Exploring early life social and executive function development in infants and risk for autism: a prospective cohort study protocol of NICU graduates and infants at risk for cerebral palsy.

BACKGROUND: Delays in early social and executive function are predictive of later developmental delays and eventual neurodevelopmental diagnoses. There is limited research examining such markers in the first year of life. High-risk infant groups commonly present with a range of neurodevelopmental challenges, including social and executive function delays, and show higher rates of autism diagnoses later in life. For example, it has been estimated that up to 30% of infants diagnosed with cerebral palsy (CP) will go on to be diagnosed with autism later in life. METHODS: This article presents a protocol of a prospective longitudinal study. The primary aim of this study is to identify early life markers of delay in social and executive function in high-risk infants at the earliest point in time, and to explore how these markers may relate to the increased risk for social and executive delay, and risk of autism, later in life. High-risk infants will include Neonatal Intensive Care Unit (NICU) graduates, who are most commonly admitted for premature birth and/or cardiovascular problems. In addition, we will include infants with, or at risk for, CP. This prospective study will recruit 100 high-risk infants at the age of 3-12 months old and will track social and executive function across the first 2 years of their life, when infants are 3-7, 8-12, 18 and 24 months old. A multi-modal approach will be adopted by tracking the early development of social and executive function using behavioural, neurobiological, and caregiver-reported everyday functioning markers. Data will be analysed to assess the relationship between the early markers, measured from as early as 3-7 months of age, and the social and executive function as well as the autism outcomes measured at 24 months. DISCUSSION: This study has the potential to promote the earliest detection and intervention opportunities for social and executive function difficulties as well as risk for autism in NICU graduates and/or infants with, or at risk for, CP. The findings of this study will also expand our understanding of the early emergence of autism across a wider range of at-risk groups.

Efficacy of Early Intervention for Infants With Cerebral Palsy in an LMIC: An RCT.

OBJECTIVE: To test efficacy of a parent-delivered multidomain early intervention (Learning through Everyday Activities with Parents [LEAP-CP]) for infants with cerebral palsy (CP) compared with equal-dose of health advice (HA), on (1) infant development; and (2) caregiver mental health. It was hypothesized that infants receiving LEAP-CP would have better motor function, and caregivers better mental health. METHODS: This was a multisite single-blind randomized control trial of infants aged 12 to 40 weeks corrected age (CA) at risk for CP (General Movements or Hammersmith Infant Neurologic Examination). Both LEAP-CP and HA groups received 15 fortnightly home-visits by a peer trainer. LEAP-CP is a multidomain active goal-directed intervention. HA is based on Key Family Practices, World Health Organization. Primary outcomes: (1) infants at 18 months CA: Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT mobility); and (2) caregiver: Depression Anxiety and Stress Scale. RESULTS: Of eligible infants, 153 of 165 (92.7%) were recruited (86 males, mean age 7.1±2.7 months CA, Gross Motor Function Classification System at 18 m CA: I = 12, II = 25, III = 9, IV = 18, V = 32). Final data were available for 118 (77.1%). Primary (PEDI-CAT mobility mean difference = 0.8 (95% CI -1.9 to 3.6) P = .54) and secondary outcomes were similar between-groups. Modified-Intention-To-Treat analysis on n = 96 infants with confirmed CP showed Gross Motor Function Classification System I and IIs allocated to LEAP-CP had significantly better scores on PEDI-CAT mobility domain (mean difference 4.0 (95% CI = 1.4 to 6.5), P = .003) compared with HA. CONCLUSIONS: Although there was no overall effect of LEAP-CP compared with dose-matched HA, LEAP-CP lead to superior improvements in motor skills in ambulant children with CP, consistent with what is known about targeted goal-directed training.

The critical need to accelerate cerebral palsy research with consumer engagement, global networks, and adaptive designs.

The prevalence of cerebral palsy (CP) varies globally, with higher rates and burden of disease in low- and middle-income countries. CP is a lifelong condition with no cure, presenting diverse challenges such as motor impairment, epilepsy, and mental health disorders. Research progress has been made but more is needed, especially given consumer demands for faster advancements and improvements in the scientific evidence base for interventions. This paper explores three strategies to accelerate CP research: consumer engagement, global clinical trial networks, and adaptive designs. Consumer engagement involving individuals with lived experience enhances research outcomes. Global clinical trial networks provide efficiency through larger and more diverse participant pools. Adaptive designs, unlike traditional randomized controlled trials, allow real-time modifications based on interim analyses, potentially answering complex questions more efficiently. The establishment of a CP Global Clinical Trials Network, integrating consumer engagement, global collaboration, and adaptive designs, marks a paradigm shift. The Network aims to address consumer-set research priorities. While challenges like ethical considerations and capacity building exist, the potential benefits for consumers, clinicians, researchers, and funding bodies are substantial. This paper underscores the urgency of transforming CP research methodologies for quicker translation of novel treatments into clinical practice to improve quality of life for those with CP.

The Knowledge Translation of Early Cerebral Palsy (KiTE CP) Study: Implementing Screening Among a High-Risk Prospective Cohort of Australian Infants.

OBJECTIVE: To describe the implementation of the international guidelines for the early diagnosis of cerebral palsy (CP) and engagement in the screening process in an Australian cohort of infants with neonatal risk factors for CP. STUDY DESIGN: Prospective cohort study of infants with neonatal risk factors recruited at <6 months corrected age from 11 sites in the states of Victoria, New South Wales, and Queensland, Australia. First, we implemented a multimodal knowledge translation strategy including barrier identification, technology integration, and special interest groups. Screening was implemented as follows: infants with clinical indications for neuroimaging underwent magnetic resonance imaging and/or cranial ultrasound. The Prechtl General Movements Assessment (GMA) was recorded clinically or using an app (Baby Moves). Infants with absent or abnormal fidgety movements on GMA videos were offered further assessment using the Hammersmith Infant Neurological Examination (HINE). Infants with atypical findings on 2/3 assessments met criteria for high risk of CP. RESULTS: Of the 597 infants (56% male) recruited, 95% (n = 565) received neuroimaging, 90% (n = 537) had scorable GMA videos (2% unscorable/8% no video), and 25% (n = 149) HINE. Overall, 19% of the cohort (n = 114/597) met criteria for high risk of CP, 57% (340/597) had at least 2 normal assessments (of neuroimaging, GMA or HINE), and 24% (n = 143/597) had insufficient assessments. CONCLUSIONS: Early CP screening was implemented across participating sites using a multimodal knowledge translation strategy. Although the COVID-19 pandemic affected recruitment rates, there was high engagement in the screening process. Reasons for engagement in early screening from parents and clinicians warrant further contextualization and investigation.

Human lower leg muscles grow asynchronously.

Muscle volume must increase substantially during childhood growth to generate the power required to propel the growing body. One unresolved but fundamental question about childhood muscle growth is whether muscles grow at equal rates; that is, if muscles grow in synchrony with each other. In this study, we used magnetic resonance imaging (MRI) and advances in artificial intelligence methods (deep learning) for medical image segmentation to investigate whether human lower leg muscles grow in synchrony. Muscle volumes were measured in 10 lower leg muscles in 208 typically developing children (eight infants aged less than 3 months and 200 children aged 5 to 15 years). We tested the hypothesis that human lower leg muscles grow synchronously by investigating whether the volume of individual lower leg muscles, expressed as a proportion of total lower leg muscle volume, remains constant with age. There were substantial age-related changes in the relative volume of most muscles in both boys and girls (p < 0.001). This was most evident between birth and five years of age but was still evident after five years. The medial gastrocnemius and soleus muscles, the largest muscles in infancy, grew faster than other muscles in the first five years. The findings demonstrate that muscles in the human lower leg grow asynchronously. This finding may assist early detection of atypical growth and allow targeted muscle-specific interventions to improve the quality of life, particularly for children with neuromotor conditions such as cerebral palsy.

Prevalence & Risk Factors for Perinatal Stroke: A Population-Based Study.

Objectives: The study objective was to calculate the birth prevalence of perinatal stroke and examine risk factors in term infants. Some risk factors are present in healthy infants, making it difficult to determine at-risk infants. Study Design: Prospective population-based perinatal stroke data were compared to the Australian general population data using chi-squared and Fisher's exact tests and multivariable logistic regression analysis. Results: Sixty perinatal stroke cases were reported between 2017 and 2019. Estimated stroke prevalence was 9.6/100,000 live births/year including 5.8 for neonatal arterial ischemic stroke and 2.9 for neonatal hemorrhagic stroke. Eighty seven percent had multiple risk factors. Significant risk factors were cesarean section (p = 0.04), 5-min Apgar score <7 (p < 0.01), neonatal resuscitation (p < 0.01) and nulliparity (p < 0.01). Conclusions: Statistically significant independent risk factors do not fully explain the cause of perinatal stroke, because they are not a direct causal pathway to stroke. These data now require validation in a case-control study.

Participate CP 2: optimising participation in physically active leisure for children with cerebral palsy - protocol for a phase III randomised controlled trial.

INTRODUCTION: Children with cerebral palsy (CP) participate less in physical activities and have increased sedentary behaviour compared with typically developing peers. Participate CP is a participation-focused therapy intervention for children with CP with demonstrated efficacy in a phase II randomised controlled trial (RCT) to increase perceived performance of physical activity participation goals. This study will test the effectiveness of Participate CP in a multisite phase III RCT. METHODS AND ANALYSIS: One hundred children with CP, aged 8-14 years, classified Gross Motor Function Classification System levels I-IV will be randomised to either (1) receive Participate CP once/week for 1 hour for 12 weeks, or (2) waitlist control, usual care group. The waitlist group will then receive Participate CP following the 26-week retention time point. Outcomes will be assessed at baseline, 12 weeks and then 26 weeks post baseline. The primary outcomes are (1) self-reported participation goal performance on the Canadian Occupational Performance Measure at 12 weeks and (2) daily time in moderate-to-vigorous physical activity. Secondary outcomes include home and community participation frequency, involvement and environmental supportiveness, contextual barriers to participation, quality of life, intrinsic motivation for physical activities, child perception of an autonomy-supportive climate for physical activities and physical literacy at 12 and 26 weeks post study entry. ETHICS AND DISSEMINATION: The Children's Health Queensland Hospital and Health Service, The University of Queensland and the New Zealand Health and Disability Ethics Committees have approved this study. Findings will be disseminated in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12618000206224.

Uncertainties regarding cerebral palsy diagnosis: opportunities to operationalize the consensus definition.

Background and Objectives: Cerebral palsy (CP), the most common motor disability of childhood, is variably diagnosed. We hypothesized that child neurologists and neurodevelopmentalists, often on the frontlines of CP diagnosis in North America, harbor uncertainties regarding the practical application of the most recent CP consensus definition from 2006. Methods: We conducted a cross-sectional survey of child neurologists and neurodevelopmentalists at the 2022 Child Neurology Society Annual Meeting. Attendees were provided the 2006 CP consensus definition and asked whether they had any uncertainties about the practical application of the definition across four hypothetical clinical vignettes. Results: Of 230 attendees, 164 responded to the closing survey questions (71%). 145/164 (88%) expressed at least one uncertainty regarding the clinical application of the 2006 definition. Overwhelmingly, these areas of uncertainty focused on: 1) Age, both with regards to the minimum age of diagnosis and the maximum age of brain disturbance or motor symptom onset, (67/164, 41%), and 2) Interpretation of the term "non-progressive" (48/164, 29%). The vast majority of respondents (157/164, 96%) answered 'Yes' to the question: Do you think we should revise the 2006 consensus definition of CP? Discussion: We propose that the uncertainties we identified could be addressed by operationalizing the 2006 consensus definition to support a more uniform CP diagnosis. To address the most common CP diagnostic uncertainties we identified, we propose 3 points of clarification based on the available literature: 1) Motor symptoms/signs should be present by 2 years old; 2) CP can and should be diagnosed as early as possible, even if activity limitation is not yet present, if motor symptoms/signs can be reasonably predicted to yield activity limitation (e.g. by using standardized examination instruments, Brain MRI, and a suggestive clinical history); and 3) The clinical motor disability phenotype should be non-progressive through 5 years old. We anticipate that operationalizing the 2006 definition of CP in this manner could clarify the uncertainties we identified among child neurologists and neurodevelopmentalists and reduce the diagnostic variability that currently exists.

Three-dimensional skeletal muscle architecture in the lower legs of living human infants.

Little is known about the skeletal muscle architecture of living humans at birth. In this study, we used magnetic resonance imaging (MRI) to measure the volumes of ten muscle groups in the lower legs of eight human infants aged less than three months. We then combined MRI and diffusion tensor imaging (DTI) to provide detailed, high-resolution reconstructions and measurements of moment arms, fascicle lengths, physiological cross-sectional areas (PCSAs), pennation angles and diffusion parameters of the medial (MG) and lateral gastrocnemius (LG) muscles. On average, the total lower leg muscle volume was 29.2 cm3. The largest muscle was the soleus muscle with a mean volume of 6.5 cm3. Compared to the LG muscles, the MG muscles had, on average, greater volumes (by ∼35%) and greater PCSAs (by ∼63%) but similar ankle-to-knee moment arm ratios (∼0.1 difference), fascicle lengths (∼5.7 mm difference) and pennation angles (∼2.7° difference). The MG data were compared with data previously collected from adults. The MG muscles of adults had, on average, a 63-fold greater volume, a 36-fold greater PCSA, and 1.7-fold greater fascicle length. This study demonstrates the feasibility of using MRI and DTI to reconstruct the three-dimensional architecture of skeletal muscles in living human infants. It is shown that, between infancy and adulthood, MG muscle fascicles grow primarily in cross-section rather than in length.

Baby Intensive Early Active Treatment (babiEAT): A Pilot Randomised Controlled Trial of Feeding Therapy for Infants with Cerebral Palsy and Oropharyngeal Dysphagia.

Cerebral palsy (CP), results in impairment of muscle function including the face, mouth, and throat, leading to oropharyngeal dysphagia (OPD), which affects 85% of children with CP. OPD increases risk of deficiencies in growth, neurological development, and aspiration pneumonia, a leading cause of death in CP. This pilot randomised controlled trial aimed to (i) assess feasibility and acceptability of a novel neuroplasticity and motor-learning feeding intervention program, Baby Intensive Early Active Treatment (babiEAT), and standard care, and (ii) explore preliminary efficacy of babiEAT on health and caregiver feeding-related quality of life (QoL). A total of 14 infants with both CP and OPD were randomly allocated to 12 weeks of babiEAT or standard care. Results indicate that babiEAT and standard care are equally feasible, and acceptable. Parents in the babiEAT group thought recommendations were significantly more effective than standard care parents, were more likely to recommend the program to a friend and reported higher QoL. babiEAT infants showed significantly greater efficiency in fluid intake, fewer compensatory strategies with cup drinking, consumption of more advanced food textures, and shorter mealtimes without impacting intake, aspiration risk, or weight. This small pilot study shows promise for babiEAT in infants with CP and OPD. Further research is needed to determine strength of its effects.

Effectiveness of early diagnosis of cerebral palsy guideline implementation: a systematic review.

INTRODUCTION: Tailored implementation interventions are required to overcome the diagnostic research-practice gap for cerebral palsy (CP). Evaluating the impact of interventions on patient outcomes is a priority. This review aimed to summarize the established evidence for the effectiveness of guideline implementations in lowering the age of CP diagnosis. EVIDENCE ACQUISITION: A systematic review was conducted according to PRISMA. CINAHL, Embase, PubMed and MEDLINE were searched (2017-October 2022). Inclusion criteria were studies that evaluated effect of CP guideline interventions on health professional behaviour or patient outcomes. GRADE was used to determine quality. Studies were coded for use of theory (Theory Coding Scheme). Meta-analysis was performed and a standardized metric used to summarize statistics of intervention effect estimates. EVIDENCE SYNTHESIS: Of (N.=249) records screened, (N.=7) studies met inclusion, comprising interventions following infants less than 2 years of age with CP risk factors (N.=6280). Guideline feasibility in clinical practice was established through health professional adherence and patient satisfaction. Efficacy of patient outcome of CP diagnosis by 12 months of age was established in all studies. Weighted averages were: (1) high-risk of CP (N.=2) 4.2 months and (2) CP diagnosis (N.=5) at 11.6 months. Meta-analysis of (N.=2) studies found a large, pooled effect size Z = 3.00 (P=0.003) favoring implementation interventions lowering age of diagnosis by 7.50 months, however study heterogeneity was high. A paucity of theoretical frameworks were identified in this review. CONCLUSIONS: Multifaceted interventions to implement the early diagnosis of CP guideline are effective in improving patient outcomes by lowering the age of CP diagnosis in high-risk infant follow-up clinics. Further targeted health professional interventions including low-risk infant populations are warranted.

Interventions for Motor Disorders in High-Risk Neonates.

Early childhood affords rapid brain development and advancement of the motor system. In High-Risk Infant Follow-Up programs, watchful waiting and monitoring of infants at high risk is shifting toward active surveillance and early diagnosis, followed by immediate targeted very early interventions. Infants with delayed motor skills benefit from developmental care, NIDCAP, and generic or specific motor training. Infants with cerebral palsy benefit from enrichment, targeted skills interventions, and task-specific motor training at high intensity. Infants with degenerative conditions benefit from enrichment but also require accommodations such as powered mobility.

ACTIVE STRIDES-CP: protocol for a randomised trial of intensive rehabilitation (combined intensive gait and cycling training) for children with moderate-to-severe bilateral cerebral palsy.

INTRODUCTION: For children with cerebral palsy (CP), who are marginally ambulant, gross motor capacity peaks between 6 and 7 years of age with a subsequent clinical decline, impacting their ability to engage in physical activity. Active Strides-CP is a novel package of physiotherapy targeting body functions, activity and participation outcomes for children with bilateral CP. This study will compare Active Strides-CP to usual care in a multisite randomised waitlist-controlled trial. METHODS AND ANALYSIS: 150 children with bilateral CP (5-15 years), classified in Gross Motor Function Classification System (GMFCS) levels III and IV will be stratified (GMFCS III vs IV, age 5-10 years; 11-15 years and trial site) and randomised to receive either (1) 8 weeks of Active Strides-CP two times/week for 1.5 hours in clinic and one time/week for 1 hour alternating home visits and telehealth (total dose=32 hours) or (2) usual care. Active Strides-CP comprises functional electrical stimulation cycling, partial body weight support treadmill training, overground walking, adapted community cycling and goal-directed training. Outcomes will be measured at baseline, immediately post-intervention at 9 weeks primary endpoint and at 26 weeks post-baseline for retention. The primary outcome is the Gross Motor Function Measure-66. Secondary outcomes include habitual physical activity, cardiorespiratory fitness, walking speed and distance, frequency/involvement of community participation, mobility, goal attainment and quality of life. Analyses will follow standard principles for randomised controlled trials using two-group comparisons on all participants on an intention-to-treat basis. Comparisons between groups for primary and secondary outcomes will be conducted using regression models. A within-trial cost utility analysis will be performed. ETHICS AND DISSEMINATION: The Children's Health Queensland Hospital and Health Service, The University of Queensland, The University of Melbourne and Curtin University Human Research Ethics Committees have approved this study. Results will be disseminated as conference abstracts and presentations, peer-reviewed articles in scientific journals, and institution newsletters and media releases. TRIAL REGISTRATION NUMBER: ACTRN12621001133820.

Harnessing neuroplasticity to improve motor performance in infants with cerebral palsy: a study protocol for the GAME randomised controlled trial.

INTRODUCTION: Cerebral palsy (CP) is the most common physical disability of childhood worldwide. Historically the diagnosis was made between 12 and 24 months, meaning data about effective early interventions to improve motor outcomes are scant. In high-income countries, two in three children will walk. This evaluator-blinded randomised controlled trial will investigate the efficacy of an early and sustained Goals-Activity-Motor Enrichment approach to improve motor and cognitive skills in infants with suspected or confirmed CP. METHODS AND ANALYSIS: Participants will be recruited from neonatal intensive care units and the community in Australia across four states. To be eligible for inclusion infants will be aged 3-6.5 months corrected for prematurity and have a diagnosis of CP or 'high risk of CP' according to the International Clinical Practice Guideline criteria. Eligible participants whose caregivers consent will be randomly allocated to receive usual care or weekly sessions at home from a GAME-trained study physiotherapist or occupational therapist, paired with a daily home programme, until age 2. The study requires 150 participants per group to detect a 0.5 SD difference in motor skills at 2 years of age, measured by the Peabody Developmental Motor Scales-2. Secondary outcomes include gross motor function, cognition, functional independence, social-emotional development and quality of life. A within-trial economic evaluation is also planned. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Sydney Children's Hospital Network Human Ethics Committee in April 2017 (ref number HREC/17/SCHN/37). Outcomes will be disseminated through peer-reviewed journal publications, presentations at international conferences and consumer websites. TRIAL REGISTRATION NUMBER: ACTRN12617000006347.

Study protocol: peer delivered early intervention (Learning through Everyday Activities with Parents for Infants at risk of Cerebral Palsy: LEAP-CP) for First Nation Australian infants at high risk of cerebral palsy - an RCT study.

INTRODUCTION: Cerebral palsy (CP) is the most common childhood physical disability with rates approximately 50% higher in First Nations Australian children. This study aims to evaluate a culturally-adapted parent-delivered early intervention programme for First Nations Australian infants at high risk of CP (Learning through Everyday Activities with Parents for infants with CP; LEAP-CP). METHODS AND ANALYSIS: This study is a randomised assessor masked controlled trial. Infants with birth/postnatal risk factors will be eligible for screening. Infants at high risk of CP ('absent fidgety' on General Movements Assessment, and/or 'suboptimal score' on the Hammersmith Infant Neurological Examination) aged 12-52 weeks corrected age will be recruited. Infants and their caregivers will be randomised to receive LEAP-CP (intervention) or health advice (comparator). LEAP-CP is a culturally-adapted programme of 30 home visits delivered by a peer trainer (First Nations Community Health Worker); and includes goal-directed active motor/cognitive strategies, CP learning games and caregiver educational modules. The control arm receives a monthly health advice visit, based on the Key Family Practices, WHO. All infants continue to receive standard (mainstream) Care as Usual. Dual child primary outcomes are Peabody Developmental Motor Scales-2 (PDMS-2) and Bayley Scales of Infant Development-III. The primary caregiver outcome is the Depression, Anxiety and Stress Scale. Secondary outcomes include function, goal attainment, vision, nutritional status and emotional availability. SAMPLE SIZE: total of 86 children (43/group) will enable an effect size of 0.65 on the PDMS-2 to be detected (80% power, α=0.05; 10% attrition). ETHICS AND DISSEMINATION: Ethics approval through Queensland ethics committees and Aboriginal Controlled Community Health Organisation Research Governance Groups, with families providing written informed consent. Findings will be disseminated with guidance from the Participatory Action Research, in collaboration with First Nations communities; peer-reviewed journal publications and national/international conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12619000969167p.

Risk factors for perinatal stroke in term infants: A case-control study in Australia.

AIM: The aetiology of perinatal stroke is poorly understood. This study aimed to prospectively confirm the risk factors and identify any previously unknown variables. METHODS: A prospective case-control study was conducted in Australia. Univariate odds ratios (ORs), associated 95% confidence intervals (CIs) and multivariable logistic regression models fitted with backwards stepwise variable selection were used. RESULTS: Sixty perinatal stroke cases reported between 2017 and 2019 included 95% (57/60) with multiple risk factors. Univariate analysis identified emergency caesarean section rather than NVD (P < 0.01), low Apgar score (<7) at 1, 5 and 10 min of age (P < 0.01), resuscitation at birth (P < 0.01), abnormal cord blood gas (P < 0.01), neonatal infection/sepsis (P < 0.01), congenital heart disease (P < 0.01) and hypoglycaemia (P < 0.01) as significant risk factors. Multivariate analysis found smoking during pregnancy (OR: 1.48; 95% CI: 1.09-1.99), 1-min Apgar score < 7 (OR: 1.54; 95% CI: 1.15-2.08), 10-min Apgar score < 7 (OR: 1.26; 95% CI: 1.02-1.54) and hypoglycaemia (OR: 1.49; 95% CI: 1.07-2.06). CONCLUSIONS: Perinatal stroke is associated with multiple risk factors. Exposure to smoking, 10-min Apgar score < 7, neonatal infection and hypoglycaemia were independent risk factors. Emergency caesarean section, resuscitation at birth and abnormal cord blood gas were additional risk factors.