations have lower AHA scores and their performance stabilizes at an older age.⁴³,⁴⁴ Therefore, the window of opportunity for progression of performance may be wider in this group.

Between-group differences were also found in gross motor function and unimanual performance. Previous studies in young children with UCP mainly focused on the more affected upper extremity.⁴⁵,⁴⁶ The results for unimanual performance and gross motor function in the present study suggest that the less affected hand and the lower extremities/trunk can be successfully trained concomitantly to the more affected upper extremity in these young children, with no loss of effectiveness on the more affected upper extremity. This is supported by a previous report⁴⁷ of intensive interventions in school-aged children with UCP that found that the addition of

<table><caption>Table 1. Baseline Participant Characteristics</caption><thead><tr><th>Characteristic</th><th>Control group (n = 24)</th><th>HABIT-ILE group (n = 25)</th></tr></thead><tbody><tr><td>Sex, No. (%)</td><td></td><td></td></tr><tr><td>Male</td><td>9 (38)</td><td>14 (56)</td></tr><tr><td>Female</td><td>15 (63)</td><td>11 (44)</td></tr><tr><td>Age, mo</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>33.16 (12.16)</td><td>35.51 (11.99)</td></tr><tr><td>Median (Q1-Q3)</td><td>32.8 (25.4-44.3)</td><td>35.3 (24.7-45.5)</td></tr><tr><td>Range</td><td>14-52</td><td>16-54</td></tr><tr><td>Lesion type, No. (%)</td><td></td><td></td></tr><tr><td>Premature</td><td>2 (8)</td><td>4 (16)</td></tr><tr><td>Perinatal asphyxia</td><td>1 (4)</td><td>1 (4)</td></tr><tr><td>Cerebrovascular accident</td><td>22 (92)</td><td>23 (92)</td></tr><tr><td>Other</td><td>2 (8)</td><td>3 (12)</td></tr><tr><td>Affected side, No. (%)</td><td></td><td></td></tr><tr><td>Right</td><td>19 (79)</td><td>20 (80)</td></tr><tr><td>Left</td><td>5 (21)</td><td>5 (20)</td></tr><tr><td>GMFM-66, No. (%)</td><td></td><td></td></tr><tr><td>I</td><td>16 (67)</td><td>17 (68)</td></tr><tr><td>II</td><td>5 (21)</td><td>5 (20)</td></tr><tr><td>III</td><td>2 (8)</td><td>1 (4)</td></tr><tr><td>IV</td><td>1 (4)</td><td>2 (8)</td></tr><tr><td>Mini-MACS, No. (%)</td><td></td><td></td></tr><tr><td>I</td><td>1 (4)</td><td>7 (28)</td></tr><tr><td>II</td><td>16 (67)</td><td>16 (64)</td></tr><tr><td>III</td><td>5 (21)</td><td>1 (4)</td></tr><tr><td>IV</td><td>1 (4)</td><td>1 (4)</td></tr><tr><td>V</td><td>1 (4)</td><td>0</td></tr><tr><td>Physiotherapy, min per wk</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>40.45 (11.84)</td><td>40.77 (9.25)</td></tr><tr><td>Median (IQR)</td><td>37.5 (30.0-45.0)</td><td>45.0 (30.0-45.0)</td></tr><tr><td>Range</td><td>30-60</td><td>30-60</td></tr><tr><td>Occupational therapy, min per wk</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>44.58 (8.91)</td><td>45.00 (9.49)</td></tr><tr><td>Median (IQR)</td><td>45.0 (45.0-45.0)</td><td>45.0 (45.0-45.0)</td></tr><tr><td>Range</td><td>30-65</td><td>30-60</td></tr><tr><td>Psychomotor therapy, min per wk</td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>44.62 (13.76)</td><td>43.75 (8.66)</td></tr><tr><td>Median (IQR)</td><td>45.0 (40.0-60.0)</td><td>45.0 (42.5-45.0)</td></tr><tr><td>Range</td><td>15-60</td><td>30-60</td></tr></tbody></table>

Abbreviations: GMFM-66, Gross Motor Function Measure; HABIT-ILE, Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; min, minutes; Mini-MACS, Manual Ability.

the lower extremities/trunk component did not affect upper extremity performance. The larger activity count for the more affected upper extremity in the HABIT-ILE than the control group highlights the importance of intensity, in terms of amount of active movement, on performance. However, although the activity count for the less affected upper extremity did not differ between groups, the unimanual performance of this upper extremity also improved more in the HABIT-ILE group, suggesting that the structured motor activities also contribute to the effectiveness of this intervention.
<table><caption>Table 2. Motor Assessments, Goals, and Questionnaireª</caption><thead><tr><th rowspan="2">Outcome</th><th colspan="3">Mean difference (95% CI)</th></tr><tr><th>Control group<sup>b</sup></th><th>HABIT-ILE group<sup>c</sup></th><th>ANCOVA, adjusted difference HABIT-ILE (control group)<sup>c</sup></th></tr></thead><tbody><tr><td colspan="4"><strong>Primary outcome</strong></td></tr><tr><td>AHA ΔT2-T0, AHA units</td><td>0.39 (2.69)</td><td>5.17 (4.76)</td><td>5.19 (2.84-7.55)</td></tr><tr><td>AHA ΔT1-T0, AHA units</td><td>0.21 (3.40)</td><td>3.60 (4.30)</td><td>3.82 (1.55-6.10)</td></tr><tr><td>AHA ΔT2-T1, AHA units</td><td>0.09 (2.95)</td><td>1.58 (2.38)</td><td>1.45 (-0.20 to 3.10)</td></tr><tr><td colspan="4"><strong>Secondary outcomes</strong></td></tr><tr><td colspan="4"><strong>GMFM-66</strong></td></tr><tr><td>ΔT2-T0, logits, %</td><td>1.21 (3.84)</td><td>5.80 (3.26)</td><td>4.72 (2.66-6.78)</td></tr><tr><td>ΔT1-T0, logits, %</td><td>-0.09 (2.44)</td><td>2.84 (3.17)</td><td>3.01 (1.38-4.63)</td></tr><tr><td>ΔT2-T1, logits, %</td><td>1.18 (3.66)</td><td>2.97 (4.03)</td><td>1.75 (-0.58 to 4.07)</td></tr><tr><td colspan="4"><strong>MA2 score of more-affected hand</strong></td></tr><tr><td colspan="4"><strong>ROM</strong></td></tr><tr><td>ΔT2-T0, %</td><td>1.99 (6.50)</td><td>14.38 (13.29)</td><td>14.12 (8.26-19.97)</td></tr><tr><td>ΔT1-T0, %</td><td>-0.31 (16.53)</td><td>10.34 (15.70)</td><td>12.56 (3.56-21.56)</td></tr><tr><td>ΔT2-T1, %</td><td>2.47 (17.22)</td><td>3.77 (9.23)</td><td>0.75 (-7.55 to 9.05)</td></tr><tr><td colspan="4"><strong>Accuracy</strong></td></tr><tr><td>ΔT2-T0, %</td><td>8.61 (11.50)</td><td>10.43 (13.25)</td><td>4.03 (-3.20 to 11.26)</td></tr><tr><td>ΔT1-T0, %</td><td>5.25 (13.70)</td><td>6.47 (15.38)</td><td>4.05 (-4.05 to 12.15)</td></tr><tr><td>ΔT1-T2, %</td><td>3.65 (17.22)</td><td>3.86 (10.84)</td><td>-0.75 (-9.51 to 8.02)</td></tr><tr><td colspan="4"><strong>Dexterity</strong></td></tr><tr><td>ΔT2-T0, %</td><td>-0.74 (8.23)</td><td>15.85 (13.73)</td><td>18.18 (12.21-24.16)</td></tr><tr><td>ΔT1-T0, %</td><td>-0.80 (15.21)</td><td>10.21 (13.88)</td><td>12.61 (4.89-20.33)</td></tr><tr><td>ΔT2-T1, %</td><td>-0.36 (15.23)</td><td>5.98 (12.54)</td><td>6.16 (-2.20 to 14.51)</td></tr><tr><td colspan="4"><strong>Fluency</strong></td></tr><tr><td>ΔT2-T0, %</td><td>5.83 (14.85)</td><td>12.71 (12.70)</td><td>8.77 (1.07-16.46)</td></tr><tr><td>ΔT1-T0, %</td><td>0.78 (14.47)</td><td>9.82 (14.60)</td><td>10.63 (2.66-18.60)</td></tr><tr><td>ΔT2-T1, %</td><td>4.19 (18.21)</td><td>2.88 (12.47)</td><td>-1.13 (-10.52 to 8.26)</td></tr><tr><td colspan="4"><strong>MA2 score of less-affected hand</strong></td></tr><tr><td colspan="4"><strong>ROM</strong></td></tr><tr><td>ΔT2-T0, %</td><td>-0.64 (8.41)</td><td>9.11 (11.56)</td><td>5.98 (1.45-10.50)</td></tr><tr><td>ΔT1-T0, %</td><td>-4.79 (17.14)</td><td>7.86 (16.97)</td><td>6.92 (-1.20 to 15.04)</td></tr><tr><td>ΔT2-T1, %</td><td>4.35 (18.37)</td><td>1.23 (11.69)</td><td>-1.03 (-10.18 to 8.12)</td></tr><tr><td colspan="4"><strong>Accuracy</strong></td></tr><tr><td>ΔT2-T0, %</td><td>3.65 (10.78)</td><td>7.33 (17.64)</td><td>3.57 (-1.37 to 8.50)</td></tr><tr><td>ΔT1-T0, %</td><td>-2.00 (18.80)</td><td>4.96 (18.45)</td><td>6.83 (-1.25 to 14.91)</td></tr><tr><td>ΔT1-T2, %</td><td>5.74 (17.68)</td><td>2.17 (10.61)</td><td>-3.57 (-12.18 to 5.05)</td></tr><tr><td colspan="4"><strong>Dexterity</strong></td></tr><tr><td>ΔT2-T0, %</td><td>0.17 (8.91)</td><td>9.49 (8.33)</td><td>8.93 (4.37-13.49)</td></tr><tr><td>ΔT1-T0, %</td><td>0.82 (8.39)</td><td>4.21 (9.42)</td><td>3.01 (-1.67 to 7.69)</td></tr><tr><td>ΔT2-T1, %</td><td>-0.69 (11.48)</td><td>5.23 (6.96)</td><td>5.92 (0.30-11.55)</td></tr><tr><td colspan="4"><strong>Fluency</strong></td></tr><tr><td>ΔT2-T0, %</td><td>1.24 (17.18)</td><td>8.16 (11.61)</td><td>2.78 (-3.28 to 8.84)</td></tr><tr><td>ΔT1-T0, %</td><td>-2.98 (20.10)</td><td>6.88 (17.39)</td><td>5.36 (-3.24 to 13.97)</td></tr><tr><td>ΔT2-T1, %</td><td>4.35 (19.89)</td><td>0.99 (13.61)</td><td>-2.78 (-13.03 to 7.48)</td></tr><tr><td colspan="4"><strong>COPM of children's performance</strong></td></tr><tr><td>ΔT2-T0</td><td>1.22 (1.17)</td><td>4.82 (1.26)</td><td>3.62 (2.91-4.32)</td></tr><tr><td>ΔT1-T0</td><td>0.20 (0.57)</td><td>4.18 (1.67)</td><td>4.00 (3.27-4.73)</td></tr><tr><td>ΔT2-T1</td><td>1.03 (1.24)</td><td>0.65 (1.37)</td><td>-0.38 (-1.16 to 0.40)</td></tr><tr><td>ΔT2-T0</td><td>0.82 (1.47)</td><td>4.18 (1.84)</td><td>3.53 (2.70-4.36)</td></tr></tbody></table>

(continued)
<table><caption>Table 2. Motor Assessments, Goals, and Questionnaireª</caption><thead><tr><th rowspan="2">Outcome</th><th colspan="3">Mean difference (95% CI)</th></tr><tr><th>Control group<sup>b</sup></th><th>HABIT-ILE group<sup>c</sup></th><th>ANCOVA, adjusted difference HABIT-ILE (control group)<sup>c</sup></th></tr></thead><tbody><tr><td colspan="4"><strong>Primary outcome</strong></td></tr><tr><td>AHA ΔT2-T0, AHA units</td><td>0.39 (2.69)</td><td>5.17 (4.76)</td><td>5.19 (2.84-7.55)</td></tr><tr><td>AHA ΔT1-T0, AHA units</td><td>0.21 (3.40)</td><td>3.60 (4.30)</td><td>3.82 (1.55-6.10)</td></tr><tr><td>AHA ΔT2-T1, AHA units</td><td>0.09 (2.95)</td><td>1.58 (2.38)</td><td>1.45 (-0.20 to 3.10)</td></tr><tr><td colspan="4"><strong>Secondary outcomes</strong></td></tr><tr><td colspan="4"><strong>GMFM-66</strong></td></tr><tr><td>ΔT2-T0, logits, %</td><td>1.21 (3.84)</td><td>5.80 (3.26)</td><td>4.72 (2.66-6.78)</td></tr><tr><td>ΔT1-T0, logits, %</td><td>-0.09 (2.44)</td><td>2.84 (3.17)</td><td>3.01 (1.38-4.63)</td></tr><tr><td>ΔT2-T1, logits, %</td><td>1.18 (3.66)</td><td>2.97 (4.03)</td><td>1.75 (-0.58 to 4.07)</td></tr><tr><td colspan="4"><strong>MA2 score of more-affected hand</strong></td></tr><tr><td colspan="4"><strong>ROM</strong></td></tr><tr><td>ΔT2-T0, %</td><td>1.99 (6.50)</td><td>14.38 (13.29)</td><td>14.12 (8.26-19.97)</td></tr><tr><td>ΔT1-T0, %</td><td>-0.31 (16.53)</td><td>10.34 (15.70)</td><td>12.56 (3.56-21.56)</td></tr><tr><td>ΔT2-T1, %</td><td>2.47 (17.22)</td><td>3.77 (9.23)</td><td>0.75 (-7.55 to 9.05)</td></tr><tr><td colspan="4"><strong>Accuracy</strong></td></tr><tr><td>ΔT2-T0, %</td><td>8.61 (11.50)</td><td>10.43 (13.25)</td><td>4.03 (-3.20 to 11.26)</td></tr><tr><td>ΔT1-T0, %</td><td>5.25 (13.70)</td><td>6.47 (15.38)</td><td>4.05 (-4.05 to 12.15)</td></tr><tr><td>ΔT1-T2, %</td><td>3.65 (17.22)</td><td>3.86 (10.84)</td><td>-0.75 (-9.51 to 8.02)</td></tr><tr><td colspan="4"><strong>Dexterity</strong></td></tr><tr><td>ΔT2-T0, %</td><td>-0.74 (8.23)</td><td>15.85 (13.73)</td><td>18.18 (12.21-24.16)</td></tr><tr><td>ΔT1-T0, %</td><td>-0.80 (15.21)</td><td>10.21 (13.88)</td><td>12.61 (4.89-20.33)</td></tr><tr><td>ΔT2-T1, %</td><td>-0.36 (15.23)</td><td>5.98 (12.54)</td><td>6.16 (-2.20 to 14.51)</td></tr><tr><td colspan="4"><strong>Fluency</strong></td></tr><tr><td>ΔT2-T0, %</td><td>5.83 (14.85)</td><td>12.71 (12.70)</td><td>8.77 (1.07-16.46)</td></tr><tr><td>ΔT1-T0, %</td><td>0.78 (14.47)</td><td>9.82 (14.60)</td><td>10.63 (2.66-18.60)</td></tr><tr><td>ΔT2-T1, %</td><td>4.19 (18.21)</td><td>2.88 (12.47)</td><td>-1.13 (-10.52 to 8.26)</td></tr><tr><td colspan="4"><strong>MA2 score of less-affected hand</strong></td></tr><tr><td colspan="4"><strong>ROM</strong></td></tr><tr><td>ΔT2-T0, %</td><td>-0.64 (8.41)</td><td>9.11 (11.56)</td><td>5.98 (1.45-10.50)</td></tr><tr><td>ΔT1-T0, %</td><td>-4.79 (17.14)</td><td>7.86 (16.97)</td><td>6.92 (-1.20 to 15.04)</td></tr><tr><td>ΔT2-T1, %</td><td>4.35 (18.37)</td><td>1.23 (11.69)</td><td>-1.03 (-10.18 to 8.12)</td></tr><tr><td colspan="4"><strong>Accuracy</strong></td></tr><tr><td>ΔT2-T0, %</td><td>3.65 (10.78)</td><td>7.33 (17.64)</td><td>3.57 (-1.37 to 8.50)</td></tr><tr><td>ΔT1-T0, %</td><td>-2.00 (18.80)</td><td>4.96 (18.45)</td><td>6.83 (-1.25 to 14.91)</td></tr><tr><td>ΔT1-T2, %</td><td>5.74 (17.68)</td><td>2.17 (10.61)</td><td>-3.57 (-12.18 to 5.05)</td></tr><tr><td colspan="4"><strong>Dexterity</strong></td></tr><tr><td>ΔT2-T0, %</td><td>0.17 (8.91)</td><td>9.49 (8.33)</td><td>8.93 (4.37-13.49)</td></tr><tr><td>ΔT1-T0, %</td><td>0.82 (8.39)</td><td>4.21 (9.42)</td><td>3.01 (-1.67 to 7.69)</td></tr><tr><td>ΔT2-T1, %</td><td>-0.69 (11.48)</td><td>5.23 (6.96)</td><td>5.92 (0.30-11.55)</td></tr><tr><td colspan="4"><strong>Fluency</strong></td></tr><tr><td>ΔT2-T0, %</td><td>1.24 (17.18)</td><td>8.16 (11.61)</td><td>2.78 (-3.28 to 8.84)</td></tr><tr><td>ΔT1-T0, %</td><td>-2.98 (20.10)</td><td>6.88 (17.39)</td><td>5.36 (-3.24 to 13.97)</td></tr><tr><td>ΔT2-T1, %</td><td>4.35 (19.89)</td><td>0.99 (13.61)</td><td>-2.78 (-13.03 to 7.48)</td></tr><tr><td colspan="4"><strong>COPM of children's performance</strong></td></tr><tr><td>ΔT2-T0</td><td>1.22 (1.17)</td><td>4.82 (1.26)</td><td>3.62 (2.91-4.32)</td></tr><tr><td>ΔT1-T0</td><td>0.20 (0.57)</td><td>4.18 (1.67)</td><td>4.00 (3.27-4.73)</td></tr><tr><td>ΔT2-T1</td><td>1.03 (1.24)</td><td>0.65 (1.37)</td><td>-0.38 (-1.16 to 0.40)</td></tr><tr><td>ΔT2-T0</td><td>0.82 (1.47)</td><td>4.18 (1.84)</td><td>3.53 (2.70-4.36)</td></tr></tbody></table>

(continued)
<table><caption>Table 2. Motor Assessments, Goals, and Questionnaireª (continued)</caption><thead><tr><th rowspan="2">Outcome</th><th colspan="3">Mean difference (95% CI)</th></tr><tr><th>Control group<sup>b</sup></th><th>HABIT-ILE group<sup>c</sup></th><th>ANCOVA, adjusted difference HABIT-ILE (control group)<sup>c</sup></th></tr></thead><tbody><tr><td><strong>COPM parent's satisfaction</strong></td><td></td><td></td><td></td></tr><tr><td>ΔT1-T0</td><td>0.07 (1.03)</td><td>3.86 (2.31)</td><td>3.97 (3.10-4.84)</td></tr><tr><td>ΔT2-T1</td><td>0.81 (1.19)</td><td>0.34 (1.69)</td><td>-0.49 (-1.36 to 0.39)</td></tr><tr><td><strong>PEDI-CAT: daily activity</strong></td><td></td><td></td><td></td></tr><tr><td>ΔT2-T0, scaled score</td><td>0.83 (1.97)</td><td>1.96 (2.08)</td><td>1.40 (0.29-2.51)</td></tr><tr><td>ΔT1-T0, scaled score</td><td>-0.13 (1.60)</td><td>1.63 (2.22)</td><td>1.90 (0.79-3.02)</td></tr><tr><td>ΔT2-T1, scaled score</td><td>0.91 (1.98)</td><td>0.13 (2.17)</td><td>-0.52 (-1.73 to 0.70)</td></tr><tr><td><strong>PEDI-CAT: mobility</strong></td><td></td><td></td><td></td></tr><tr><td>ΔT2-T0, scaled score</td><td>0.65 (1.58)</td><td>1.39 (2.59)</td><td>0.86 (-0.33 to 2.04)</td></tr><tr><td>ΔT1-T0, scaled score</td><td>-0.13 (1.73)</td><td>0.54 (1.86)</td><td>0.70 (-0.35 to 1.75)</td></tr><tr><td>ΔT2-T1, scaled score</td><td>0.70 (1.87)</td><td>0.88 (2.92)</td><td>0.30 (-1.16 to 1.76)</td></tr></tbody></table>

Abbreviations: AHA, Assisting Hand Assessment; GMFM-66, Gross Motor Function Measure; HABIT-ILE, Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; MA2, Melbourne Assessment 2; ROM, range of motion; COPM, Canadian Occupational Performance Measure; PEDI-CAT, Pediatric Evaluation of Disability; TO, first testing session (baseline); T1, second testing session; T2, 3 months after TO.

ª Inventory-Computer Adaptive Test; Δ, score difference between assessment times.

ᵇP = .49.

ᶜP < .001.

<figure><img src="image_5.png" /><figcaption>Figure 2. Changes in Motor and Functional Goals After Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) Training</figcaption></figure>

Blue dots indicate the mean of the treatment group (HABIT-ILE); orange dots indicate mean of the control group. For all dots, the whiskers represent the standard error. AHA indicates Assisting Hand Assessment; COPM, Canadian Occupational Performance Measure; GMFM, Gross Motor Function Measure; TO, first testing session (baseline); T1, second testing session 2 weeks after TO; T2, third testing session 3 months after TO.

This is in agreement with a previous longitudinal study showing the influence of therapy content on improvement in children with CP.⁴⁸

In addition, most improvements in motor outcomes at the end of the HABIT-ILE were maintained at the
<table><caption>Table 2. Motor Assessments, Goals, and Questionnaireª (continued)</caption><thead><tr><th rowspan="2">Outcome</th><th colspan="3">Mean difference (95% CI)</th></tr><tr><th>Control group<sup>b</sup></th><th>HABIT-ILE group<sup>c</sup></th><th>ANCOVA, adjusted difference HABIT-ILE (control group)<sup>c</sup></th></tr></thead><tbody><tr><td colspan="4">COPM parent's satisfaction</td></tr><tr><td>ΔT1-T0</td><td>0.07 (1.03)</td><td>3.86 (2.31)</td><td>3.97 (3.10-4.84)</td></tr><tr><td>ΔT2-T1</td><td>0.81 (1.19)</td><td>0.34 (1.69)</td><td>-0.49 (-1.36 to 0.39)</td></tr><tr><td colspan="4">PEDI-CAT: daily activity</td></tr><tr><td>ΔT2-T0, scaled score</td><td>0.83 (1.97)</td><td>1.96 (2.08)</td><td>1.40 (0.29-2.51)</td></tr><tr><td>ΔT1-T0, scaled score</td><td>-0.13 (1.60)</td><td>1.63 (2.22)</td><td>1.90 (0.79-3.02)</td></tr><tr><td>ΔT2-T1, scaled score</td><td>0.91 (1.98)</td><td>0.13 (2.17)</td><td>-0.52 (-1.73 to 0.70)</td></tr><tr><td colspan="4">PEDI-CAT: mobility</td></tr><tr><td>ΔT2-T0, scaled score</td><td>0.65 (1.58)</td><td>1.39 (2.59)</td><td>0.86 (-0.33 to 2.04)</td></tr><tr><td>ΔT1-T0, scaled score</td><td>-0.13 (1.73)</td><td>0.54 (1.86)</td><td>0.70 (-0.35 to 1.75)</td></tr><tr><td>ΔT2-T1, scaled score</td><td>0.70 (1.87)</td><td>0.88 (2.92)</td><td>0.30 (-1.16 to 1.76)</td></tr></tbody></table>

Abbreviations: AHA, Assisting Hand Assessment; GMFM-66, Gross Motor Function Measure; HABIT-ILE, Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; MA2, Melbourne Assessment 2; ROM, range of motion; COPM, Canadian Occupational Performance Measure; PEDI-CAT, Pediatric Evaluation of Disability; TO, first testing session (baseline); T1, second testing session; T2, 3 months after TO.

ª Inventory-Computer Adaptive Test; Δ, score difference between assessment times.

ᵇ P = .49.

ᶜ P < .001.

<figure><img src="image_4.png" /><figcaption>Figure 2. Changes in Motor and Functional Goals After Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) Training</figcaption></figure>

Blue dots indicate the mean of the treatment group (HABIT-ILE); orange dots indicate mean of the control group. For all dots, the whiskers represent the standard error. AHA indicates Assisting Hand Assessment; COPM, Canadian Occupational Performance Measure; GMFM, Gross Motor Function Measure; TO, first testing session (baseline); T1, second testing session 2 weeks after TO; T2, third testing session 3 months after TO.

This is in agreement with a previous longitudinal study showing the influence of therapy content on improvement in children with CP.⁴⁸

In addition, most improvements in motor outcomes at the end of the HABIT-ILE were maintained at the
<table><caption>Table 3. Changes in Assisting Hand Assessment as a Function of Age Group and Manual Ability Levelª</caption><thead><tr><th rowspan="2">Subgroup analyzed</th><th colspan="2">Mean difference (SD)</th><th colspan="3">ANCOVA, adjusted difference HABIT-ILE (control group)</th><th rowspan="2">Heterogeneity test, P value</th></tr><tr><th>Control group</th><th>HABIT-ILE group</th><th>Mean difference (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>AHA ΔT2-T0, AHA unit</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Younger than 36 mo</td><td>-0.23 (2.80)</td><td>6.38 (5.91)</td><td>7.46 (4.33-10.59)</td><td>&lt;.001</td><td rowspan="2">.04</td></tr><tr><td>Older than 36 mo</td><td>1.20 (2.44)</td><td>3.73 (2.45)</td><td>2.65 (-0.65 to 5.96)</td><td>.11</td></tr><tr><td>Mini-MACS</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Level I, AHA ΔT2-T0, AHA unit</td><td>2.00 (0.00)</td><td>4.29 (2.29)</td><td>2.34 (-6.16 to 10.85)</td><td>.58</td><td rowspan="3">.25</td></tr><tr><td>Level II, AHA ΔT2-T0, AHA unit</td><td>0.07 (3.15)</td><td>4.80 (5.43)</td><td>4.74 (1.88-7.60)</td><td>.002</td></tr><tr><td>Levels III-V, AHA ΔT2-T0, AHA unit</td><td>0.86 (1.57)</td><td>11.00 (1.41)</td><td>10.10 (3.70-16.49)</td><td>.003</td></tr></tbody></table>

Abbreviations: AHA, Assisting Hand Assessment; ANCOVA, analysis of covariance; HABIT-ILE, Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; Mini-MACS, Manual Ability Classification System for children with cerebral palsy aged 1 to 4; TO, first testing session (baseline); T2, 3 months after TO.

ª Classification system for children 1 to 4 years; level I includes children with minor manipulative limitations, if any; level V includes children with severe manipulative disabilities; Δ, score difference between assessment times.

3-month follow-up (Tables 2, Figure 2), similarly to previous studies of this intervention in school-aged children.³²,⁴⁹ This finding suggests that participation in an intensive intervention at such a young age opens a window of opportunity to promote new motor improvements in the ensuing weeks and months, probably through the improvement in motor performance and motor learning abilities acquired during the therapy, as well as the motivation to learn new skills.

The changes in the PEDI-CAT and the COPM scores could indicate that HABIT-ILE positively impacted on the child's daily life activities and the mastering of functional goals. The magnitude of the change in both outcomes was similar to previous studies in school-aged children with UCP after HABIT-ILE.⁴⁹ In addition, the improvements found in the present study were greater than those found in studies involving only upper extremities training in young children with UCP.⁴⁶ This highlights the importance of including gross motor function training in intensive interventions at this age to improve the performance of daily life activities, despite the sometimes lengthy time required to lead the parents and children through the goal definition process.

The functional changes observed in this study most probably result from neuroplastic changes induced by HABIT-ILE.¹²,¹³ These neuroplastic changes are probably relevant in children with CP because the persistent inflammation provoked by the early lesion⁵⁰ alters a number of processes in the gray and white matter.⁵¹⁻⁵³ Several features of the intervention likely potentiate neuroplastic changes, such as the motivating, child-friendly, enriched environment designed to promote motor experiences. In animal models, this type of stimulation improves cognitive, motor, and social function and is associated with morphological brain changes.⁵⁴⁻⁵⁶ In addition, HABIT-ILE promotes the acquisition of new mo-

tor skills.¹²,¹³ Several animal model studies have found changes in white matter, notably in the corticospinal tract, associated with the effects of motor training, in particular when the difficulty of the task is progressively increased during the training.⁵⁷,⁵⁸ Therefore, intensive therapies may promote activity-dependent neuroplasticity, avoid maladaptive changes, and stimulate adaptative neuroreorganization.

## Limitations

Despite our efforts to control for confounding factors by using the strictest method available, some factors, such as the cognitive level of participants, may have impacted our results. The activity count data of both upper extremities could not be analyzed in all the children of each group; however, the results seem to reflect the overall behavior of the study group. Another limitation could be the lack of evidence relating to other interventions using similar protocols with which to compare our results. Lastly, the results of our secondary outcomes should be considered as exploratory because we did not perform adjustment for multiple comparisons.

## Conclusions

This multicenter RCT provides new evidence supporting the effectiveness of HABIT-ILE provided as an early intervention for young children with UCP, as compared with spontaneous, unstructured motor activity. As recommended recently,⁵⁹ the next step is to promote the integration of this type of early intervention into clinical guidelines. This would promote the use of therapies based on scientific evidence in the rehabilitation process of children with CP from a young age.

## ARTICLE INFORMATION

**Accepted for Publication:** September 10, 2023.

**Published Online:** November 6, 2023.
doi:10.1001/jamapediatrics.2023.4809

**Correction:** This article was corrected on December 18, 2023, to fix errors in the Abstract and an author name.

**Open Access:** This is an open access article distributed under the terms of the CC-BY License. © 2023 Araneda R et al. JAMA Pediatrics.

**Author Affiliations:** Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium (Araneda, Ebner-Karestinos, Saussez, Carton de Tournai, Herman, Bleyenheuft); Exercise and Rehabilitation Science Institute, Faculty of Rehabilitation Science, Universidad Andres Bello, Santiago, Chile (Araneda, Ebner-Karestinos); Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy (Paradis, Guzzetta); Haute Ecole Léonard de Vinci, Parnasse-ISEI, Brussels, Belgium (Klöcker); Forme

et Fonctionnement Humain Unit, Department of Motor Sciences, CeREF - Haute Ecole Louvain en Hainaut, Belgium (Saussez); Université d'Angers, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS) - EA7315 F-49000 France (Demas, Dinomais); Instituts de formation du Centre Hospitalier de Laval, Laval, France (Demas); INSERM UMR 1101, LaTIM, Brest, France (Bailly, Brochard); Pediatric Rehabilitation Department, Fondation Ildys, Brest, France (Bailly, Bouvier, Brochard); Western Brittany University, Brest,
<table><caption>Table 3. Changes in Assisting Hand Assessment as a Function of Age Group and Manual Ability Levelª</caption><thead><tr><th rowspan="2">Subgroup analyzed</th><th colspan="2">Mean difference (SD)</th><th colspan="3">ANCOVA, adjusted difference HABIT-ILE (control group)</th></tr><tr><th>Control group</th><th>HABIT-ILE group</th><th>Mean difference (95% CI)</th><th>P value</th><th>Heterogeneity test, P value</th></tr></thead><tbody><tr><td>AHA ΔT2-T0, AHA unit</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Younger than 36 mo</td><td>-0.23 (2.80)</td><td>6.38 (5.91)</td><td>7.46 (4.33-10.59)</td><td>&lt;.001</td><td rowspan="2">.04</td></tr><tr><td>Older than 36 mo</td><td>1.20 (2.44)</td><td>3.73 (2.45)</td><td>2.65 (-0.65 to 5.96)</td><td>.11</td></tr><tr><td>Mini-MACS</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Level I, AHA ΔT2-T0, AHA unit</td><td>2.00 (0.00)</td><td>4.29 (2.29)</td><td>2.34 (-6.16 to 10.85)</td><td>.58</td><td rowspan="3">.25</td></tr><tr><td>Level II, AHA ΔT2-T0, AHA unit</td><td>0.07 (3.15)</td><td>4.80 (5.43)</td><td>4.74 (1.88-7.60)</td><td>.002</td></tr><tr><td>Levels III-V, AHA ΔT2-T0, AHA unit</td><td>0.86 (1.57)</td><td>11.00 (1.41)</td><td>10.10 (3.70-16.49)</td><td>.003</td></tr></tbody></table>

Abbreviations: AHA, Assisting Hand Assessment; ANCOVA, analysis of covariance; HABIT-ILE, Hand-Arm Bimanual Intensive Therapy Including Lower Extremities; Mini-MACS, Manual Ability Classification System for children with cerebral palsy aged 1 to 4; TO, first testing session (baseline); T2, 3 months after TO.

ª Classification system for children 1 to 4 years; level I includes children with minor manipulative limitations, if any; level V includes children with severe manipulative disabilities; Δ, score difference between assessment times.

3-month follow-up (Tables 2, Figure 2), similarly to previous studies of this intervention in school-aged children.³²,⁴⁹ This finding suggests that participation in an intensive intervention at such a young age opens a window of opportunity to promote new motor improvements in the ensuing weeks and months, probably through the improvement in motor performance and motor learning abilities acquired during the therapy, as well as the motivation to learn new skills.

The changes in the PEDI-CAT and the COPM scores could indicate that HABIT-ILE positively impacted on the child's daily life activities and the mastering of functional goals. The magnitude of the change in both outcomes was similar to previous studies in school-aged children with UCP after HABIT-ILE.⁴⁹ In addition, the improvements found in the present study were greater than those found in studies involving only upper extremities training in young children with UCP.⁴⁶ This highlights the importance of including gross motor function training in intensive interventions at this age to improve the performance of daily life activities, despite the sometimes lengthy time required to lead the parents and children through the goal definition process.

The functional changes observed in this study most probably result from neuroplastic changes induced by HABIT-ILE.¹²,¹³ These neuroplastic changes are probably relevant in children with CP because the persistent inflammation provoked by the early lesion⁵⁰ alters a number of processes in the gray and white matter.⁵¹⁻⁵³ Several features of the intervention likely potentiate neuroplastic changes, such as the motivating, child-friendly, enriched environment designed to promote motor experiences. In animal models, this type of stimulation improves cognitive, motor, and social function and is associated with morphological brain changes.⁵⁴⁻⁵⁶ In addition, HABIT-ILE promotes the acquisition of new mo-

tor skills.¹²,¹³ Several animal model studies have found changes in white matter, notably in the corticospinal tract, associated with the effects of motor training, in particular when the difficulty of the task is progressively increased during the training.⁵⁷,⁵⁸ Therefore, intensive therapies may promote activity-dependent neuroplasticity, avoid maladaptive changes, and stimulate adaptative neuroreorganization.

## Limitations

Despite our efforts to control for confounding factors by using the strictest method available, some factors, such as the cognitive level of participants, may have impacted our results. The activity count data of both upper extremities could not be analyzed in all the children of each group; however, the results seem to reflect the overall behavior of the study group. Another limitation could be the lack of evidence relating to other interventions using similar protocols with which to compare our results. Lastly, the results of our secondary outcomes should be considered as exploratory because we did not perform adjustment for multiple comparisons.

## Conclusions

This multicenter RCT provides new evidence supporting the effectiveness of HABIT-ILE provided as an early intervention for young children with UCP, as compared with spontaneous, unstructured motor activity. As recommended recently,⁵⁹ the next step is to promote the integration of this type of early intervention into clinical guidelines. This would promote the use of therapies based on scientific evidence in the rehabilitation process of children with CP from a young age.

## ARTICLE INFORMATION

**Accepted for Publication:** September 10, 2023.

**Published Online:** November 6, 2023.
doi:10.1001/jamapediatrics.2023.4809

**Correction:** This article was corrected on December 18, 2023, to fix errors in the Abstract and an author name.

**Open Access:** This is an open access article distributed under the terms of the CC-BY License. © 2023 Araneda R et al. JAMA Pediatrics.

**Author Affiliations:** Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium (Araneda, Ebner-Karestinos, Saussez, Carton de Tournai, Herman, Bleyenheuft); Exercise and Rehabilitation Science Institute, Faculty of Rehabilitation Science, Universidad Andres Bello, Santiago, Chile (Araneda, Ebner-Karestinos); Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy (Paradis, Guzzetta); Haute Ecole Léonard de Vinci, Parnasse-ISEI, Brussels, Belgium (Klöcker); Forme

et Fonctionnement Humain Unit, Department of Motor Sciences, CeREF - Haute Ecole Louvain en Hainaut, Belgium (Saussez); Université d'Angers, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS) - EA7315 F-49000 France (Demas, Dinomais); Instituts de formation du Centre Hospitalier de Laval, Laval, France (Demas); INSERM UMR 1101, LaTIM, Brest, France (Bailly, Brochard); Pediatric Rehabilitation Department, Fondation Ildys, Brest, France (Bailly, Bouvier, Brochard); Western Brittany University, Brest,
France (Bouvier, Brochard); University Hospital of Brest, Brest, France (Souki, Le Gal, Nowak, Brochard); INSERM CIC 1412, Brest, France (Le Gal, Nowak); Division of Child Development and Growth, Department of Pediatrics, University of Geneva, Geneva, Switzerland (Sizonenko); Paediatric Neurology and Neurorehabilitation Unit, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland (Newman); CHU Angers, Département de Médecine Physique et de Réadaptations, CHU Angers-Capucins, F-49933, France (Dinomais); Department of Nursing and Physiotherapy and Research Institute on Health Sciences (UINICS-Idisba), University of the Balearic Islands, Palma de Mallorca, Spain (Riquelme); Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (Guzzetta).

**Author Contributions:** Drs Brochard and Bleyenheuft had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
**Concept and design:** Araneda, Nowak, Sizonenko, Newman, Dinomais, Riquelme, Guzzetta, Brochard, Bleyenheuft.

**Acquisition, analysis, or interpretation of data:** Araneda, Ebner-Karestinos, Paradis, Klöcker, Saussez, Demas, Bailly, Bouvier, Carton de Tournai, Herman, Souki, Le Gal, Dinomais, Guzzetta, Brochard, Bleyenheuft.

**Drafting of the manuscript:** Araneda, Ebner-Karestinos, Souki, Dinomais, Brochard, Bleyenheuft.

**Critical review of the manuscript for important intellectual content:** Araneda, Ebner-Karestinos, Paradis, Klöcker, Saussez, Demas, Bailly, Bouvier, Carton de Tournai, Herman, Le Gal, Nowak, Sizonenko, Newman, Dinomais, Riquelme, Guzzetta, Brochard, Bleyenheuft.

**Statistical analysis:** Souki, Le Gal, Nowak, Brochard. Obtained funding: Bailly, Sizonenko, Newman, Dinomais, Brochard, Bleyenheuft.

**Administrative, technical, or material support:** Araneda, Ebner-Karestinos, Paradis, Saussez, Demas, Bailly, Bouvier, Carton de Tournai, Herman, Newman, Dinomais, Bleyenheuft.

**Supervision:** Araneda, Ebner-Karestinos, Paradis, Demas, Bailly, Newman, Guzzetta, Brochard, Bleyenheuft.

**Conflict of Interest Disclosures:** Dr Araneda reported grants from the Fondation Paralysie Cerebrale. Dr Paradis reported grants from the Marguerite-Marie Delacroix Foundation during the conduct of the study. Dr Saussez reported grants from the Fund for Scientific Research-Fund for Research Training in Industry and Agriculture during the conduct of the study. Dr Le Gal reported grants from Pfizer and Myers Squibb and personal fees from Pfizer, Sanofi, and Aspen Pharmacies outside the submitted work. Dr Nowak reported grants from the Fondation de France paid to their organization during the conduct of the study. Dr Sizonenko reported grants from the Fondation Paralysie Cérébrale during the conduct of the study. Dr Dinomais reported grants from La Fondation Paralysie Cérébrale during the conduct of the study. Dr Guzzetta reported grants from the Fondation Paralysie Cerebral HABIT-ILE and the Italian Ministry of Health RC Linea 1 during the conduct of the study and grants from Horizon outside the submitted work. Dr Brochard reported grants from La fondation Paralysie Cérébrale during the conduct of the study. Dr Bleyenheuft reported grants from the Fondation Paralysie Cérébrale for this research

project allocated after selection by a scientific committee during the conduct of the study, grants from the Fondation JED Belgique, Biowin, and Actions de Recherches Concertées/Université catholique de Louvainbrain outside the submitted work. No other disclosures were reported.

**Data Sharing Statement:** See Supplement 3.

REFERENCES

1. Straub K, Okrzut JE. Effects of cerebral palsy on neuropsychological function. *J Dev Phys Disabil.* 2009;21(2):153-167. doi:10.1007/s10882-009-9130-3

2. Graham HK, Rosenbaum P, Paneth N, et al. Cerebral palsy. *Nat Rev Dis Primers.* 2016;2:15082. doi:10.1038/nrdp.2015.82

3. Krägeloh-Mann I, Cans C. Cerebral palsy update. *Brain Dev.* 2009;31(7):537-544. doi:10.1016/j.braindev.2009.03.009

4. Stiles J, Jernigan TL. The basics of brain development. *Neuropsychol Rev.* 2010;20(4): 327-348. doi:10.1007/s11065-010-9148-4

5. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human central nervous system: what is happening when? *Early Hum Dev.* 2006;82(4): 257-266. doi:10.1016/j.earlhumdev.2005.10.013

6. Bekteshi S, Monbaliu E, McIntyre S, et al. Towards functional improvement of motor disorders associated with cerebral palsy. *Lancet Neurol.* 2023;22(3):229-243. doi:10.1016/S1474-4422 (23)00004-2

7. Chabrier S, Pouyfaucon M, Chatelin A, et al. From congenital paralysis to post-early brain injury developmental condition: where does cerebral palsy actually stand? *Ann Phys Rehabil Med.* 2020; 63(5):431-438. doi:10.1016/j.rehab.2019.07.003

8. Arnould C, Bleyenheuft Y, Thonnard JL. Hand functioning in children with cerebral palsy. *Front Neurol.* 2014;5:48. doi:10.3389/fneur.2014.00048

9. Reid LB, Rose SE, Boyd RN. Rehabilitation and neuroplasticity in children with unilateral cerebral palsy. *Nat Rev Neurol.* 2015;11(7):390-400. doi:10.1038/nrneurol.2015.97

10. Novak I, McIntyre S, Morgan C, et al. A systematic review of interventions for children with cerebral palsy: state of the evidence. *Dev Med Child Neurol.* 2013;55(10):885-910. doi:10.1111/dmcn.12246

11. Sakzewski L, Ziviani J, Boyd RN. Efficacy of upper limb therapies for unilateral cerebral palsy: a meta-analysis. *Pediatrics.* 2014;133(1):e175-e204. doi:10.1542/peds.2013-0675

12. Araneda R, Dricot L, Ebner-Karestinos D, et al. Brain activation changes following motor training in children with unilateral cerebral palsy: an fMRI study. *Ann Phys Rehabil Med.* 2021;64(3):101502. doi:10.1016/j.rehab.2021.101502

13. Bleyenheuft Y, Dricot L, Ebner-Karestinos D, et al. Motor skill training may restore impaired corticospinal tract fibers in children with cerebral palsy. *Neurorehabil Neural Repair.* 2020;34(6): 533-546. doi:10.1177/1545968320918841

14. Baker A, Niles N, Kysh L, Sargent B. Effect of motor intervention for infants and toddlers with cerebral palsy: a systematic review and meta-analysis. *Pediatr Phys Ther.* 2022;34(3): 297-307. doi:10.1097/PEP.0000000000000914

15. Damiano DL, Longo E. Early intervention evidence for infants with or at risk for cerebral

palsy: an overview of systematic reviews. *Dev Med Child Neurol.* 2021;63(7):771-784. doi:10.1111/dmcn.14855

16. Hadders-Algra M, Boxum AG, Hielkema T, Hamer EG. Effect of early intervention in infants at very high risk of cerebral palsy: a systematic review. *Dev Med Child Neurol.* 2017;59(3):246-258. doi:10.1111/dmcn.13331

17. Morgan C, Darrah J, Gordon AM, et al. Effectiveness of motor interventions in infants with cerebral palsy: a systematic review. *Dev Med Child Neurol.* 2016;58(9):900-909. doi:10.1111/dmcn.13105

18. Pavão SL, dos Santos AN, Woollacott MH, Rocha NA. Assessment of postural control in children with cerebral palsy: a review. *Res Dev Disabil.* 2013;34(5):1367-1375. doi:10.1016/j.ridd.2013.01.034

19. Bleyenheuft Y, Gordon AM. Hand-arm bimanual intensive therapy including lower extremities (HABIT-ILE) for children with cerebral palsy. *Phys Occup Ther Pediatr.* 2014;34(4):390-403. doi:10.3109/01942638.2014.932884

20. Araneda R, Klöcker A, Ebner-Karestinos D, et al. Feasibility and effectiveness of HABIT-ILE in children aged 1 to 4 years with cerebral palsy: a pilot study. *Ann Phys Rehabil Med.* 2021;64(3):101381. doi:10.1016/j.rehab.2020.03.006

21. Eyre JA, Taylor JP, Villagra F, Smith M, Miller S. Evidence of activity-dependent withdrawal of corticospinal projections during human development. *Neurology.* 2001;57(9):1543-1554. doi:10.1212/WNL.57.9.1543

22. Martin JH. The corticospinal system: from development to motor control. *Neuroscientist.* 2005;11(2):161-173. doi:10.1177/1073858404270843

23. Eliasson AC, Krumlinde-Sundholm L, Rösblad B, et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. *Dev Med Child Neurol.* 2006;48(7): 549-554. doi:10.1017/S0012162206001162

24. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. *Dev Med Child Neurol.* 1997; 39(4):214-223. doi:10.1111/j.1469-8749.1997.tb07414.x

25. Krumlinde-Sundholm L, Holmefur M, Kottorp A, Eliasson AC. The Assisting Hand Assessment: current evidence of validity, reliability, and responsiveness to change. *Dev Med Child Neurol.* 2007;49(4):259-264. doi:10.1111/j.1469-8749.2007.00259.x

26. Greaves S, Imms C, Dodd K, Krumlinde-Sundholm L. Development of the Mini-Assisting Hand Assessment: evidence for content and internal scale validity. *Dev Med Child Neurol.* 2013;55(11):1030-1037. doi:10.1111/dmcn.12212

27. Avery LM, Russell DJ, Raina PS, Walter SD, Rosenbaum PL. Rasch analysis of the Gross Motor Function Measure: validating the assumptions of the Rasch model to create an interval-level measure. *Arch Phys Med Rehabil.* 2003;84(5): 697-705. doi:10.1016/S0003-9993(02)04896-7

28. Randall M, Carlin JB, Chondros P, Reddihough D. Reliability of the Melbourne assessment of unilateral upper limb function. *Dev Med Child Neurol.* 2001;43(11):761-767. doi:10.1017/S0012162201001396

29. Randall M, Imms C, Carey L. Establishing validity of a modified Melbourne Assessment for
France (Bouvier, Brochard); University Hospital of Brest, Brest, France (Souki, Le Gal, Nowak, Brochard); INSERM CIC 1412, Brest, France (Le Gal, Nowak); Division of Child Development and Growth, Department of Pediatrics, University of Geneva, Geneva, Switzerland (Sizonenko); Paediatric Neurology and Neurorehabilitation Unit, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland (Newman); CHU Angers, Département de Médecine Physique et de Réadaptations, CHU Angers-Capucins, F-49933, France (Dinomais); Department of Nursing and Physiotherapy and Research Institute on Health Sciences (UINICS-Idisba), University of the Balearic Islands, Palma de Mallorca, Spain (Riquelme); Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (Guzzetta).

**Author Contributions:** Drs Brochard and Bleyenheuft had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
**Concept and design:** Araneda, Nowak, Sizonenko, Newman, Dinomais, Riquelme, Guzzetta, Brochard, Bleyenheuft.

**Acquisition, analysis, or interpretation of data:** Araneda, Ebner-Karestinos, Paradis, Klöcker, Saussez, Demas, Bailly, Bouvier, Carton de Tournai, Herman, Souki, Le Gal, Dinomais, Guzzetta, Brochard, Bleyenheuft.

**Drafting of the manuscript:** Araneda, Ebner-Karestinos, Souki, Dinomais, Brochard, Bleyenheuft.

**Critical review of the manuscript for important intellectual content:** Araneda, Ebner-Karestinos, Paradis, Klöcker, Saussez, Demas, Bailly, Bouvier, Carton de Tournai, Herman, Le Gal, Nowak, Sizonenko, Newman, Dinomais, Riquelme, Guzzetta, Brochard, Bleyenheuft.

**Statistical analysis:** Souki, Le Gal, Nowak, Brochard. Obtained funding: Bailly, Sizonenko, Newman, Dinomais, Brochard, Bleyenheuft.

**Administrative, technical, or material support:** Araneda, Ebner-Karestinos, Paradis, Saussez, Demas, Bailly, Bouvier, Carton de Tournai, Herman, Newman, Dinomais, Bleyenheuft.

**Supervision:** Araneda, Ebner-Karestinos, Paradis, Demas, Bailly, Newman, Guzzetta, Brochard, Bleyenheuft.

**Conflict of Interest Disclosures:** Dr Araneda reported grants from the Fondation Paralyse Cerebrale. Dr Paradis reported grants from the Marguerite-Marie Delacroix Foundation during the conduct of the study. Dr Saussez reported grants from the Fund for Scientific Research-Fund for Research Training in Industry and Agriculture during the conduct of the study. Dr Le Gal reported grants from Pfizer and Myers Squibb and personal fees from Pfizer, Sanofi, and Aspen Pharmacies outside the submitted work. Dr Nowak reported grants from the Fondation de France paid to their organization during the conduct of the study. Dr Sizonenko reported grants from the Fondation Paralyse Cérébrale during the conduct of the study. Dr Dinomais reported grants from La Fondation Paralyse Cérébrale during the conduct of the study. Dr Guzzetta reported grants from the Fondation Paralyse Cerebral HABIT-ILE and the Italian Ministry of Health RC Linea 1 during the conduct of the study and grants from Horizon outside the submitted work. Dr Brochard reported grants from La fondation Paralyse Cérébrale during the conduct of the study. Dr Bleyenheuft reported grants from the Fondation Paralyse Cérébrale for this research

project allocated after selection by a scientific committee during the conduct of the study, grants from the Fondation JED Belgique, Biowin, and Actions de Recherches Concertées/Université catholique de Louvainbrain outside the submitted work. No other disclosures were reported.

**Data Sharing Statement:** See Supplement 3.

REFERENCES

1. Straub K, Obrzut JE. Effects of cerebral palsy on neuropsychological function. *J Dev Phys Disabil. 2009;21(2):153-167. doi:10.1007/s10882-009-9130-3

2. Graham HK, Rosenbaum P, Paneth N, et al. Cerebral palsy. *Nat Rev Dis Primers. 2016;2:15082. doi:10.1038/nrdp.2015.82

3. Krägeloh-Mann I, Cans C. Cerebral palsy update. *Brain Dev. 2009;31(7):537-544. doi:10.1016/j.braindev.2009.03.009

4. Stiles J, Jernigan TL. The basics of brain development. *Neuropsychol Rev. 2010;20(4): 327-348. doi:10.1007/s11065-010-9148-4

5. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human central nervous system: what is happening when? *Early Hum Dev. 2006;82(4): 257-266. doi:10.1016/j.e耳lharlumdev.2005.10.013

6. Bekteshi S, Monbaliu E, McIntyre S, et al. Towards functional improvement of motor disorders associated with cerebral palsy. *Lancet Neurol. 2023;22(3):229-243. doi:10.1016/S1474-4422 (23)00004-2

7. Chabrier S, Pouyfaucon M, Chatelin A, et al. From congenital paralysis to post-early brain injury developmental condition: where does cerebral palsy actually stand? *Ann Phys Rehabil Med. 2020; 63(5):431-438. doi:10.1016/j.rehab.2019.07.003

8. Arnould C, Bleyenheuft Y, Thonnard JL. Hand functioning in children with cerebral palsy. *Front Neurol. 2014;5:48. doi:10.3389/fneur.2014.00048

9. Reid LB, Rose SE, Boyd RN. Rehabilitation and neuroplasticity in children with unilateral cerebral palsy. *Nat Rev Neurol. 2015;11(7):390-400. doi:10.1038/nrneurol.2015.97

10. Novak I, McIntyre S, Morgan C, et al. A systematic review of interventions for children with cerebral palsy: state of the evidence. *Dev Med Child Neurol. 2013;55(10):885-910. doi:10.1111/dmcn.12246

11. Sakzewski L, Ziviani J, Boyd RN. Efficacy of upper limb therapies for unilateral cerebral palsy: a meta-analysis. *Pediatrics. 2014;133(1):e175-e204. doi:10.1542/peds.2013-0675

12. Araneda R, Dricot L, Ebner-Karestinos D, et al. Brain activation changes following motor training in children with unilateral cerebral palsy: an fMRI study. *Ann Phys Rehabil Med. 2021;64(3):101502. doi:10.1016/j.rehab.2021.101502

13. Bleyenheuft Y, Dricot L, Ebner-Karestinos D, et al. Motor skill training may restore impaired corticospinal tract fibers in children with cerebral palsy. *Neurorehabil Neural Repair. 2020;34(6): 533-546. doi:10.1177/1545968320918841

14. Baker A, Niles N, Kysh L, Sargent B. Effect of motor intervention for infants and toddlers with cerebral palsy: a systematic review and meta-analysis. *Pediatr Phys Ther. 2022;34(3): 297-307. doi:10.1097/PEP.0000000000000914

15. Damiano DL, Longo E. Early intervention evidence for infants with or at risk for cerebral

palsy: an overview of systematic reviews. *Dev Med Child Neurol. 2021;63(7):771-784. doi:10.1111/dmcn.14855

16. Hadders-Algra M, Boxum AG, Hielkema T, Hamer EG. Effect of early intervention in infants at very high risk of cerebral palsy: a systematic review. *Dev Med Child Neurol. 2017;59(3):246-258. doi:10.1111/dmcn.13331

17. Morgan C, Darrah J, Gordon AM, et al. Effectiveness of motor interventions in infants with cerebral palsy: a systematic review. *Dev Med Child Neurol. 2016;58(9):900-909. doi:10.1111/dmcn.13105

18. Pavão SL, dos Santos AN, Woollacott MH, Rocha NA. Assessment of postural control in children with cerebral palsy: a review. *Res Dev Disabil. 2013;34(5):1367-1375. doi:10.1016/j.ridd.2013.01.034

19. Bleyenheuft Y, Gordon AM. Hand-arm bimanual intensive therapy including lower extremities (HABIT-ILE) for children with cerebral palsy. *Phys Occup Ther Pediatr. 2014;34(4):390-403. doi:10.3109/01942638.2014.932884

20. Araneda R, Klöcker A, Ebner-Karestinos D, et al. Feasibility and effectiveness of HABIT-ILE in children aged 1 to 4 years with cerebral palsy: a pilot study. *Ann Phys Rehabil Med. 2021;64(3):101381. doi:10.1016/j.rehab.2020.03.006

21. Eyre JA, Taylor JP, Villagra F, Smith M, Miller S. Evidence of activity-dependent withdrawal of corticospinal projections during human development. *Neurology. 2001;57(9):1543-1554. doi:10.1212/WNL.57.9.1543

22. Martin JH. The corticospinal system: from development to motor control. *Neuroscientist. 2005;11(2):161-173. doi:10.1177/1073858404270843

23. Eliasson AC, Krumlinde-Sundholm L, Rösblad B, et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. *Dev Med Child Neurol. 2006;48(7): 549-554. doi:10.1017/S0012162206001162

24. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. *Dev Med Child Neurol. 1997; 39(4):214-223. doi:10.1111/j.1469-8749.1997.tb07414.x

25. Krumlinde-Sundholm L, Holmefur M, Kottorp A, Eliasson AC. The Assisting Hand Assessment: current evidence of validity, reliability, and responsiveness to change. *Dev Med Child Neurol. 2007;49(4):259-264. doi:10.1111/j.1469-8749.2007.00259.x

26. Greaves S, Imms C, Dodd K, Krumlinde-Sundholm L. Development of the Mini-Assisting Hand Assessment: evidence for content and internal scale validity. *Dev Med Child Neurol. 2013;55(11):1030-1037. doi:10.1111/dmcn.12212

27. Avery LM, Russell DJ, Raina PS, Walter SD, Rosenbaum PL. Rasch analysis of the Gross Motor Function Measure: validating the assumptions of the Rasch model to create an interval-level measure. *Arch Phys Med Rehabil. 2003;84(5): 697-705. doi:10.1016/S0003-9993(02)04896-7

28. Randall M, Carlin JB, Chondros P, Reddihough D. Reliability of the Melbourne assessment of unilateral upper limb function. *Dev Med Child Neurol. 2001;43(11):761-767. doi:10.1017/S0012162201001396

29. Randall M, Imms C, Carey L. Establishing validity of a modified Melbourne Assessment for
children ages 2 to 4 years. *American Journal of Occupational Therapy*. 2008;62(4):373-383. doi:10.5014/ajot.62.4.373

**30.** Law M, Baptiste S, McColl M, Opzoomer A, Polatajko H, Pollock N. The Canadian occupational performance measure: an outcome measure for occupational therapy. *Canadian Journal of Occupational Therapy*. 1990;57(2):82-87. doi:10.5014/ajot.62.4.373

**31.** Kramer JM, Liljenquist K, Coster WJ. Validity, reliability, and usability of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test for autism spectrum disorders. *Dev Med Child Neurol*. 2016;58(3):255-261. doi:10.1111/dmcn.12837

**32.** Bleyenheuft Y, Arnould C, Brandao MB, Bleyenheuft C, Gordon AM. Hand and Arm Bimanual Intensive Therapy Including Lower Extremity (HABIT-ILE) in Children With Unilateral Spastic Cerebral Palsy: A Randomized Trial. *Neurorehabil Neural Repair*. 2015;29(7):645-657. doi:10.1177/1545968314562109

**33.** Bleyenheuft Y, Ebner-Karestinos D, Surana B, et al. Intensive upper- and lower-extremity training for children with bilateral cerebral palsy: a quasi-randomized trial. *Dev Med Child Neurol*. 2017;59(6):625-633. doi:10.1111/dmcn.13379

**34.** Van Cauwenberghe E, Gubbels J, De Bourdeaudhuij I, Cardon G. Feasibility and validity of accelerometer measurements to assess physical activity in toddlers. *Int J Behav Nutr Phys Act*. 2011;8:67. doi:10.1186/1479-5868-8-67

**35.** Bruijns BA, Truelove S, Johnson AM, Gilliland J, Tucker P. Infants' and toddlers' physical activity and sedentary time as measured by accelerometry: a systematic review and meta-analysis. *Int J Behav Nutr Phys Act*. 2020;17(1):14. doi:10.1186/s12966-020-0912-4

**36.** Brégou Bourgeois A, Mariani B, Aminian K, Zambelli PY, Newman CJ. Spatio-temporal gait analysis in children with cerebral palsy using, foot-worn inertial sensors. *Gait Posture*. 2014;39(1): 436-442. doi:10.1016/j.gaitpost.2013.08.029

**37.** Newman CJ, Bruchez R, Roches S, et al. Measuring upper limb function in children with hemiparesis with 3D inertial sensors. *Childs Nerv Syst*. 2017;33(12):2159-2168. doi:10.1007/s00381-017-3580-1

**38.** Araneda R, Sizonenko SV, Newman CJ, et al; Early HABIT-ILE group. Functional, neuroplastic and biomechanical changes induced by early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (e-HABIT-ILE) in pre-school children with unilateral cerebral palsy: study protocol of a

randomized control trial. *BMC Neurol*. 2020;20(1): 133. doi:10.1186/s12883-020-01705-4

**39.** Eliasson AC, Shaw K, Berg E, Krumlinde-Sundholm L. An ecological approach of Constraint Induced Movement Therapy for 2-3-year-old children: a randomized control trial. *Dev Med Disabil*. 2011;32(6):2820-2828. doi:10.1016/j.ridd.2011.05.024

**40.** Vickers AJ. The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: a simulation study. *BMC Med Res Methodol*. 2001;1:6. doi:10.1186/1471-2288-1-6

**41.** Krumlinde-Sundholm L. Reporting outcomes of the Assisting Hand Assessment: what scale should be used? *Dev Med Child Neurol*. 2012;54(9):807-808. doi:10.1111/j.1469-8749.2012.04361.x

**42.** Friel KM, Williams PT, Serradj N, Chakrabarty S, Martin JH. Activity-based therapies for repair of the corticospinal system injured during development. *Front Neurol*. 2014;5:229. doi:10.3389/fneur. 2014.00229

**43.** Eliasson AC, Nordstrand L, Backheden M, Holmefur M. Longitudinal development of hand use in children with unilateral spastic cerebral palsy from 18 months to 18 years. *Dev Med Child Neurol*. 2023;65(3):376-384. doi:10.1111/dmcn.15370

**44.** Klevberg GL, Jahnsen R, Elkjaer S, Zucknick M. Hand use development in children with unilateral cerebral palsy. *Dev Med Child Neurol*. 2021;63(12): 1462-1468. doi:10.1111/dmcn.14957

**45.** Eliasson AC, Nordstrand L, Ek L, et al. The effectiveness of Baby-CIMT in infants younger than 12 months with clinical signs of unilateral-cerebral palsy; an explorative study with randomized design. *Res Dev Disabil*. 2018;72:191-201. doi:10.1016/j.ridd.2017.11.006

**46.** Ferre CL, Brandão M, Surana B, Dew AP, Moreau NG, Gordon AM. Caregiver-directed home-based intensive bimanual training in young children with unilateral spastic cerebral palsy: a randomized trial. *Dev Med Child Neurol*. 2017;59 (5):497-504. doi:10.1111/dmcn.13330

**47.** Saussez G, Brandão MB, Gordon AM, Bleyenheuft Y. Including a lower-extremity component during hand-arm bimanual intensive training does not attenuate improvements of the upper extremities: a retrospective study of randomized trials. *Front Neurol*. 2017;8:495. doi:10.3389/fneur.2017.00495

**48.** Brandão MB, Ferre C, Kuo HC, et al. Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy.

Neurorehabil Neural Repair. 2014;28(5):452-461. doi:10.1177/1545968313516871

**49.** Araneda R, Herman E, Delcour L, et al. Mirror movements after bimanual intensive therapy in children with unilateral cerebral palsy: a randomized controlled trial. *Dev Med Child Neurol*. 2022;64(11):1383-1391. doi:10.1111/dmcn.15257

**50.** Paton MCB, Finch-Edmondson M, Dale RC, et al. Persistent inflammation in cerebral palsy: pathogenic mediator or comorbidity? A scoping review. *J Clin Med*. 2022;11(24):7368. doi:10.3390/jcm11247368

**51.** Favrais G, van de Looij Y, Fleiss B, et al. Systemic inflammation disrupts the developmental program of white matter. *Ann Neurol*. 2011;70(4):550-565. doi:10.1002/ana.22489

**52.** Leviton A, Gressens P. Neuronal damage accompanies perinatal white-matter damage. *Trends Neurosci*. 2007;30(9):473-478. doi:10.1016/j.tins.2007.05.009

**53.** Van Steenwinckel J, Schang AL, Sigaut S, et al. Brain damage of the preterm infant: new insights into the role of inflammation. *Biochem Soc Trans*. 2014;42(2):557-563. doi:10.1042/BST20130284

**54.** Online SM, Abraham WC. Environmental enrichment effects on synaptic and cellular physiology of hippocampal neurons. *Neuropharmacology*. 2019;145(Pt A):3-12. doi:10.1016/j.neuropharm.2018.04.007

**55.** Phillips C, Baktir MA, Srivatsan M, Salehi A. Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. *Front Cell Neurosci*. 2014;8:170. doi:10.3389/fncel.2014. 00170

**56.** van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. *Nat Rev Neurosci*. 2000;1(3):191-198. doi:10.1038/35044558

**57.** McKenzie IA, Ohayon D, Li H, et al. Motor skill learning requires active central myelination. *Science*. 2014;346(6207):318-322. doi:10.1126/science. 1254960

**58.** Xiao L, Ohayon D, McKenzie IA, et al. Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. *Nat Neurosci*. 2016;19(9):1210-1217. doi:10.1038/nn.4351

**59.** Demont A, Gedda M, Lager C, et al. Evidence-based, implementable motor rehabilitation guidelines for individuals with cerebral palsy. *Neurology*. 2022;99(7):283-297. doi:10.1212/WNL.0000000000200936
children ages 2 to 4 years. *American Journal of Occupational Therapy*. 2008;62(4):373-383. doi:10.5014/ajot.62.4.373

**30.** Law M, Baptiste S, McColl M, Opzoomer A, Polatajko H, Pollock N. The Canadian occupational performance measure: an outcome measure for occupational therapy. *Canadian Journal of Occupational Therapy*. 1990;57(2):82-87. doi:10.5014/ajot.62.4.373

**31.** Kramer JM, Liljenquist K, Coster WJ. Validity, reliability, and usability of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test for autism spectrum disorders. *Dev Med Child Neurol*. 2016;58(3):255-261. doi:10.1111/dmcn.12837

**32.** Bleyenheuft Y, Arnould C, Brandao MB, Bleyenheuft C, Gordon AM. Hand and Arm Bimanual Intensive Therapy Including Lower Extremity (HABIT-ILE) in Children With Unilateral Spastic Cerebral Palsy: A Randomized Trial. *Neurorehabil Neural Repair*. 2015;29(7):645-657. doi:10.1177/1545968314562109

**33.** Bleyenheuft Y, Ebner-Karestinos D, Surana B, et al. Intensive upper- and lower-extremity training for children with bilateral cerebral palsy: a quasi-randomized trial. *Dev Med Child Neurol*. 2017;59(6):625-633. doi:10.1111/dmcn.13379

**34.** Van Cauwenberghe E, Gubbels J, De Bourdeaudhuij I, Cardon G. Feasibility and validity of accelerometer measurements to assess physical activity in toddlers. *Int J Behav Nutr Phys Act*. 2011;8:67. doi:10.1186/1479-5868-8-67

**35.** Bruijns BA, Truelove S, Johnson AM, Gilliland J, Tucker P. Infants' and toddlers' physical activity and sedentary time as measured by accelerometry: a systematic review and meta-analysis. *Int J Behav Nutr Phys Act*. 2020;17(1):14. doi:10.1186/s12966-020-0912-4

**36.** Brégou Bourgeois A, Mariani B, Aminian K, Zambelli PY, Newman CJ. Spatio-temporal gait analysis in children with cerebral palsy using, foot-worn inertial sensors. *Gait Posture*. 2014;39(1): 436-442. doi:10.1016/j.gaitpost.2013.08.029

**37.** Newman CJ, Bruchez R, Roches S, et al. Measuring upper limb function in children with hemiparesis with 3D inertial sensors. *Childs Nerv Syst*. 2017;33(12):2159-2168. doi:10.1007/s00381-017-3580-1

**38.** Araneda R, Sizonenko SV, Newman CJ, et al; Early HABIT-ILE group. Functional, neuroplastic and biomechanical changes induced by early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (e-HABIT-ILE) in pre-school children with unilateral cerebral palsy: study protocol of a

randomized control trial. *BMC Neurol*. 2020;20(1): 133. doi:10.1186/s12883-020-01705-4

**39.** Eliasson AC, Shaw K, Berg E, Krumlinde-Sundholm L. An ecological approach of Constraint Induced Movement Therapy for 2-3-year-old children: a randomized control trial. *Dev Med Disabil*. 2011;32(6):2820-2828. doi:10.1016/j.ridd.2011.05.024

**40.** Vickers AJ. The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: a simulation study. *BMC Med Res Methodol*. 2001;1:6. doi:10.1186/1471-2288-1-6

**41.** Krumlinde-Sundholm L. Reporting outcomes of the Assisting Hand Assessment: what scale should be used? *Dev Med Child Neurol*. 2012;54(9):807-808. doi:10.1111/j.1469-8749.2012.04361.x

**42.** Friel KM, Williams PT, Serradj N, Chakrabarty S, Martin JH. Activity-based therapies for repair of the corticospinal system injured during development. *Front Neurol*. 2014;5:229. doi:10.3389/fneur. 2014.00229

**43.** Eliasson AC, Nordstrand L, Backheden M, Holmefur M. Longitudinal development of hand use in children with unilateral spastic cerebral palsy from 18 months to 18 years. *Dev Med Child Neurol*. 2023;65(3):376-384. doi:10.1111/dmcn.15370

**44.** Klevberg GL, Jahnsen R, Elkjaer S, Zucknick M. Hand use development in children with unilateral cerebral palsy. *Dev Med Child Neurol*. 2021;63(12): 1462-1468. doi:10.1111/dmcn.14957

**45.** Eliasson AC, Nordstrand L, Ek L, et al. The effectiveness of Baby-CIMT in infants younger than 12 months with clinical signs of unilateral-cerebral palsy; an explorative study with randomized design. *Res Dev Disabil*. 2018;72:191-201. doi:10.1016/j.ridd.2017.11.006

**46.** Ferre CL, Brandão M, Surana B, Dew AP, Moreau NG, Gordon AM. Caregiver-directed home-based intensive bimanual training in young children with unilateral spastic cerebral palsy: a randomized trial. *Dev Med Child Neurol*. 2017;59 (5):497-504. doi:10.1111/dmcn.13330

**47.** Saussez G, Brandão MB, Gordon AM, Bleyenheuft Y. Including a lower-extremity component during hand-arm bimanual intensive training does not attenuate improvements of the upper extremities: a retrospective study of randomized trials. *Front Neurol*. 2017;8:495. doi:10.3389/fneur.2017.00495

**48.** Brandão MB, Ferre C, Kuo HC, et al. Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy.

Neurorehabil Neural Repair. 2014;28(5):452-461. doi:10.1177/1545968313516871

**49.** Araneda R, Herman E, Delcour L, et al. Mirror movements after bimanual intensive therapy in children with unilateral cerebral palsy: a randomized controlled trial. *Dev Med Child Neurol*. 2022;64(11):1383-1391. doi:10.1111/dmcn.15257

**50.** Paton MCB, Finch-Edmondson M, Dale RC, et al. Persistent inflammation in cerebral palsy: pathogenic mediator or comorbidity? A scoping review. *J Clin Med*. 2022;11(24):7368. doi:10.3390/jcm11247368

**51.** Favrais G, van de Looij Y, Fleiss B, et al. Systemic inflammation disrupts the developmental program of white matter. *Ann Neurol*. 2011;70(4):550-565. doi:10.1002/ana.22489

**52.** Leviton A, Gressens P. Neuronal damage accompanies perinatal white-matter damage. *Trends Neurosci*. 2007;30(9):473-478. doi:10.1016/j.tins.2007.05.009

**53.** Van Steenwinckel J, Schang AL, Sigaut S, et al. Brain damage of the preterm infant: new insights into the role of inflammation. *Biochem Soc Trans*. 2014;42(2):557-563. doi:10.1042/BST20130284

**54.** Online SM, Abraham WC. Environmental enrichment effects on synaptic and cellular physiology of hippocampal neurons. *Neuropharmacology*. 2019;145(Pt A):3-12. doi:10.1016/j.neuropharm.2018.04.007

**55.** Phillips C, Baktir MA, Srivatsan M, Salehi A. Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. *Front Cell Neurosci*. 2014;8:170. doi:10.3389/fncel.2014. 00170

**56.** van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. *Nat Rev Neurosci*. 2000;1(3):191-198. doi:10.1038/35044558

**57.** McKenzie IA, Ohayon D, Li H, et al. Motor skill learning requires active central myelination. *Science*. 2014;346(6207):318-322. doi:10.1126/science. 1254960

**58.** Xiao L, Ohayon D, McKenzie IA, et al. Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. *Nat Neurosci*. 2016;19(9):1210-1217. doi:10.1038/nn.4351

**59.** Demont A, Gedda M, Lager C, et al. Evidence-based, implementable motor rehabilitation guidelines for individuals with cerebral palsy. *Neurology*. 2022;99(7):283-297. doi:10.1212/WNL.0000000000200936