Designing strategies to support Implementation of iNtensive Therapy for Early Reach through PLAY (INTERPLAY) for young children with cerebral palsy: a study protocol.

BACKGROUND: Intensive manual therapy is important for improving lifelong upper limb motor outcomes for infants and toddlers with cerebral palsy. This play-based therapy is delivered by caregivers who are coached by occupational therapists. However, access to this therapy is very limited for Canadian children with cerebral palsy younger than two years old. This project aims to first identify barriers and facilitators and then design implementation strategies to support early intensive manual therapy delivery for infants and toddlers with cerebral palsy across Canada. METHODS: A mixed-methods sequential explanatory design will be used with four consecutive phases. The updated Consolidated Framework for Implementation Research will guide the study. Quantitative data will be collected from a survey in Phase One. Participants will be recruited from three groups: (1) Caregivers of children with cerebral palsy six years old and younger who are eligible for manual therapy; (2) occupational therapists who treat children with cerebral palsy; and (3) healthcare administrators or people responsible for managing pediatric occupational therapy programs. In Phase Two, quantitative data from the survey will be used to map to implementation strategies known to be effective at addressing the identified modifiable barriers and facilitators. Phase Three will collect qualitative data from semi-structured interviews for the purpose of explaining Phase One quantitative findings in greater depth, and for understanding the appropriateness of strategies identified in Phase Two. The participant recruitment strategy and interview guide content for Phase Three will be informed by results of Phase One. Phase Four will use a modified nominal group technique to refine and prioritize an implementation strategy toolbox. Results will be widely disseminated to knowledge users to provide them with tailorable strategies to increase delivery of early intensive manual interventions. DISCUSSION: This study will provide a comprehensive understanding of the barriers and facilitators to implementation of early intensive manual therapy for young children with cerebral palsy in Canada. A toolbox of evidence-based and tailorable implementation strategies will be disseminated nationally to support uptake of early intensive manual therapy into clinical practice for young children with cerebral palsy.

Executive functioning, ADHD symptoms and resting state functional connectivity in children with perinatal stroke.

Perinatal stroke describes a group of focal, vascular brain injuries that occur early in development, often resulting in lifelong disability. Two types of perinatal stroke predominate, arterial ischemic stroke (AIS) and periventricular venous infarction (PVI). Though perinatal stroke is typically considered a motor disorder, other comorbidities commonly exist including attention-deficit hyperactivity disorder (ADHD) and deficits in executive function. Rates of ADHD symptoms are higher in children with perinatal stroke and deficits in executive function may also occur but underlying mechanisms are not known. We measured resting state functional connectivity in children with perinatal stroke using previously established dorsal attention, frontoparietal, and default mode network seeds. Associations with parental ratings of executive function and ADHD symptoms were examined. A total of 120 participants aged 6-19 years [AIS N = 31; PVI N = 30; Controls N = 59] were recruited. In comparison to typically developing peers, both the AIS and PVI groups showed lower intra- and inter-hemispheric functional connectivity values in the networks investigated. Group differences in between-network connectivity were also demonstrated, showing weaker anticorrelations between task-positive (frontoparietal and dorsal attention) and task-negative (default mode) networks in stroke groups compared to controls. Both within-network and between-network functional connectivity values were highly associated with parental reports of executive function and ADHD symptoms. These results suggest that differences in functional connectivity exist both within and between networks after perinatal stroke, the degree of which is associated with ADHD symptoms and executive function.

Patient and public involvement in pragmatic trials: online survey of corresponding authors of published trials.

BACKGROUND: There are few data on patient and public involvement (PPI) in pragmatic trials. We aimed to describe the prevalence and nature of PPI within pragmatic trials, describe variation in prevalence of PPI by trial characteristics and compare prevalence of PPI reported by trial authors to that reported in trial publications. METHODS: We applied a search filter to identify pragmatic trials published from 2014 to 2019 in MEDLINE. We invited the corresponding authors of pragmatic trials to participate in an online survey about their specific trial. RESULTS: Of 3163 authors invited, 2585 invitations were delivered, 710 (27.5%) reported on 710 unique trials and completed the survey; 334 (47.0%) conducted PPI. Among those who conducted PPI, for many the aim was to increase the research relevance (86.3%) or quality (76.5%). Most PPI partners were engaged at protocol development stages (79.1%) and contributed to the co-design of interventions (70.9%) or recruitment or retention strategies (60.5%). Patient and public involvement was more common among trials involving children, trials conducted in the United Kingdom, cluster randomized trials, those explicitly labelled as "pragmatic" in the study manuscript, and more recent trials. Less than one-quarter of trials (22.8%) that reported PPI in the survey also reported PPI in the trial manuscript. INTERPRETATION: Nearly half of trialists in this survey reported conducting PPI and listed several benefits of doing so, but researchers who did not conduct PPI often cited a lack of requirement for it. Patient and public involvement appears to be significantly underreported in trial publications. Consistent and standardized reporting is needed to promote transparency about PPI methods, outcomes, challenges and benefits.

Functional Neuroplasticity and Motor Skill Change Following Gross Motor Interventions for Children With Diplegic Cerebral Palsy.

BACKGROUND: Gross motor intervention designs for children with diplegic cerebral palsy (DCP) require an improved understanding of the children's potential for neuroplasticity. OBJECTIVE: To identify relations between functional neuroplasticity and motor skill changes following gross motor interventions for children with DCP. METHODS: There were 17 participants with DCP (ages 8-16 years; 6 females; Gross Motor Function Classification System Level I [n = 9] and II [n = 8]). Each completed a 6-week gross motor intervention program that was directed toward achievement of individualized motor/physical activity goals. Outcomes were assessed pre/post and 4 to 6 months post-intervention (follow-up). An active ankle dorsiflexion task was completed during functional magnetic resonance imaging. The ratio of motor cortical activation volume in each hemisphere was calculated using a laterality index. The Challenge was the primary gross motor skill measure. Change over time and relations among outcomes were evaluated. RESULTS: Challenge scores improved post-intervention (4.57% points [SD 4.45], P = .004) and were maintained at follow-up (0.75% [SD 6.57], P = 1.000). The laterality index for dominant ankle dorsiflexion increased (P = .033), while non-dominant change was variable (P = .534). Contralateral activation (laterality index ≥+0.75) was most common for both ankles. Challenge improvements correlated with increased ipsilateral activity (negative laterality index) during non-dominant dorsiflexion (r = -.56, P = .045). Smaller activation volume during non-dominant dorsiflexion predicted continued gross motor gains at follow-up (R2 = .30, P = .040). CONCLUSIONS: Motor cortical activation during non-dominant ankle dorsiflexion is a modest indicator of the potential for gross motor skill change. Further investigation of patterns of neuroplastic change will improve our understanding of effects. CLINICALTRIALS.GOV REGISTRY: NCT02584491 and NCT02754128.

Structural brain network lateralization across childhood and adolescence.

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub-nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross-sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right-handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school-age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization.

Structural connectivity of the sensorimotor network within the non-lesioned hemisphere of children with perinatal stroke.

Perinatal stroke occurs early in life and often leads to a permanent, disabling weakness to one side of the body. To test the hypothesis that non-lesioned hemisphere sensorimotor network structural connectivity in children with perinatal stroke is different from controls, we used diffusion imaging and graph theory to explore structural topology between these populations. Children underwent diffusion and anatomical 3T MRI. Whole-brain tractography was constrained using a brain atlas creating an adjacency matrix containing connectivity values. Graph theory metrics including betweenness centrality, clustering coefficient, and both neighbourhood and hierarchical complexity of sensorimotor nodes were compared to controls. Relationships between these connectivity metrics and validated sensorimotor assessments were explored. Eighty-five participants included 27 with venous stroke (mean age = 11.5 ± 3.7 years), 26 with arterial stroke (mean age = 12.7 ± 4.0 years), and 32 controls (mean age = 13.3 ± 3.6 years). Non-lesioned primary motor (M1), somatosensory (S1) and supplementary motor (SMA) areas demonstrated lower betweenness centrality and higher clustering coefficient in stroke groups. Clustering coefficient of M1, S1, and SMA were inversely associated with clinical motor function. Hemispheric betweenness centrality and clustering coefficient were higher in stroke groups compared to controls. Hierarchical and average neighbourhood complexity across the hemisphere were lower in stroke groups. Developmental plasticity alters the connectivity of key nodes within the sensorimotor network of the non-lesioned hemisphere following perinatal stroke and contributes to clinical disability.

Frontal interhemispheric structural connectivity, attention, and executive function in children with perinatal stroke.

Perinatal stroke affects ∼1 in 1000 births and concomitant cognitive impairments are common but poorly understood. Rates of Attention Deficit/Hyperactivity Disorder (ADHD) are increased 5-10× and executive dysfunction can be disabling. We used diffusion imaging to investigate whether stroke-related differences in frontal white matter (WM) relate to cognitive impairments. Anterior forceps were isolated using tractography and sampled along the tract. Resulting metrics quantified frontal WM microstructure. Associations between WM metrics and parent ratings of ADHD symptoms (ADHD-5 rating scale) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)) were explored. Eighty-three children were recruited (arterial ischemic stroke [AIS] n = 26; periventricular venous infarction [PVI] n = 26; controls n = 31). WM metrics were altered for stroke groups compared to controls. Along-tract analyses showed differences in WM metrics in areas approximating the lesion as well as more remote differences at midline and in the nonlesioned hemisphere. WM metrics correlated with parental ratings of ADHD and executive function such that higher diffusivity values were associated with poorer function. These findings suggest that underlying microstructure of frontal white matter quantified via tractography may provide a relevant biomarker associated with cognition and behavior in children with perinatal stroke.

Comparison of sports skills movement training to lower limb strength training for independently ambulatory children with cerebral palsy: a randomised feasibility trial.

PURPOSE: The best approach to delivering advanced gross motor skills interventions for children with cerebral palsy (CP) is unknown. This study's aim was to assess trial feasibility and compare effectiveness of sports skills movement training (Brain change after Fun, Athletic Sports skills Training [BeFAST]) to conventional lower limb strength training (Brain change after Strength Training focusing ON Gait [BeSTRONG]) for improving advanced gross motor skills of children with CP. METHODS: Twenty independently ambulatory children with CP (mean age 12 ± 2.6 years) were randomly assigned to a 6-week programme of BeFAST or BeSTRONG, individualised to participant goals. Primary scientific outcome measures were the Challenge and Canadian Occupational Performance Measure (COPM) assessed pre/post and 4-month post-intervention. Process, resource, and management indicators assessed trial feasibility. RESULTS: There was no between group difference for the Challenge (p = 0.325), however significant post-intervention Challenge improvements were observed in BeFAST (p = 0.031) but not BeSTRONG (p = 0.055). Between group post-intervention scores were higher in BeFAST for COPM Performance (p = 0.001), and relative gains were maintained 4-month post-intervention. Pre-set criteria were met for 84% of feasibility indicators. CONCLUSIONS: Sports skills movement training may be an effective option to support advanced gross motor skill gains and target goals of independently ambulatory children with CP. Trial feasibility, including early evidence of effectiveness, indicates readiness for a full-scale randomised trial.Implications for rehabilitationChildren with cerebral palsy have potential to improve advanced gross motor skills.Strength training is a commonly used approach in gross motor therapy programmes.Sports skill training may be an effective option that better targets children's goals.

Perinatal stroke: mapping and modulating developmental plasticity.

Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain-computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.

Imaging Developmental and Interventional Plasticity Following Perinatal Stroke.

Perinatal stroke occurs around the time of birth and leads to lifelong neurological disabilities including hemiparetic cerebral palsy. Magnetic resonance imaging (MRI) has revolutionized our understanding of developmental neuroplasticity following early injury, quantifying volumetric, structural, functional, and metabolic compensatory changes after perinatal stroke. Such techniques can also be used to investigate how the brain responds to treatment (interventional neuroplasticity). Here, we review the current state of knowledge of how established and emerging neuroimaging modalities are informing neuroplasticity models in children with perinatal stroke. Specifically, we review structural imaging characterizing lesion characteristics and volumetrics, diffusion tensor imaging investigating white matter tracts and networks, task-based functional MRI for localizing function, resting state functional imaging for characterizing functional connectomes, and spectroscopy examining neurometabolic changes. Key challenges and exciting avenues for future investigations are also considered.

Developmental neuroplasticity of the white matter connectome in children with perinatal stroke.

OBJECTIVE: To employ diffusion imaging connectome methods to explore network development in the contralesional hemisphere of children with perinatal stroke and its relationship to clinical function. We hypothesized alterations in global efficiency of the intact hemisphere would correlate with clinical disability. METHODS: Children with unilateral perinatal arterial (n = 26) or venous (n = 27) stroke and typically developing controls (n = 32) underwent 3T diffusion and T1 anatomical MRI and completed established motor assessments. A validated atlas coregistered to whole-brain tractography for each individual was used to estimate connectivity between 47 regions. Graph theory metrics (assortativity, hierarchical coefficient of regression, global and local efficiency, and small worldness) were calculated for the left hemisphere of controls and the intact contralesioned hemisphere of both stroke groups. Validated clinical motor assessments were then correlated with connectivity outcomes. RESULTS: Global efficiency was higher in arterial strokes compared to venous strokes (p < 0.001) and controls (p < 0.001) and was inversely associated with all motor assessments (all p < 0.012). Additional graph theory metrics including assortativity, hierarchical coefficient of regression, and local efficiency also demonstrated consistent differences in the intact hemisphere associated with clinical function. CONCLUSIONS: The structural connectome of the contralesional hemisphere is altered after perinatal stroke and correlates with clinical function. Connectomics represents a powerful tool to understand whole brain developmental plasticity in children with disease-specific cerebral palsy.

Transcranial Static Magnetic Field Stimulation of the Motor Cortex in Children.

BACKGROUND: Non-invasive neuromodulation is an emerging therapy for children with early brain injury but is difficult to apply to preschoolers when windows of developmental plasticity are optimal. Transcranial static magnetic field stimulation (tSMS) decreases primary motor cortex (M1) excitability in adults but effects on the developing brain are unstudied. OBJECTIVE/HYPOTHESIS: We aimed to determine the effects of tSMS on cortical excitability and motor learning in healthy children. We hypothesized that tSMS over right M1 would reduce cortical excitability and inhibit contralateral motor learning. METHODS: This randomized, sham-controlled, double-blinded, three-arm, cross-over trial enrolled 24 healthy children aged 10-18 years. Transcranial Magnetic Stimulation (TMS) assessed cortical excitability via motor-evoked potential (MEP) amplitude and paired pulse measures. Motor learning was assessed via the Purdue Pegboard Test (PPT). A tSMS magnet (677 Newtons) or sham was held over left or right M1 for 30 min while participants trained the non-dominant hand. A linear mixed effect model was used to examine intervention effects. RESULTS: All 72 tSMS sessions were well tolerated without serious adverse effects. Neither cortical excitability as measured by MEPs nor paired-pulse intracortical neurophysiology was altered by tSMS. Possible behavioral effects included contralateral tSMS inhibiting early motor learning (p < 0.01) and ipsilateral tSMS facilitating later stages of motor learning (p < 0.01) in the trained non-dominant hand. CONCLUSION: tSMS is feasible in pediatric populations. Unlike adults, tSMS did not produce measurable changes in MEP amplitude. Possible effects of M1 tSMS on motor learning require further study. Our findings support further exploration of tSMS neuromodulation in young children with cerebral palsy.

Structural and functional connectivity of motor circuits after perinatal stroke: A machine learning study.

Developmental neuroplasticity allows young brains to adapt via experiences early in life and also to compensate after injury. Why certain individuals are more adaptable remains underexplored. Perinatal stroke is an ideal human model of neuroplasticity with focal lesions acquired near birth in a healthy brain. Machine learning can identify complex patterns in multi-dimensional datasets. We used machine learning to identify structural and functional connectivity biomarkers most predictive of motor function. Forty-nine children with perinatal stroke and 27 controls were studied. Functional connectivity was quantified by fluctuations in blood oxygen-level dependent (BOLD) signal between regions. White matter tractography of corticospinal tracts quantified structural connectivity. Motor function was assessed using validated bimanual and unimanual tests. RELIEFF feature selection and random forest regression models identified predictors of each motor outcome using neuroimaging and demographic features. Unilateral motor outcomes were predicted with highest accuracy (8/54 features r = 0.58, 11/54 features, r = 0.34) but bimanual function required more features (51/54 features, r = 0.38). Connectivity of both hemispheres had important roles as did cortical and subcortical regions. Lesion size, age at scan, and type of stroke were predictive but not highly ranked. Machine learning regression models may represent a powerful tool in identifying neuroimaging biomarkers associated with clinical motor function in perinatal stroke and may inform personalized targets for neuromodulation.

Opening the Door to Physical Activity for Children With Cerebral Palsy: Experiences of Participants in the BeFAST or BeSTRONG Program.

This study explored children's experiences of participating in one-to-one physical training programs to identify how programs can best promote physical activity participation for children with cerebral palsy. A qualitative descriptive design with self-determination theory was used. Semistructured interviews were conducted with 6 children with cerebral palsy, age 8-14 years, who participated in a fundamental-movement-skills or lower-limb strength-training program. A hybrid approach of deductive and inductive analysis was used. Four themes developed: World around me (i.e., social/physical environments), Made for me (i.e., individualizing programs), Teach me how (i.e., teaching strategies facilitated skill learning), and I know me (i.e., sense of self). Results include recommendations for delivery of physical training programs. Using an individualized approach in a structured one-to-one program that employs skill-teaching strategies and self-reflection opportunities may provide a foundation to increase physical activity participation, related self-confidence, and desire to participate.

Comparison of a robotic-assisted gait training program with a program of functional gait training for children with cerebral palsy: design and methods of a two group randomized controlled cross-over trial.

BACKGROUND: Enhancement of functional ambulation is a key goal of rehabilitation for children with cerebral palsy (CP) who experience gross motor impairment. Physiotherapy (PT) approaches often involve overground and treadmill-based gait training to promote motor learning, typically as free walking or with body-weight support. Robotic-assisted gait training (RAGT), using a device such as the Lokomat®Pro, may permit longer training duration, faster and more variable gait speeds, and support walking pattern guidance more than overground/treadmill training to further capitalize on motor learning principles. Single group pre-/post-test studies have demonstrated an association between RAGT and moderate to large improvements in gross motor skills, gait velocity and endurance. A single published randomized controlled trial (RCT) comparing RAGT to a PT-only intervention showed no difference in gait kinematics. However, gross motor function and walking endurance were not evaluated and conclusions were limited by a large PT group drop-out rate. METHODS/DESIGN: In this two-group cross-over RCT, children are randomly allocated to the RAGT or PT arm (each with twice weekly sessions for eight weeks), with cross-over to the other intervention arm following a six-week break. Both interventions are grounded in motor learning principles with incorporation of individualized mobility-based goals. Sessions are fully operationalized through manualized, menu-based protocols and post-session documentation to enhance internal and external validity. Assessments occur pre/post each intervention arm (four time points total) by an independent assessor. The co-primary outcomes are gross motor functional ability (Gross Motor Function Measure (GMFM-66) and 6-minute walk test), with secondary outcome measures assessing: (a) individualized goals; (b) gait variables and daily walking amounts; and (c) functional abilities, participation and quality of life. Investigators and statisticians are blinded to study group allocation in the analyses, and assessors are blinded to treatment group. The primary analysis will be the pre- to post-test differences (change scores) of the GMFM-66 and 6MWT between RAGT and PT groups. DISCUSSION: This study is the first RCT comparing RAGT to an active gait-related PT intervention in paediatric CP that addresses gait-related gross motor, participation and individualized outcomes, and as such, is expected to provide comprehensive information as to the potential role of RAGT in clinical practice. Trial registration ClinicalTrials.gov NCT02196298.

Postural adjustments to support surface perturbations during reaching depend upon body-target reference frame.

We investigated whether target position relative to the body modifies the postural adjustments produced when reaching movements are perturbed by unexpected displacements of the support surface. Eleven healthy participants reached to a target located at their midline, acromion height and at 130% their outstretched arm length. They stood on two force plates mounted on a moveable platform, capable of delivering horizontal forward ramp-and-hold perturbations. Three types of trial were given: reach only (R), perturbations only (P) and reaching movements during which a perturbation was given at a random delay after reach onset (RP). The target could be mounted either on a frame suspended from the ceiling such that it remained world-fixed (exocentric target, RP/X) or at an equivalent position on the moving platform so that it moved with the body (egocentric target, RP/E). Arm and body 3D kinematics and muscle activity from the right tibialis anterior (rTA) and soleus (rSOL) muscles were recorded. Normalised rTA activity was significantly lower in RP than in P trials. Furthermore, long-latency rTA muscle activity was lower in RP/E than in RP/X conditions when perturbations were given during either the arm deceleration phase of reaching. The rSOL muscle activity was lowest for the RP/E (arm deceleration) condition. When balance is perturbed during reaching, the manner in which the target moves relative to the body determines the muscle activity produced in the lower-limb muscles. Furthermore, a target that moves with the body requires a different regulation of muscle activity compared with one that moves independently of the body.

Postural configuration does not alter unperturbed or perturbed reach movement kinematics.

This study investigated whether postural configuration has a significant effect upon the kinematics of arm movements when humans performed unconstrained reach movements to visual targets. Eight subjects were required to reach to static visual targets (unperturbed REACH movements) or correct reach movements when the position of a target unexpectedly changed during the execution of a planned movement (perturbed reaches, or online corrections, OC). Subjects were required to execute REACH and OC movements in sitting and standing (STAND) positions. The height of the targets, distance from the right shoulder (acromion) and eccentricity in terms of the body midline were standardized between the two postural conditions before movements begun. Unperturbed REACH movements were executed to a central target placed at 130 % of outstretched arm length, along the midline (0°). Perturbed (OC) movements involved subjects initiating an arm movement to the 0° target upon its illumination. Two hundred milliseconds after the onset of the hand movement, the 0° target was extinguished and the target at 60° to the right of the midline (still at 130% outstretched arm distance) illuminated. Subjects had to correct their reach movements online to the new target. Results demonstrated that, despite evident differences in postural kinematics between the four experimental conditions (e.g. pelvis obliquity and trunk/pelvis rotation), postural configuration had little or no effect upon the endpoint kinematics of the finger. Most importantly, the STAND position, with its greater postural constraints, did not affect the time taken to initiate an OC, nor did it lengthen the time taken to complete the REACH or OC movements. Our results suggest, therefore, that postural constraints are accounted for by the central nervous system when executing complex arm reaching movements.