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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.

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Adults with severe cerebral palsy (CP) are susceptible to malnutrition and metabolic disorders due to limited daily physical activity and challenges related to eating. We hypothesized that the condition of being underweight arises from inadequate energy intake due to difficulties in eating, rather than heightened total energy expenditure or an elevated resting metabolic rate. The present study encompassed 17 adults with severe CP (classified as GMFSC III-V). Energy intake, utilization, and expenditure were gauged via thorough dietary recordings and double-labeled water (DLW) analyses. Resting metabolic rates were assessed through indirect calorimetry, and metabolic health was investigated via blood samples. Oral motor function, eating assessment during meals, and weight fluctuations throughout the experimental period were also evaluated. We found significant correlations between weight, oral impairments (p < 0.01), and eating difficulties (p < 0.05). While total energy expenditure and daily consumption were similar between underweight (UW) and overweight (OW) individuals, significant variability in both expenditure and intake was evident within the UW group. Particularly, those with lower BMIs experienced heightened mealtime impairments and complications. Our present findings indicate that eating difficulties are the central concern for UW status in this population.

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Monitoring and quantifying movement behavior is crucial for improving the health of individuals with cerebral palsy (CP). We have modeled and trained an image-based Convolutional Neural Network (CNN) to recognize specific movement classifiers relevant to individuals with CP. This study evaluates CNN's performance and determines the feasibility of 24-h recordings. Seven sensors provided accelerometer and gyroscope data from 14 typically developed adults during videotaped physical activity. The performance of the CNN was assessed against test data and human video annotation. For feasibility testing, one typically developed adult and one adult with CP wore sensors for 24 h. The CNN demonstrated exceptional performance against test data, with a mean accuracy of 99.7%. Its general true positives (TP) and true negatives (TN) were 1.00. Against human annotators, performance was high, with mean accuracy at 83.4%, TP 0.84, and TN 0.83. Twenty-four-hour recordings were successful without data loss or adverse events. Participants wore sensors for the full wear time, and the data output were credible. We conclude that monitoring real-world movement behavior in individuals with CP is possible with multiple wearable sensors and CNN. This is of great value for identifying functional decline and informing new interventions, leading to improved outcomes.

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Functional magnetic resonance imaging (fMRI) studies on the sense of agency (SoA) have yielded heterogeneous findings identifying regional brain activity during tasks that probed SoA. In this review, we argue that the reason behind this between-study heterogeneity is a "synecdochic" way the field conceptualizes and studies SoA. Typically, a single feature is experimentally manipulated and then this is interpreted as covering all aspects of SoA. The purpose of this paper is to give an overview of the fMRI studies of SoA and attempt to provide meaningful categories whereby the heterogeneous findings may be classified. This classification is based on a separation of the experimental paradigms (Feedback Manipulations of ongoing movements, Action-Effect, and Sensory Attenuation) and type of report employed (implicit, explicit reports of graded or dichotic nature, and whether these concern self-other distinctions or sense of control). We only find that Feedback Manipulation and Action-Effect share common activation in supplementary motor area, insula and cerebellum in positive SoA and inferior frontal gyrus in the negative SoA, but observe large networks related to SoA only in Feedback Manipulation studies. To illustrate the advantages of this approach, we discuss the findings from an fMRI study which we conducted, within this framework.

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INTRODUCTION: Contractures are frequent causes of reduced mobility in children with cerebral palsy (CP) already at the age of 2-3 years. Reduced muscle use and muscle growth have been suggested as key factors in the development of contractures, suggesting that effective early prevention may have to involve stimuli that can facilitate muscle growth before the age of 1 year. The present study protocol was developed to assess the effectiveness of an early multicomponent intervention, CONTRACT, involving family-oriented and supervised home-based training, diet and electrical muscle stimulation directed at facilitating muscle growth and thus reduce the risk of contractures in children at high risk of CP compared with standard care. METHODS AND ANALYSIS: A two-group, parallel, open-label randomised clinical trial with blinded assessment (n=50) will be conducted. Infants diagnosed with CP or designated at high risk of CP based on abnormal neuroimaging or absent fidgety movement determined as part of General Movement Assessment, age 9-17 weeks corrected age (CA) will be recruited. A balanced 1:1 randomisation will be made by a computer. The intervention will last for 6 months aiming to support parents in providing daily individualised, goal-directed activities and primarily in lower legs that may stimulate their child to move more and increase muscle growth. Guidance and education of the parents regarding the nutritional benefits of docosahexaenic acid (DHA) and vitamin D for the developing brain and muscle growth will be provided. Infants will receive DHA drops as nutritional supplements and neuromuscular stimulation to facilitate muscle growth. The control group will receive standard care as offered by their local hospital or community. Outcome measures will be taken at 9, 12, 18, 24, 36 and 48 months CA. Primary and secondary outcome measure will be lower leg muscle volume and stiffness of the triceps surae musculotendinous unit together with infant motor profile, respectively. ETHICS AND DISSEMINATION: Full approval from the local ethics committee, Danish Committee System on Health Research Ethics, Region H (H-19041562). Experimental procedures conform with the Declaration of Helsinki. TRIAL REGISTRATION NUMBER: NCT04250454. EXPECTED RECRUITMENT PERIOD: 1 January 2021-1 January 2025.

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Living with a congenital brain lesion may have detrimental effects on the ability to do everyday activities, but contrary to acquired brain lesions, people and in particular children, with congenital brain lesions may have limited or no experience of how their bodies work. This absence of experience gives rise to challenges for habilitation of sensorimotor abilities and derived cognitive abilities. How can motor and cognitive abilities be achieved and trained in an individual with no experience of potential abilities? In this article, we aim to review the existing knowledge about the development of sensorimotor integration. Further, we will discuss this knowledge in the light of two neurocognitive theories: embodied cognition and predictive coding. Moreover, using developmental knowledge and theory in combination, we will argue that early sensorimotor development serves as a foundation for later cognitive development. Finally, we try to use these elements in a strategy to make interventions as early as possible, with the purpose of improving sensorimotor and cognitive abilities in children with congenital brain lesions.

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Accumulating evidence suggests that parieto-frontal connections play a role in adjusting body ownership during the Rubber Hand Illusion (RHI). Using a motor version of the rubber hand illusion paradigm, we applied single-site and dual-site transcranial magnetic stimulation (TMS) to investigate cortico-spinal and parietal-frontal connectivity during perceived rubber hand ownership. Healthy volunteers received a conditioning TMS pulse over left anterior intraparietal sulcus (aIPS) and a test TMS pulse over left primary motor cortex (M1). Motor Evoked Potentials (MEPs) were recorded at rest and during three RHI conditions: (i) agency and ownership, (ii) agency but no ownership and (iii) neither agency nor ownership. Parietal-motor communication differed among experimental conditions. The induction of action ownership was associated with an inhibitory parietal-to-motor connectivity, which was comparable to the aIPS-to-M1 inhibition present at rest. This aIPS-to-M1 inhibition disappeared during movement conditions not inducing ownership. Cortico-spinal excitability was not significantly modulated during the motor RHI as indicated by the task-constant MEP amplitude elicited by the M1 test pulse alone. Our results indicate that the perceived ownership over the rubber hand is associated with normal parietal-motor communication. This communication is disturbed if the sensorimotor conflict between one's own hand and the rubber hand is not resolved.

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BACKGROUND: Learning and memory have been shown to be influenced by combination of dietary supplements and exercise in animal models, but there is little available evidence from human subjects. The aim of this pilot study was to investigate the effect of combining a motor- and cognitive exercise program with dietary supplementation consisting of 500 mg docosahexaenoic acid (DHA), 10 µg vitamin D3 and 1000 mg uridine (DDU-supplement) in 16 prepubescent children (age 8-11 years). METHODS: We designed a randomized, placebo-controlled, double-blinded study lasting 6 weeks in which DDU-supplement or placebo was ingested daily. During the intervention period, all children trained approximately 30 min 3 days/week using an internet-based cognitive and motor training program (Mitii). Prior to and post the intervention period dietary record, blood sampling, physical exercise tests and motor and cognitive tests were performed. RESULTS: Fourteen of the 16 children completed the intervention and ingested the supplement as required. 6 weeks DDU-supplementation resulted in a significant increase in the blood concentration of vitamin D2+3 and DHA (p = 0.023 and p < 0.001, respectively). Power calculation based on one of the cognitive tasks revealed a proper sample size of 26 children. CONCLUSION: All children showed improved performance in the trained motor- and cognitive tasks, but it was not possible to demonstrate any significant effects on the cognitive tests from the dietary supplementation. However, DDU-supplementation did result in increased blood concentration of DHA and vitamin D2+3. TRIAL REGISTRATION: Clinical registration ID: NCT02426554 (clinical Trial.gov). January 2015 retrospectively registered.

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KEY POINTS: The early postnatal development of functional corticospinal connections in human infants is not fully clarified. Corticospinal drive to upper and lower limb muscle shows developmental changes with an increased functional coupling in infants between 9 and 25 weeks in the beta frequency band. The changes in functional coupling coincide with the developmental period where fidgety movements are present in healthy infants. Data support a possible sensitive period where functional connections between corticospinal tract fibres and spinal motoneurones undergo activity-dependent reorganization. ABSTRACT: The early postnatal development of functional corticospinal connections in human infants is not fully clarified. We used EEG and EMG to investigate the development of corticomuscular and intramuscular coherence as indicators of functional corticospinal connectivity in healthy infants aged 1-66 weeks. EEG was recorded over leg and hand area of motor cortex. EMG recordings were made from right ankle dorsiflexor and right wrist extensor muscles. Quantification of the amount of corticomuscular coherence in the 20-40 Hz frequency band showed a significantly larger coherence for infants aged 9-25 weeks compared to younger and older infants. Coherence between paired EMG recordings from tibialis anterior muscle in the 20-40 Hz frequency band was also significantly larger for the 9-25 week age group. A low-amplitude, broad-duration (40-50 ms) central peak of EMG-EMG synchronization was observed for infants younger than 9 weeks, whereas a short-lasting (10-20 ms) central peak was observed for EMG-EMG synchronization in older infants. This peak was largest for infants aged 9-25 weeks. These data suggest that the corticospinal drive to lower and upper limb muscles shows significant developmental changes with an increase in functional coupling in infants aged 9-25 weeks, a period which coincides partly with the developmental period of normal fidgety movements. We propose that these neurophysiological findings may reflect the existence of a sensitive period where the functional connections between corticospinal tract fibres and spinal motoneurones undergo activity-dependent reorganization. This may be relevant for the timing of early therapy interventions in infants with pre- and perinatal brain injury.

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AIM: Lack of muscle growth relative to bone growth may be responsible for development of contractures in children with cerebral palsy (CP). Here, we used ultrasonography to compare growth of the medial gastrocnemius muscle in children with and without CP. METHOD: Twenty-six children with spastic CP (15 males, 11 females; mean age 35mo, range 8-65mo) and 101 typically developing children (47 males, 54 females; mean age 29mo, range 1-69mo) were included. Functional abilities of children with CP equalled levels I to III in the Gross Motor Function Classification System. Medial gastrocnemius muscle volume was constructed from serial, transverse, two-dimensional ultrasonography images. RESULTS: In typically developing children, medial gastrocnemius volume increased linearly with age. Among children with CP, medial gastrocnemius volume increased less with age and deviated significantly from typically developing children at 15 months of age (p<0.05). Bone length increased with age without significant difference (p=0.49). INTERPRETATION: Muscle growth in children with CP initially follows that of typically developing children, but decreases at 15 months of age. This may be related to reduced physical activity and neural activation of the muscle. Interventions stimulating muscle growth in young children with CP may be important to prevent contractures.

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In the present study we tested whether sense of agency (SoA) is reflected by changes in coupling between right medio-frontal/supplementary motor area (SMA) and inferior parietal cortex (IPC). Twelve healthy adult volunteers participated in the study. They performed a variation of a line-drawing task (Nielsen, 1963; Fourneret and Jeannerod, 1998), in which they moved a cursor on a digital tablet with their right hand without seeing the hand. Visual feedback displayed on a computer monitor was either in correspondence with or deviated from the actual movement. This made participants uncertain as to the agent of the movement and they reported SoA in approximately 50% of trials when the movement was computer-generated. We tested whether IPC-preSMA coupling was associated with SoA, using dynamic causal modeling (DCM) for induced responses (Chen et al., 2008; Herz et al., 2012). Nine different DCMs were constructed for the early and late phases of the task, respectively. All models included two regions: a superior medial gyrus (preSMA) region and a right supramarginal gyrus (IPC) region. Bayesian models selection (Stephan et al., 2009) favored a model with input to IPC and modulation of the forward connection to SMA in the late task phase, and a model with input to preSMA and modulation of the backward connection was favored for the early task phase. The analysis shows that IPC source activity in the 50-60 Hz range modulated preSMA source activity in the 40-70 Hz range in the presence of SoA compared with no SoA in the late task phase, but the test of the early task phase did not reveal any differences between presence and absence of SoA. We show that SoA is associated with a directionally specific between frequencies coupling from IPC to preSMA in the higher gamma (É£) band in the late task phase. This suggests that SoA is a retrospective perception, which is highly dependent on interpretation of the outcome of the performed action.

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A large body of fMRI and lesion-literature has provided evidence that the Inferior Parietal Cortex (IPC) is important for sensorimotor integration and sense of agency (SoA). We used repetitive transcranial magnetic stimulation (rTMS) to explore the role of the IPC during a validated SoA detection task. 12 healthy, right-handed adults were included. The effects of rTMS on subjects' SoA during self-controlled movements were explored. The experiment consisted of 1/3 self-controlled movements and (2)/3 computer manipulated movements that introduced uncertainty as to whether the subjects were agents of an observed movement. Subjects completed three sessions, in which subjects received online rTMS over the right IPC (active condition), over the vertex (CZ) (sham condition) or no TMS but a sound-matched control. We found that rTMS over right IPC significantly altered SoA of the non-perturbed movements. Following IPC stimulation subjects were more likely to experience self-controlled movements as being externally perturbed compared to the control site (P = 0.002) and the stimulation-free control (P = 0.042). The data support the importance of IPC activation during sensorimotor comparison in order to correctly determine the agent of movements.

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Declines in the ability to learn motor skills in older adults are commonly attributed to deficits in the encoding of sensorimotor information during motor practice. We investigated whether aging also impairs motor memory consolidation by assessing the susceptibility to memory interference and off-line gains in motor skill learning after practice in children, young, and older adults. Subjects performed a ballistic task (A) followed by an accuracy-tracking task (B) designed to disrupt the consolidation of A. Retention tests of A were performed immediately and 24 hours after B. Older adults showed greater susceptibility to memory interference and no off-line gains in motor skill learning. Performing B produced memory interference and reduced off-line gains only in the older group. However, older adults also showed deficits in memory consolidation independent of the interfering effects of B. Age-related declines in motor skill learning are not produced exclusively by deficits in the encoding of sensorimotor information during practice. Aging also increases the susceptibility to memory interference and reduces off-line gains in motor skill learning after practice.

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The ability to decide which of the two stimuli is presented first can be probed using a temporal order judgment (TOJ) task. When the stimuli are delivered to the fingers, TOJ decisions can be confounded by the fact that the hands can be moved to different locations in space. How and where this confounded information is processed in the brain is poorly understood. In the present set of experiments, we addressed this knowledge gap by using single-pulse transcranial magnetic stimulation (TMS) to disrupt processing in the right or left posterior parietal cortex (PPC) during a vibrotactile TOJ task with stimuli applied to the right and left index fingers. In the first experiment, participants held their hands in an uncrossed configuration, and we found that when the index finger contralateral to the site of TMS was stimulated first, there was a significant increase in TOJ errors. This increase did not occur when stimuli were delivered to the ipsilateral finger first. In the second experiment, participants held their hands in a crossed configuration and the pattern of errors was reversed relative to the first experiment. In both the first two experiments, significant increases in TOJ error were present with TMS over either hemisphere, regardless of arm configuration; however, they were larger overall following TMS over the right PPC. Control experiments using sham TMS indicated the systematic modulation in error was not due to nonspecific effects of the stimulation. Additionally, we showed that these TMS-induced changes in TOJ errors were not due to a reduced ability to detect the timing of the vibrotactile stimuli. Taken together, these results demonstrate that both the right and left PPC contribute to the processing underlying vibrotactile TOJs by integrating vibrotactile information and proprioceptive information related to arm position in space.

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BACKGROUND: Children diagnosed with spastic Cerebral Palsy (CP) often show perceptual and cognitive problems, which may contribute to their functional deficit. Here we investigated if altered ability to determine whether an observed movement is performed by themselves (sense of agency) contributes to the motor deficit in children with CP. METHODS: Three groups; 1) CP children, 2) healthy peers, and 3) healthy adults produced straight drawing movements on a pen-tablet which was not visible for the subjects. The produced movement was presented as a virtual moving object on a computer screen. Subjects had to evaluate after each trial whether the movement of the object on the computer screen was generated by themselves or by a computer program which randomly manipulated the visual feedback by angling the trajectories 0, 5, 10, 15, 20 degrees away from target. RESULTS: Healthy adults executed the movements in 310 seconds, whereas healthy children and especially CP children were significantly slower (p < 0.002) (on average 456 seconds and 543 seconds respectively). There was also a statistical difference between the healthy and age matched CP children (p = 0.037). When the trajectory of the object generated by the computer corresponded to the subject's own movements all three groups reported that they were responsible for the movement of the object. When the trajectory of the object deviated by more than 10 degrees from target, healthy adults and children more frequently than CP children reported that the computer was responsible for the movement of the object. CP children consequently also attempted to compensate more frequently from the perturbation generated by the computer. CONCLUSIONS: We conclude that CP children have a reduced ability to determine whether movement of a virtual moving object is caused by themselves or an external source. We suggest that this may be related to a poor integration of their intention of movement with visual and proprioceptive information about the performed movement and that altered sense of agency may be an important functional problem in children with CP.

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Accurate motor execution is achieved by estimating future sensory states via a forward model of limb dynamics. In the current experiment, we probed the time course over which state estimation evolves during movement planning by combining a bimanual arm crossing movement with a temporal order judgment (TOJ) task. Human participants judged which of two successive vibrotactile stimuli delivered to each index finger arrived first as they were preparing to either cross or uncross their hands. TOJ error rate was found to systematically vary in a time- and direction-dependent manner. When planning to cross the hands, error rate systematically increased as the vibrotactile stimuli were delivered closer in time to the onset of the movement. By contrast, planning to uncross the hands led to a gradual reduction in error rate as movement planning progressed. In both cases, these changes occurred before the actual alteration in hand configuration. We suggest that these systematic changes in error represent an interaction between the evolving state estimation processes and decisions regarding the timing of successive events.

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