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Several vaccines against chikungunya fever have been developed and tested, and one has been recently licensed. We performed a meta-analysis to estimate the immunogenicity and safety of all chikungunya vaccines that have been progressed to clinical trial evaluation (VLA1553; mRNA-1388/VAL-181388; PXVX0317/VRC-CHKVLP059-00-VP; ChAdOx1 Chik; MV-CHIK). We included trials retrieved from MedLine, Scopus, and ClinicalTrials.gov. The outcomes were the rates of seroconversion/seroresponse and serious adverse events (SAEs) after the primary immunization course. We retrieved a total of 14 datasets, including >4000 participants. All candidate chikungunya vaccines were able to elicit an immunogenic response in ≥96% of vaccinated subjects, regardless of the vaccination schedule and platform used, and the seroconversion/seroresponse rates remained high 6 to 12 months after vaccination for most vaccines. Four of the five candidate vaccines showed a good overall safety profile (no data were available for ChAdOx1 Chik), with no significant increase in the risk of SAEs among the vaccinated, and a low absolute risk of product-related SAEs. Overall, the present findings support the potential use of the candidate vaccines for the prevention of chikungunya and the current indication for use in adult travelers to endemic regions of the licensed VLA 1553 vaccine. In order to extend chikungunya vaccination to a wider audience, further studies are needed on individuals from endemic countries and frail populations.

Unilateral spastic Cerebral Palsy (UCP) results from congenital brain injury, and Magnetic Resonance Imaging (MRI) has a role in understanding the etiology and severity of brain insult. In UCP, functional impairment predominantly occurs in the upper limb (UL) of the more affected side, where manual ability and dexterity are typically reduced. Also, mirror movements (MMs), are often present in UCP, with a further possible negative functional impact. This study aims to investigate the relationships among neuroanatomical characteristics of brain injury at MRI, manual functional impairment and MMs, in children with UCP. Thirty-five children with UCP participated in the study (20, M = 15, F, mean age 9.2 ± 3.5 years). Brain lesions at MRI were categorized according to the Magnetic Resonance Classification System (MRICS) and by using a semi-quantitative MRI (sqMRI) scale. Gross manual performance was assessed through Manual Ability Classification System (MACS) and the Box and Block Test (BBT), and MMs by Woods and Teuber scale, for both hands. Non-parametric correlation analyses were run to determine the relationship between neuroanatomical and functional features. Regression models were run to explore the contribution of neuroanatomical features and MMs to UL function. Correlation analyses revealed moderate to strong associations between sqMRI scores contralateral to the more affected side and UL functional impairment on MACS and BBT, with more severe brain injuries significantly correlating with poorer function in the more affected hand. No association emerged between brain lesion severity scores and MMs. MRICS showed no association with MACS or BBT, while a significant correlation emerged between MRICS category and MMs in the more affected hand, with brain lesion category that are suggestive of presumed earlier injury being associated with more severe MMs. Finally, exploratory regression analyses showed that neuroanatomical characteristics of brain injury and MMs contributed to the variability of UL functional impairment. This study contributes to the understanding of the neuroanatomical and neurological correlates of some aspects of manual functional impairment in UCP by using a simple clinical brain MRI assessment.

IntroductionThe use of Information and Communication Technology (ICT) for assessing and treating cognitive and motor disorders is promoting home-based telerehabilitation. This approach involves ongoing monitoring within a motivating context to help patients generalize their skills. It can also reduce healthcare costs and geographic barriers by minimizing hospitalization. This systematic review focuses on investigating key aspects of telerehabilitation protocols for children with neurodevelopmental or neurological disorders, including technology used, outcomes, caregiver involvement, and dosage, to guide clinical practice and future research.MethodThis systematic review adhered to PRISMA guidelines and was registered in PROSPERO. The PICO framework was followed to define the search strategy for technology-based telerehabilitation interventions targeting the pediatric population (aged 0–18) with neurological or neurodevelopmental disorders. The search encompassed Medline/PubMed, EMBASE, and Web of Science databases. Independent reviewers were responsible for selecting relevant papers and extracting data, while data harmonization and analysis were conducted centrally.ResultsA heterogeneous and evolving situation emerged from our data. Our findings reported that most of the technologies adopted for telerehabilitation are commercial devices; however, research prototypes and clinical software were also employed with a high potential for personalization and treatment efficacy. The efficacy of these protocols on health or health-related domains was also explored by categorizing the outcome measures according to the International Classification of Functioning, Disability, and Health (ICF). Most studies targeted motor and neuropsychological functions, while only a minority of papers explored language or multi-domain protocols. Finally, although caregivers were rarely the direct target of intervention, their role was diffusely highlighted as a critical element of the home-based rehabilitation setting.DiscussionThis systematic review offers insights into the integration of technological devices into telerehabilitation programs for pediatric neurologic and neurodevelopmental disorders. It highlights factors contributing to the effectiveness of these interventions and suggests the need for further development, particularly in creating dynamic and multi-domain rehabilitation protocols. Additionally, it emphasizes the importance of promoting home-based and family-centered care, which could involve caregivers more actively in the treatment, potentially leading to improved clinical outcomes for children with neurological or neurodevelopmental conditions.Systematic review registrationPROSPERO (CRD42020210663).

Abstract Background Nowadays, wearable sensors are widely used to quantify physical and motor activity during daily life, and they also represent innovative solutions for healthcare. In the clinical framework, the assessment of motor behaviour is entrusted to clinical scales, but they are dependent on operator experience. Thanks to their intrinsic objectivity, sensor data are extremely useful to provide support to clinicians. Moreover, wearable sensors are user-friendly and compliant to be used in an ecological environment (i.e., at home). This paper aims to propose an innovative approach useful to predict clinical assessment scores of infants’ motor activity. Materials and methods Starting from data acquired by accelerometers placed on infants’ wrists and trunk during playtime, we exploit the method of functional data analysis to implement new models combining quantitative data and clinical scales. In particular, acceleration data, transformed into activity indexes and combined with baseline clinical data, represent the input dataset for functional linear models. Conclusions Despite the small number of data samples available, results show correlation between clinical outcome and quantitative predictors, indicating that functional linear models could be able to predict the clinical evaluation. Future works will focus on a more refined and robust application of the proposed method, based on the acquisition of more data for validating the presented models. Trial registration number: ClincalTrials.gov; NCT03211533. Registered: July, 7th 2017. ClincalTrials.gov; NCT03234959. Registered: August, 1st 2017.

The TAK-003 dengue vaccine was licensed in Europe in December 2022, and the official recommendations from most EU countries are still under formulation. To support policymakers, we performed a meta-analysis to quantify TAK-003’s immunogenicity, efficacy and safety among seronegative and seropositive populations after the administration of one or two vaccine doses. We included trials retrieved from MEDLINE, Scopus and ClinicalTrials.gov. The outcomes were the rates of seroconversion, virologically confirmed dengue fever and serious adverse events after each vaccine dose. Data were combined using random-effect proportion or head-to-head meta-analyses. We retrieved a total of 19 datasets, including >20,000 participants. TAK-003 showed an excellent safety profile, and the immunogenicity after two doses against the four DENV serotypes was ≥90% among both adults and children/adolescents who were either seronegative or seropositive at baseline. A single dose was able to elicit a high immunogenic response among adults (≥70%) and children/adolescents (≥90%). The primary two-dose immunization course halved the risk of all types of virologically confirmed dengue fever among seropositive children/adolescents, but seronegative minors were only protected against the diseases caused by DENV-1 and DENV-2. Overall, the results support the use of TAK-003 for the prevention of dengue fever in the pediatric population of endemic countries. Uncertainties remain on the use of a single vaccine dose in non-endemic countries.

[This corrects the article DOI: 10.1371/journal.pone.0250420.].

Se narra la experiencia de una película en la cárcel inspirada en Pier Paolo Pasolini. NON È SOGNO (NO ES SUEÑO) es una película grabada con los presos de la cárcel de Capanne (Perugia) que comienza con los ensayos de una escena de Che cosa sono le nuvole? de Pasolini, aquella en la que Ninetto Davoli y Totò se preguntan acerca del juicio y la verdad. Un dispositivo pensado para crear un espacio lúdico, para romper la visión sobre “la cárcel de los otros”. La actuación se convierte en una puesta en escena de la vida, de la historia propia, actuación de una verdad humana.

Abstract Autistic traits represent a continuum dimension across the population, with autism spectrum disorder (ASD) being the extreme end of the distribution. Accumulating evidence shows that neuroanatomical and neurofunctional profiles described in relatives of ASD individuals reflect an intermediate neurobiological pattern between the clinical population and healthy controls. This suggests that quantitative measures detecting autistic traits in the general population represent potential candidates for the development of biomarkers identifying early pathophysiological processes associated with ASD. Functional near-infrared spectroscopy (fNIRS) has been extensively employed to investigate neural development and function. In contrast, the potential of fNIRS to define reliable biomarkers of brain activity has been barely explored. Features of non-invasiveness, portability, ease of administration, and low-operating costs make fNIRS a suitable instrument to assess brain function for differential diagnosis, follow-up, analysis of treatment outcomes, and personalized medicine in several neurological conditions. Here, we introduce a novel standardized procedure with high entertaining value to measure hemodynamic responses (HDR) in the occipital cortex of adult subjects and children. We found that the variability of evoked HDR correlates with the autistic traits of children, assessed by the Autism-Spectrum Quotient. Interestingly, HDR amplitude was especially linked to social and communication features, representing the core symptoms of ASD. These findings establish a quick and easy strategy for measuring visually-evoked cortical activity with fNIRS that optimize the compliance of young subjects, setting the background for testing the diagnostic value of fNIRS visual measurements in the ASD clinical population.

Abstract The literature on time perception in individuals with ADHD is extensive but inconsistent, probably reflecting the use of different tasks and performances indexes. A sample of 40 children/adolescents (20 with ADHD, 20 neurotypical) was engaged in two identical psychophysical tasks measuring auditory time thresholds in the milliseconds (0.25–1 s) and seconds (0.75–3 s) ranges. Results showed a severe impairment in ADHD for milliseconds thresholds (Log10BF = 1.9). The deficit remained strong even when non-verbal IQ was regressed out and correlation with age suggests a developmental delay. In the seconds range, thresholds were indistinguishable between the two groups (Log10BF = − 0.5) and not correlated with milliseconds thresholds. Our results largely confirm previous evidence suggesting partially separate mechanisms for time perception in the ranges of milliseconds and seconds. Moreover, since the evidence suggests that time perception of milliseconds stimuli might load relatively less on cognitive control and working memory, compared to longer durations, the current results are consistent with a pure timing deficit in individuals with ADHD.

Abstract Background SLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense variant A391T is associated with increased risk for multiple neurological and systemic disorders and with decreased serum Mn. Patients with SLC39A8-CDG present with different clinical and neuroradiological features linked to variable transferrin glycosylation profile. Galactose and Mn supplementation therapy results in the biochemical and clinical amelioration of treated patients. Results Here, we report clinical manifestations, neuroradiological features and glycophenotypes associated with novel SLC39A8 variants (c.1048G > A; p.Gly350Arg and c.131C > G; p.Ser44Trp) in two siblings of the same Italian family. Furthermore, we describe a third patient with overlapping clinical features harbouring the homozygous missense variant A391T. The clinical phenotype of the three patients was characterized by severe developmental disability, dystonic postural pattern and dyskinesia with a more severe progression of the disease in the two affected siblings. Neuroimaging showed a Leigh syndrome-like pattern involving the basal ganglia, thalami and white matter. In the two siblings, atrophic cerebral and cerebellum changes consistent with SLC39A8-CDG were detected as well. Serum transferrin isoelectric focusing (IEF) yielded variable results with slight increase of trisialotransferrin isoforms or even normal pattern. MALDI-MS showed the presence of hypogalactosylated transferrin N-glycans, spontaneously decreasing during the disease course, only in one affected sibling. Total serum N-glycome depicted a distinct pattern for the three patients, with increased levels of undergalactosylated and undersialylated precursors of fully sialylated biantennary glycans, including the monosialo-monogalacto-biantennary species A2G1S1. Conclusions Clinical, MRI and glycosylation features of patients are consistent with SLC39A8-CDG. We document two novel variants associated with Leigh syndrome-like disease presentation of SLC39A8-CDG. We show, for the first time, a severe neurological phenotype overlapping with that described for SLC39A8-CDG in association with the homozygous A391T missense variant. We observed a spontaneous amelioration of transferrin N-glycome, highlighting the efficacy of MS-based serum glycomics as auxiliary tool for the diagnosis and clinical management of therapy response in patients with SLC39A8-CDG. Further studies are needed to analyse more in depth the influence of SLC39A8 variants, including the common missense variant, on the expression and function of ZIP8 protein, and their impact on clinical, biochemical and neuroradiological features.

Abstract Background Preterm infants and infants with perinatal brain injury show a higher incidence of neurodevelopmental disorders (NDD). The Infant Motor Profile (IMP) is a clinical assessment which evaluates the complexity of early motor behaviour. More data are needed to confirm its predictive ability and concurrent validity with other common and valid assessments such as the Alberta Infant Motor Scale (AIMS) and Prechtl’s General Movement Assessment (GMA). The present study aims to evaluate the concurrent validity of the IMP with the AIMS, to assess its association with the GMA, to evaluate how the IMP reflects the severity of the brain injury and to compare the ability of the IMP and the AIMS to predict an abnormal outcome in 5-month-old infants at risk of NDD. Methods 86 infants at risk of NDD were retrospectively recruited among the participants of two clinical trials. Preterm infants with or without perinatal brain injury and term infants with brain injury were assessed at 3 months corrected age (CA) using the GMA and at 5 months CA using the IMP and the AIMS. The neurodevelopmental outcome was established at 18 months. Results Results confirm a solid concurrent validity between the IMP Total Score and the AIMS (Spearman’s ρ 0.76; p

Abstract Background Creatine (Cr), an amino acid derivative, is one of the most important sources of energy acting as both a spatial and temporal energy buffer through its phosphorylated analogue phosphocreatine (PCr) and creatine kinase (CK). Maternal Cr biosynthesis and metabolism seem to play an important role in pregnancy, as shown in preclinical and in healthy human pregnancy studies. Patients with Arginine:Glycine Amidino-Transferase deficiency (AGAT-d), due to the deficit of the first enzyme involved in Cr synthesis, are at a disadvantage due to their failure to synthesize Cr and their dependence on external intake, in contrast to normal subjects, where changes in Cr biosynthesis supply their needs. We report the outcomes of a pregnancy in an AGAT-d woman, and the challenge we faced in managing her treatment with oral Cr to ensure optimal conditions for her fetus. Case presentation A 22-year-old AGAT-d woman referred to our Institute for the management of her first conception at 11 weeks of fetal gestational age. Sonographic monitoring at 20 w GA indicated a reduction of fetal growth, in particular of the head circumference that was below the 3rd centile. Biochemical monitoring of Cr in biological fluids of the mother revealed a decline of the Cr concentrations, in particular in the urine sample, requiring prompt correction of the Cr dose. At 35 weeks of gestation the patient delivered a male infant, heterozygous for GATM mutation, with normal brain Cr levels; at one year the baby achieved typical developmental milestones. Conclusions This rare pregnancy demonstrates that Cr levels in the blood and urine of the mother with AGAT-d decreased since the first months of gestation. The increase of the Cr daily dose administered to the mother seems to have produced beneficial effects also on the fetus.

The coming of an unforeseen and hostile event such as the COVID-19 pandemic has brought about various changes in everyone's daily life. During the lockdown period, a huge number of restrictions were imposed, hence interrupting a wide range of activities previously proven to be necessary for some people. Due to the circumstances, rehabilitation treatments for children with neurodevelopmental disorders have been suspended, resulting in consequent distress for the children themselves and their parents. To overcome this problem, a tele-rehabilitation approach has proven to be an excellent solution to give continuity to children's rehabilitation. The tele-rehabilitation approach allows access to rehabilitation services directly from home. During lockdown due to the COVID-19 pandemic, the Virtual Reality Rehabilitation System (VRRS) HomeKit, developed by Khymeia, was employed as a rehabilitation system for the treatment of posture and balance of an adolescent with disabilities for the first time ever. Specifically, a 17-year-old female patient was enrolled and evaluated by the clinical staff before and after the home-training sessions. The system was delivered to the patient's home so that she could perform the tasks in a familiar environment, while under the supervision of the clinical staff. Through a specific platform, using different modules of the system, therapists could remotely check that the proposed exercises were properly performed and provide feedback and/or increase the difficulty according to the patient's needs and progress. Therefore, the treatment performed was carried out at home in a personalized, intensive, and playful way; characteristics do not present in a traditional treatment. Our results are promising and demonstrate both the efficacy of rehabilitation exercises carried out at home and the feasibility of home-based rehabilitation, when using the VRRS HomeKit even with adolescents. The VRRS HomeKit presents some limitations, such as the need to have the line connection and free space at home, the presence of technical issues, and the education of parents and patients to understand the instructions. Despite the limitations, this study provides the basis for continuing the experience of tele-rehabilitation on patients with a motor disorder also by customizing the exercises to their characteristics.

Navigation is a complex process, requiring target localization, route planning or retrieval, and physical displacement. Executive functions (EFs) such as working memory, inhibition and planning are fundamental for succeeding in this complex activity and are often impaired in Attention Deficit and Hyperactivity Disorder (ADHD). Our aim was to analyze the feasibility of a new ecological navigation task, the Virtual City paradigm™ (VC™) to test visuo-spatial memory and EFs in children with ADHD. Visuo-spatial short and working memory, inhibition and planning skills were tested with standardized tasks. The VC™, a new paradigm developed by our group, used the Virtual CarpetTM technology, consisting of a virtual town with houses, streets and crossroads projected on the ground. It includes a motion capture system, tracking body movement in 3D in real time. In one condition, children were required to walk through the city and reach a sequence of houses. In the other, before walking, they had to plan the shortest path to reach the houses, inhibiting the prepotent response to start walking. The results show a good feasibility of the paradigm (feasibility checklist and ad hoc questionnaire), being ecological and motivating. VC™ measures of span positively correlated with visuo-spatial short and working memory measures, suggesting that VC™ heavily relies on efficient spatial memory. Individual subject analyses suggested that children with ADHD may approach this task differently from typically developing children. Larger samples of ADHD and healthy children may further explore the specific role of EFs and memory, potentially opening new avenues for intervention.

Abstract Background To systematically review and analyse the effects of Action Observation Training on adults and children with brain damage. Methods Seven electronic databases (Cochrane, EBSCO, Embase, Eric, PubMed, Scopus and Web of Science) were searched up to 16 September 2018 to select Randomized Controlled Trials focused on adults and children with brain damage that included AOT training on upper and/or lower limb carried out for at least 1 week. Identification of studies and data extraction was conducted with two reviewers working independently. Oxford Centre for Evidence-based Medicine (March2009) – Levels of Evidence and Physiotherapy Evidence Database scale were used to grade studies. The data collected from the articles were analysed using software R, version 3.4.3. Hedge’s g values were calculated and effect size estimates were pooled across studies. Separate meta-analyses were carried out for each ICF domain (i.e. body function and activity) for upper and lower limb. Results Out of the 210 records identified after removing duplicates, 22 were selected for systematic review and 19 were included in the meta-analysis. Thirteen studies included in the meta-analysis focused on upper limb rehabilitation (4 in children and 9 in adults) and 6 on lower limb rehabilitation (only studies in adults). A total of 626 patients were included in the meta-analysis. An overall statistically significant effect size was found for upper limb body function (0.44, 95% CI: [0.24, 0.64], p

Abstract Background Detecting differences in upper limb use in children with unilateral cerebral palsy (UCP) is challenging and highly dependent on examiner experience. The recent introduction of technologies in the clinical environment, and in particular the use of wearable sensors, can provide quantitative measurement to overcome this issue. This study aims to evaluate ActiGraph GT3X+ as a tool for measuring asymmetry in the use of the two upper limbs (ULs) during the assessment with a standardized clinical tool, the Assisting Hand Assessment (AHA) in UCP patients aged 3–25 years compared to age-matched typically developing (TD) subjects. Methods Fifty children with UCP and 50 TD subjects were assessed with AHA while wearing ActiGraphs GT3X+ on both wrists. The mean activity of each hand (dominant and non-dominant, MADH and MANDH, respectively) and the asymmetry index (AI) were calculated. Two linear mixed model analyses were carried out to evaluate how dependent actigraphic variables (i.e. MANDH and AI) varied by group (TD vs UCP) and among levels of manual ability based on Manual Ability Classification System (MACS). In both models age, sex, side of hemiplegia, presence/absence of mirror movements were specified as random effects. Results The MANDH was significantly lower in UCP compared to TD, while the AI was significantly higher in UCP compared to TD. Moreover, in UCP group there were significant differences related to MACS levels, both for MANDH and AI. None of the random variables (i.e. age, sex, side, presence/absence of mirror movements) showed significant interaction with MANDH and AI. Conclusions These results confirm that actigraphy could provide, in a standardized setting, a quantitative description of differences between upper limbs activity. Trial registration ClincalTrials.gov, NCT03054441. Registered 15 February 2017.

Infant massage (IM) can be considered an early intervention program that leads to the environmental enrichment framework. The effectiveness of IM to promote neurodevelopment in preterm infants has been proved, but studies on infants with early brain damage are still lacking. The main aim of this study was to assess the feasibility, acceptability and usability of IM, carried out by parents at home, on infants at high risk for Cerebral Palsy. An IM daily diary and an ad hoc questionnaire, called Infant Massage Questionnaire Parent-Infant Experiences (IMQPE), were developed. IMQPE consisted of a total of 30 questions, divided into 5 areas. The parents were trained to carry out the IM with a home-based course, conducted by an expert therapist. The intensive IM program was set according to a defined daily length of at least 20 min, with a frequency of at least 5 days per week for a total of 8 weeks. Data collection consisted in the selection of the variables around the characteristics, both of the infants and the mothers, IM dosage and frequency, different body parts of the infants involved and IMQPE scores. Variable selection was carried out by minimizing the Bayesian Information Criteria (BIC) over all possible variable subsets. Nineteen high-risk infants, aged 4.83 ± 1.22 months, received IM at home for 8 weeks. The massage was given by the infants' mothers with a mean daily session dose of 27.79 ± 7.88 min and a total of 21.04 ± 8.49 h. 89.74% and 100% of mothers performed the IM for the minimum daily dosage and the frequency recommended, respectively. All the families filled in the IMQPE, with a Total mean score of 79.59% and of 82.22% in General Information on IM, 76.30% in Infant's intervention-related changes, 76.85% in IM Suitability, 79.07% in Infant's acceptance and 83.52% in Time required for the training. Different best predictors in mothers and in infants have been found. These data provide evidence of the feasibility of performing IM at home on infants at high risk for CP. Study registration: www.clinicaltrial.com (NCT03211533 and NCT03234959).

Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders—Childhood Rating Scale 4–18 Revised (MD-CRS 4–18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4–18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4–18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.

Background: Developmental Coordination Disorder (DCD) causes difficulties in postural control which are crucial to assess due to their impact on everyday life. There is a lack of suitable tools to acquire quantitative data and deeply analyze postural control, especially during the developmental age. The aim of this study is to investigate postural control skills in children with DCD and typically developing children (TD) using the Virtual Reality Rehabilitation System (VRRS). Methods: 18 children with DCD and 30 TD children (mean age 9.12 ± 2.65 and 7.12 ± 2.77 years, respectively) were tested by using the Movement Assessment Battery for Children Second Edition (MABC-2) and a VRRS stabilometric balance platform. A t-test was performed to identify differences in the VRRS parameters between the two groups. Furthermore, we investigated whether a correlation exists between the VRRS data and the MABC-2. Results: Significant differences (p < 0.05) in mean distance and frequency of the COP are found in the two groups. These parameters also correlate with the MABC-2 total score (p ≤ 0.05) and balance subscales (p ≤ 0.05). Conclusions: This study opens a new frontier for the assessment of postural skills in children with DCD and represents a potential basis for a tailored rehabilitation program, from which their postural stability and, consequently, their everyday life will benefit.

IntroductionCognitive difficulties and neuropsychological alterations in Duchenne and Becker muscular dystrophy (DMD, BMD) boys are not yet sufficiently explored, although this topic could have a relevant impact, finding novel biomarkers of disease both at genetics and neuroimaging point of view. The current study aims to: 1) analyze the neuropsychological profile of a group of DMD and BMD boys without cognitive impairment with an assessment of their executive functions; 2) explore the structural connectivity in DMD, BMD, and age-matched controls focusing on cortico-subcortical tracts that connect frontal cortex, basal ganglia, and cerebellum via the thalamus; 3) explore possible correlations between altered structural connectivity and clinical neuropsychological measures.Materials and methodsThis pilot study included 15 boys (5 DMD subjects, 5 BMD subjects, and 5 age-matched typically developing, TD). They were assessed using a neuropsychological assessment protocol including cognitive and executive functioning assessment and performed a 1.5T MRI brain exam including advance Diffusion Weighted Imaging (DWI) method for tractography. Structural connectivity measurements were extracted along three specific tracts: Cortico-Ponto-Cerebellar Tract (CPCT), Cerebellar-Thalamic Tract (CTT), and Superior Longitudinal Fasciculus (SLF). Cortical-Spinal Tract (CST) was selected for reference, as control tract.ResultsRegarding intellectual functioning, a major impairment in executive functions compared to the general intellectual functioning was observed both for DMD (mean score = 86.20; SD = 11.54) and for BMD children (mean score = 88; SD = 3.67). Mean FA resulted tendentially always lower in DMD compared to both BMD and TD groups for all the examined tracts. The differences in FA were statistically significant for the right CTT (DMD vs BMD, p = 0.002, and DMD vs TD, p = 0.0015) and the right CPCT (DMD vs TD, p = 0.008). Concerning DMD, significant correlations emerged between FA-R-CTT and intellectual quotients (FIQ, p = 0.044; ρs = 0.821), and executive functions (Denomination Total, p = 0.044, ρs = 0.821; Inhibition Total, p = 0.019, ρs = 0.900). BMD showed a significant correlation between FA-R-CPCT and working memory index (p = 0.007; ρs = 0.949).Discussion and conclusionIn this pilot study, despite the limitation of sample size, the findings support the hypothesis of the involvement of a cerebellar-thalamo-cortical loop for the neuropsychological profile of DMD, as the CTT and the CPCT are involved in the network and the related brain structures are known to be implied in executive functions. Our results suggest that altered WM connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies. The wider multicentric study could help to better establish the role of cerebellar connectivity in neuropsychological profile for dystrophinopathies, identifying possible novel diagnostic and prognostic biomarkers.

Pre-term spastic diplegia (pSD) due to periventricular leukomalacia is a form of cerebral palsy in which weaknesses in executive functions are reported beyond the core visuo-spatial deficits. The study aimed at improving executive functioning and visuo-spatial skills with an evidence-based training focused on working memory in children with pSD. The intervention study followed a stepped wedge design. 19 children with pSD (11 female and 8 male; age range: 4;1–13;1 years), mild to moderate upper limb impairment and Verbal Intelligence Quotient (VIQ) >80 participated to the study. The children were trained with a home-based adaptive working memory training (CogMed®) over a 5-week period. The primary outcome measure was the CogMed Improvement index; pre- and post-test explorative neuropsychological assessment was conducted with a subset of tests from the NEPSY-II battery. Working memory training in children with pSD significantly improved trained working memory abilities (CogMed indices) as well as non-trained skills, such as visuo-spatial skills, inhibition of automatic responses and phonological processing. The results suggest that standard rehabilitation schedules for children with pSD should be integrated with trainings on executive functions.

Infants with perinatal brain injury are at high risk for Cerebral Palsy (CP). Progresses in detection of early signs of brain injury and of CP allow early intervention (EI) programs for improving the outcome of these infants. CareToy system (CT), developed within a European project (Trial Registration: NCT01990183), allows providing, by means of tele-rehabilitation, a highly personalized, family-centered, home-based EI for young infants, remotely managed by clinicians. CareToy, already used with pre-terms without brain injury, has been adapted for high-risk infants in a project funded by the Italian Ministry of Health, and the CareToy-Revised (CareToy-R) has been realized (Trial registration: NCT03211533 and NCT03234959). Before assessing its efficacy, it was crucial to evaluate the acceptability, usability, and feasibility of CareToy-R EI. Nineteen high-risk infants with perinatal brain injury, aged 5.95 ± 2.13 months (range 3.12–10.78 months), carried out an 8-week training with CareToy-R at home, performing customized playful activities with their parents, tailored to their rehabilitative needs, remotely managed by clinicians. The feasibility of training and study procedures was assessed through criteria derived from literature; acceptability and usability have been analyzed from data about individual training and an ad hoc questionnaire. All CareToy-R trainings were planned by the clinical staff with a daily personalized use for each infant between 30 and 45 min (mean 34.37 min). The amount of executed training by the infants was very high (daily mean 30.30 min), with no differences related to infant age, sex, and gestational age. All the nine feasibility criteria were achieved, family compliance to the project was very good, data collection was completed and the CareToy-R system worked properly and easily for parents. The answers to the questionnaire had a total mean score of 84.49% and they ranged from a minimum of 81.05% (in “easy to use” area) to a maximum of 86.49% (“changes due to the training” area), with no differences related to nationality or familiarity with technology of the mothers. This study reports preliminary evidence to the feasibility of a home-based EI with CareToy-R system in infants at high risk for CP. Results of the RCT will provide data about the potential effectiveness of this approach.

Unilateral Cerebral Palsy (UCP), the most frequent form of Cerebral Palsy, usually affects more the upper limb (UL) than the lower limb. Rehabilitation programs are addressed to improve manual abilities and UL use. In recent years, Information and Communication Technology (ICT) has been introduced in rehabilitation to increase treatment opportunities for patients, and also in home-based intervention. Moreover, the discovery of the Mirror Neuron System allowed to insert a new paradigm of treatment that is the Action Observation Training (AOT). The aim of the present study was to investigate the feasibility of a new rehabilitative home-based approach, called Tele-UPCAT (Tele-monitored UPper Limb Children Action Observation Training), based on the principles of AOT, in a group of Italian children and adolescents with UCP. This investigation was to provide information about the possibility of introducing ICT in telerehabilitation field. Twenty-nine children aged 11.73 ± 3.65 years (range 6.00–18.75) with a diagnosis of UCP participated in the study. They carried out 15 days of training based on the AOT paradigm with Tele-UPCAT system while wearing Actigraphs on both wrists. The feasibility of both training and study design and procedures was assessed through nine criteria taken from existent literature and from a questionnaire designed and realized ad hoc for the purpose, based on standard items of usability and acceptability. All feasibility criteria were met: 80% of training sessions were completed in the planned time and no significant technical issues were found. From the questionnaire, total scores were all above 82.15%, while the four sections obtained the following scores: (i) customization of exercises 80.00%; (ii) acceptability at home, 77.50%; (iii) required effort 80.00%; and (iv) suitability of manual and software 95.00%. No differences were found for age and sex. Tele-UPCAT demonstrated to be feasible as a home-based AOT for children and adolescents with UCP. Trial registration NCT03094455.

Educational Robotics (ER) is a new learning approach that is known mainly for its effects on scientific academic subjects such as science, technology, engineering, and mathematics. Recent studies indicate that ER can also affect cognitive development by improving critical reasoning and planning skills. This study aimed to quantify the ability of ER to empower Executive Functions (EF), including the ability to control, update, and program information, in 5- and 6-year-old children attending first grade, a crucial evolutionary window for the development of such abilities. A total of 187 typically developing children were enrolled and randomly allocated into two experimental conditions: A, for immediate ER training, and B, for waitlist. ER-Laboratories (ER-Lab) for small groups were organized at schools, using a child-friendly, bee-shaped robot called Bee-Bot® (Campus Store). Activities were intensive, enjoyable, and progressively more challenging over the 20 twice-weekly sessions. Outcome measures, based on standardized tests, were used to quantify the effects of ER on EF. Compared to the control group, the ER-Lab group showed significantly better ability to actively manipulate information in short-term memory and suppress automatic responses in favor of goal-appropriate actions. This RCT study provides the first quantitative evidence of the positive effects of ER activities for improving working memory and inhibition in the early school years.

Abstract Understanding development of bimanual upper limb (UL) activities in both typical and atypical conditions in children is important for: i) tailoring rehabilitation programs, ii) monitoring progress, iii) determining outcomes and iv) evaluating effectiveness of treatment/rehabilitation. Recent technological advances, such as wearable sensors, offer possibilities to perform standard medical monitoring. Body-worn motion sensors, mainly accelerometers, have shown very promising results but, so far, these studies have mainly focused on adults. The main aim of this review was to report the evidence of UL activity of both typically developing (TD) children and children with neurodevelopmental disorders (NDDs) that are reliably reported and comparable, using a combination of multiple wearable inertial sensors, both in laboratory and natural settings. Articles were selected from three research databases (PubMed, Web of Science and EBSCO). Included studies reported data on children aged 0–20 years old simultaneously wearing at least two inertial sensors on upper extremities. The collected and reported data were relevant in order to describe the amount of physical activity performed by the two ULs separately. A total of 21 articles were selected: 11 including TD, and 10 regarding NDDs. For each article, a review of both clinical and technical data was performed. We considered inertial sensors used for following aims: (i) to establish activity intensity cut-points; (ii) to investigate validity and reliability of specified markers, placement and/or number of inertial sensors; (iii) to evaluate duration and intensity of natural UL movements, defined motor tasks and tremor; and (iv) to assess efficacy of certain rehabilitation protocols. Our conclusions were that inertial sensors are able to detect differences in use between both hands and that all reviewed studies support use of accelerometers as an objective outcome measure, appropriate in assessing UL activity in young children with NDDs and determining intervention effectiveness. Further research on responsiveness to interventions and consistency with use in real-world settings is needed. This information could be useful in planning UL rehabilitation strategies.

Abstract Background Congenital brain lesions expose infants to be at high-risk for being affected by neurodevelopmental disorders such as cerebral palsy (CP). Early interventions programs can significantly impact and improve their neurodevelopment. Recently, in the framework of the European CareToy (CT) Project (www.caretoy.eu), a new medical device has been created to deliver an early, intensive, customized, intervention program, carried out at home by parents but remotely managed by expert and trained clinicians. Reviewing results of previous studies on preterm infants without congenital brain lesion, the CT platform has been revised and a new system created (CT-R). This study describes the protocol of a randomised controlled trial (RCT) aimed to evaluate, in a sample of infants at high-risk for CP, the efficacy of CT-R intervention compared to the Infant Massage (IM) intervention. Methods/design This RCT will be multi-centre, paired and evaluator-blinded. Eligible subjects will be preterm or full-term infants with brain lesions, in first year of age with predefined specific gross motor abilities. Recruited infants will be randomized into CT-R and IM groups at baseline (T0). Based on allocation, infants will perform an 8-week programme of personalized CareToy activities or Infant Massage. The primary outcome measure will be the Infant Motor Profile. On the basis of power calculation, it will require a sample size of 42 infants. Moreover, Peabody Developmental Motor Scales-Second Edition, Teller Acuity Cards, standardized video-recordings of parent-infant interaction and wearable sensors (Actigraphs) will be included as secondary outcome measures. Finally, parents will fill out questionnaires (Bayley Social-Emotional, Parents Stress Index). All outcome measures will be carried out at the beginning (T0) and at end of 8-weeks intervention period, primary endpoint (T1). Primary outcome and some secondary outcomes will be carried out also after 2 months from T1 and at 18 months of age (T2 and T3, respectively). The Bayley Cognitive subscale will be used as additional assessment at T3. Discussion This study protocol paper is the first study aimed to test CT-R system in infants at high-risk for CP. This paper will present the scientific background and trial methodology. Trial registration NCT03211533 and NCT03234959 (www.clinicaltrials.gov).

Abstract Background Upper limb (UL) deficits in children with unilateral cerebral palsy (uCP) have traditionally been targeted with motor execution treatment models, such as modified Constraint-Induced Movement Therapy (mCIMT). However, new approaches based on a neurophysiological model such as Action-Observation Training (AOT) may provide new opportunities for enhanced motor learning. The aim of this study is to describe a randomised controlled trial (RCT) protocol investigating the effects of an intensive treatment model, combining mCIMT and AOT compared to mCIMT alone on UL function in children with uCP. Additionally, the role of neurological factors as potential biomarkers of treatment response will be analysed. Methods An evaluator-blinded RCT will be conducted in 42 children aged between 6 and 12 years. Before randomization, children will be stratified according to their House Functional Classification Scale, age and type of corticospinal tract wiring. A 2-week day-camp will be set up in which children receive intensive mCIMT therapy for 6 hours a day on 9 out of 11 consecutive days (54 h) including AOT or control condition (15 h). During AOT, these children watch video sequences showing goal-directed actions and subsequently execute the observed actions with the more impaired UL. The control group performs the same actions after watching computer games without human motion. The primary outcome measure will be the Assisting Hand Assessment. Secondary outcomes comprise clinical assessments across body function, activity and participation level of the International Classification of Function, Disability and Health. Furthermore, to quantitatively evaluate UL movement patterns, a three-dimensional motion analysis will be conducted. UL function will be assessed at baseline, immediately before and after intervention and at 6 months follow up. Brain imaging comprising structural and functional connectivity measures as well as Transcranial Magnetic Stimulation (TMS) to evaluate corticospinal tract wiring will be acquired before the intervention. Discussion This paper describes the methodology of an RCT with two main objectives: (1) to evaluate the added value of AOT to mCIMT on UL outcome in children with uCP and (2) to investigate the role of neurological factors as potential biomarkers of treatment response. Trial registration NCT03256357 registered on 21st August 2017 (retrospectively registered).

Introduction: Constraint-induced movement therapy (CIMT) improves upper limb (UL) motor execution in unilateral cerebral palsy (uCP). As these children also show motor planning deficits, action-observation training (AOT) might be of additional value. Here, we investigated the combined effect of AOT to CIMT and identified factors influencing treatment response. Methods: A total of 44 children with uCP (mean 9 years 6 months, SD 1 year 10 months) participated in a 9-day camp wearing a splint for 6 h/day and were allocated to the CIMT + AOT ( n = 22) and the CIMT + placebo group ( n = 22). The CIMT + AOT group received 15 h of AOT (i.e. video-observation) and executed the observed tasks, whilst the CIMT + AOT group watched videos free of biological motion and executed the same tasks. The primary outcome measure was bimanual performance. Secondary outcomes included measures of body function and activity level assessed before (T1), after the intervention (T2), and at 6 months follow-up (T3). Influencing factors included behavioural and neurological characteristics. Results: Although no between-groups differences were found ( p > 0.05; η 2 = 0–16), the addition of AOT led to higher gains in children with initially poorer bimanual performance ( p = 0.02; η 2 = 0.14). Both groups improved in all outcome measures after the intervention and retained the gains at follow up ( p

Aim: To systematically explore the relationship between type and severity of brain lesion on Magnetic Resonance Imaging (MRI) and visual function in a large cohort of children with periventricular leukomalacia (PVL). Methods: 94 children with bilateral cerebral palsy (CP) and history of PVL were recruited at Stella Maris Scientific Institute in Pisa (Italy). We included data of participants (72) with at least one MRI after the age of three years and an evaluation of visual function including fixation, following, saccades, nystagmus, acuity, visual field, stereopsis and color perception.Brain lesions location and extent were assessed by a semi-quantitative MRI-scale for children with CP. Results: Brain lesion severity strongly correlated with visual function total score (global MRI score p = .000; hemispheric score p = .001 and subcortical score p = .000). Moreover, visual acuity, visual field, stereopsis and colour were compromised when a cortical damage was present, while ocular motricity (and in particular fixation and saccades) were compromised in presence of subcortical brain damage. Interpretation: Structural MRI is valuable for understanding the relationship between brain lesion severity and visual function in children with CP.

Children with Special Needs represent a highly heterogeneous group in terms of neurofunctional, behavioral, and socio-cognitive characteristics, but they have in common a frequent impairment of Executive Functions. Educational Robotics is generally dedicated to study the effects of constructing and programming robots based on children’s learning and academic achievement. Recently, we found that being engaged in progressively more challenging robot planning and monitoring (ER-Lab) promotes visual–spatial working memory and response inhibition in early childhood during typical development, and that an ER-Lab can be a feasible rehabilitative tool for children with Special Needs. The present study aimed to verify the efficacy of the ER-Lab on Executive Functions in children with Special Needs for the first time by using an RCT within their school environment. To pursue these aims, this study reports the results obtained in 42 first-grade children with Special Needs engaged in school Educational Robotics Laboratories (ER-Lab) to promote Executive Functions by means of enjoyable, intensive, and incrementally more challenging activities requiring them to program a bee-shaped robot called Bee-bot® (Campus Store). Several adaptations were done to meet different motor, cognitive, and social needs. All children were evaluated by means of standardized tests performed by each child before and at the end of the ER-Lab activities. Children with Special Needs had significantly improved inhibition skills, and children with attentional impairment had more benefits in their inhibition of motor responses tasks with respect to children with a language deficit. Results of the study and future perspectives on how ER-Lab programs could become a powerful tool in classrooms with children with special needs are discussed.

This paper describes a new Educational Robotic (ER) approach aimed to empower higher cognitive functions in school-setting. As robot programming requires to mentally plan a complex sequence of actions before the motor act, ER may indeed promote several crucial cognitive processes underlying learning. The steps needed and the mental acts for robot programming may involve Executive Functions (EF), that are complex higher cognitive processes, particularly crucial in the early development, because they are the base for abstraction and logical reasoning, decision-making, sequential thinking, maintaining and updating information in memory and problem-solving. Recent studies attempting to attest with a scientific approach the effect of ER on executive functioning are described. They concern both classroom with typical development or special educational needs and rehabilitation environment for children with developmental disorder. Robotica Educativa e potenziamento dei processi cognitivi esecutivi: dallo sviluppo tipico ai bisogni educativi speciali Il presente lavoro descrive come la Robotica Educativa (RE) possa essere utilizzata per potenziare alcune funzioni cognitive di controllo. Le azioni necessarie e gli atti mentali per la programmazione di un robot implicano le Funzioni Esecutive (FE), processi cognitivi di alto ordine, particolarmente importanti durante lo sviluppo cognitivo perché coinvolti nel ragionamento logico e nell’astrazione, nel decision-making, nel pensiero sequenziale, nel problem-solving e nel mantenimento/ aggiornamento delle informazioni in memoria. Nell’articolo sono sintetizzati e discussi gli studi con cui abbiamo cercato di provare con metodi scientifici l’effetto della RE sulle FE, nel gruppo classe per bambini con sviluppo tipico o con bisogni educativi speciali, e in ambito riabilitativo per bambini con disturbo del neurosviluppo.

On 11 March 2020, a national lockdown was imposed by the Italian government to contain the spread of COVID19 disease. This is an observational longitudinal study conducted at Fondazione Stella Maris (FSM), Italy to investigate lockdown-related emotional and behavioural changes in paediatric neuropsychiatric population. Families having children (1.5–18 years) with neuropsychiatric disorders referred to FSM have been contacted and proposed to fulfil two online questionnaires (General questionnaire and Child Behaviour Check List (CBCL)) to (i) compare (paired two-sample t-tests) the CBCL scores during lockdown with previous ones, and (ii) investigate the influence (multiple linear regression models) of variables such as age, diagnosis grouping (neurological, neurodevelopmental, emotional, and behavioural disorders) and financial hardship. One hundred and forty-one parents fulfilled the questionnaires. Anxiety and somatic problems increased in 1.5–5 years subpopulation, while obsessive-compulsive, post-traumatic and thought problems increased in 6–18 years subpopulation. In the regression models, younger age in the 1.5–5 years subpopulation resulted as “protective” while financial hardship experienced by families during lockdown was related to psychiatric symptoms increasing in the 6–18 years subpopulation. Some considerations, based on first clinical impressions, are provided in text together with comments in relation to previous and emerging literature on the topic.

Transcranial Direct Current Stimulation (tDCS) is an emerging tool to improve upper limb motor functions after stroke acquired in adulthood; however, there is a paucity of reports on its efficacy for upper limb motor rehabilitation in congenital or early-acquired stroke. In this pilot study we have explored, for the first time, the immediate effects, and their short-term persistence, of a single application of anodal tDCS on chronic upper limb motor disorders in children and young individuals with Unilateral Cerebral Palsy (UCP). To this aim, in a crossover sham-controlled study, eight subjects aged 10-28 years with UCP underwent two sessions of active and sham tDCS. Anodal tDCS (1.5 mA, 20 min) was delivered over the primary motor cortex (M1) of the ipsilesional hemisphere. Results showed, only following the active stimulation, an immediate improvement in unimanual gross motor dexterity of hemiplegic, but not of nonhemiplegic, hand in Box and Block test (BBT). Such improvement remained stable for at least 90 minutes. Performance of both hands in Hand Grip Strength test was not modified by anodal tDCS. Improvement in BBT was unrelated to participants’ age or lesion size, as revealed by MRI data analysis. No serious adverse effects occurred after tDCS; some mild and transient side effects (e.g., headache, tingling, and itchiness) were reported in a limited number of cases. This study provides an innovative contribution to scientific literature on the efficacy and safety of anodal tDCS in UCP. This trial is registered with NCT03137940.

Parenting a preterm infant is more challenging than a full-term one. Parent involvement in early intervention programs seems to have positive psychosocial effects on both the child and parent. CareToy is an innovative smart system that provides an intensive individualized home-based family-centred EI in preterm infants between 3 and 9 age-corrected months. A RCT study, preceded by a pilot study, has been recently carried out to evaluate the effects of CareToy intervention on neurodevelopmental outcomes with respect to Standard Care. This study aims at evaluating the effects of CareToy early intervention on parenting stress in preterm infants. Parents (mother and father) of a subgroup of infants enrolled in the RCT filled out a self-report questionnaire on parenting stress (Parenting Stress Index-Short Form (PSI-SF)) before (T0) and after (T1) the CareToy or Standard Care period (4 weeks), according to the allocation of their preterm infant. For twins, an individual questionnaire for each one was filled out. Results obtained from mothers and fathers were separately analysed with nonparametric tests. 44 mothers and 44 fathers of 44 infants (24 CareToy/20 Standard Care) filled out the PSI-SF at T0 and at T1. CareToy intervention was mainly managed by mothers. A significant (p

Childhood apraxia of speech (CAS) is a paediatric speech sound disorder in which precision and consistency of speech movements are impaired. Most children with idiopathic CAS have normal structural brain MRI. We hypothesize that children with CAS have altered structural connectivity in speech/language networks compared to controls and that these altered connections are related to functional speech/language measures. Whole brain probabilistic tractography, using constrained spherical deconvolution, was performed for connectome generation in 17 children with CAS and 10 age-matched controls. Fractional anisotropy (FA) was used as a measure of connectivity and the connections with altered FA between CAS and controls were identified. Further, the relationship between altered FA and speech/language scores was determined. Three intra-hemispheric/interhemispheric subnetworks showed reduction of FA in CAS compared to controls, including left inferior (opercular part) and superior (dorsolateral, medial and orbital part) frontal gyrus, left superior and middle temporal gyrus and left post-central gyrus (subnetwork 1); right supplementary motor area, left middle and inferior (orbital part) frontal gyrus, left precuneus and cuneus, right superior occipital gyrus and right cerebellum (subnetwork 2); right angular gyrus, right superior temporal gyrus and right inferior occipital gyrus (subnetwork 3). Reduced FA of some connections correlated with diadochokinesis, oromotor skills, expressive grammar and poor lexical production in CAS. These findings provide evidence of structural connectivity anomalies in children with CAS across specific brain regions involved in speech/language function. We propose altered connectivity as a possible epiphenomenon of complex pathogenic mechanisms in CAS which need further investigation.

Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS.

This study aimed at comparing implicit sequence learning in individuals affected by Duchenne Muscular Dystrophy without intellectual disability and age-matched typically developing children. A modified version of the Serial Reaction Time task was administered to 32 Duchenne children and 37 controls of comparable chronological age. The Duchenne group showed a reduced rate of implicit learning even if in the absence of global intellectual disability. This finding provides further evidence of the involvement of specific aspects of cognitive function in Duchenne muscular dystrophy and on its possible neurobiological substrate.

Reorganization of somatosensory function influences the clinical recovery of subjects with congenital unilateral brain lesions. Ultrahigh-field (UHF) functional MRI (fMRI) with the use of a 7 T magnet has the potential to contribute fundamentally to the current knowledge of such plasticity mechanisms. The purpose of this study was to obtain preliminary information on the possible advantages of the study of somatosensory reorganization at UHF fMRI. We enrolled 6 young adults (mean age 25 ± 6 years) with congenital unilateral brain lesions (4 in the left hemisphere and 2 in the right hemisphere; 4 with perilesional motor reorganization and 2 with contralesional motor reorganization) and 7 healthy age-matched controls. Nondominant hand sensory assessment included stereognosis and 2-point discrimination. Task-dependent fMRI was performed to elicit a somatosensory activation by using a safe and quantitative device developed ad hoc to deliver a reproducible gentle tactile stimulus to the distal phalanx of thumb and index fingers. Group analysis was performed in the control group. Individual analyses in the native space were performed with data of hemiplegic subjects. The gentle tactile stimulus showed great accuracy in determining somatosensory cortex activation. Single-subject gentle tactile stimulus showed an S1 activation in the postcentral gyrus and an S2 activation in the inferior parietal insular cortex. A correlation emerged between an index of S1 reorganization (distance between expected and reorganized S1) and sensory deficit (p

Little is known about the action observation network (AON) in children with unilateral cerebral palsy (UCP). Using fMRI, we aimed to explore AON and sensory-motor network (SMN) in UCP children and compare them to typically developed (TD) children and analyse the relationship between AON (re-)organization and several neurophysiological and clinical measures. Twelve UCP children were assessed with clinical scales and transcranial magnetic stimulation (TMS). For the fMRI study, they underwent a paradigm based on observation of complex and simple object-manipulation tasks executed by dominant and nondominant hand. Moreover, UCP and TD children carried out a further fMRI session to explore SMN in both an active motor and passive sensory task. AON in the UCP group showed higher lateralization, negatively related to performances on clinical scales, and had greater activation of unaffected hemisphere as compared to the bilateral representation in the TD group. In addition, a good congruence was found between bilateral or contralateral activation of AON and activation of SMN and TMS data. These findings indicate that our paradigm might be useful in exploring AON and the response to therapy in UCP subjects.

Aim: To provide first evidence of construct validity of a semi-quantitative scale for brain structural MRI (sqMRI scale) in children with unilateral cerebral palsy (UCP) secondary to periventricular white matter (PWM) lesions, by examining the relationship with hand sensorimotor function and whole brain structural connectivity. Methods: Cross-sectional study of 50 children with UCP due to PWM lesions using 3 T (MRI), diffusion MRI and assessment of hand sensorimotor function. We explored the relationship of lobar, hemispheric and global scores on the sqMRI scale, with fractional anisotropy (FA), as a measure of brain white matter microstructure, and with hand sensorimotor measures (Assisting Hand Assessment, AHA; Jebsen–Taylor Test for Hand Function, JTTHF; Melbourne Assessment of Unilateral Upper Limb Function, MUUL; stereognosis; 2-point discrimination). Results: Lobar and hemispheric scores on the sqMRI scale contralateral to the clinical side of hemiplegia correlated with sensorimotor paretic hand function measures and FA of a number of brain structural connections, including connections of brain areas involved in motor control (postcentral, precentral and paracentral gyri in the parietal lobe). More severe lesions correlated with lower sensorimotor performance, with the posterior limb of internal capsule score being the strongest contributor to impaired hand function. Conclusion: The sqMRI scale demonstrates first evidence of construct validity against impaired motor and sensory function measures and brain structural connectivity in a cohort of children with UCP due to PWM lesions. More severe lesions correlated with poorer paretic hand sensorimotor function and impaired structural connectivity in the hemisphere contralateral to the clinical side of hemiplegia. The quantitative structural MRI scoring may be a useful clinical tool for studying brain structure–function relationships but requires further validation in other populations of CP.

Telerehabilitation, defined as the method by which communication technologies are used to provide remote rehabilitation, although still underused, could be as efficient and effective as the conventional clinical rehabilitation practices. In the literature, there are descriptions of the use of telerehabilitation in adult patients with various diseases, whereas it is seldom used in clinical practice with child and adolescent patients. We have developed a new audiovisual telerehabilitation (AVT) system, based on the multisensory capabilities of the human brain, to provide a new tool for adults and children with visual field defects in order to improve ocular movements toward the blind hemifield. The apparatus consists of a semicircular structure in which visual and acoustic stimuli are positioned. A camera is integrated into the mechanical structure in the center of the panel to control eye and head movements. Patients can use this training system with a customized software on a tablet. From hospital, the therapist has complete control over the training process, and the results of the training sessions are automatically available within a few minutes on the hospital website. In this paper, we report the AVT system protocol and the preliminary results on its use by three adult patients. All three showed improvements in visual detection abilities with long-term effects. In the future, we will test this apparatus with children and their families. Since interventions for impairments in the visual field have a substantial cost for individuals and for the welfare system, we expect that our research could have a profound socio-economic impact avoiding prolonged and intensive hospital stays.

Multisensory processes permit combinations of several inputs, coming from different sensory systems, allowing for a coherent representation of biological events and facilitating adaptation to environment. For these reasons, their application in neurological and neuropsychological rehabilitation has been enhanced in the last decades. Recent studies on animals and human models have indicated that, on one hand multisensory integration matures gradually during post-natal life and development is closely linked to environment and experience and, on the other hand, that modality-specific information seems to do not benefit by redundancy across multiple sense modalities and is more readily perceived in unimodal than in multimodal stimulation. In this review, multisensory process development is analyzed, highlighting clinical effects in animal and human models of its manipulation for rehabilitation of sensory disorders. In addition, new methods of early intervention based on multisensory-based rehabilitation approach and their applications on different infant populations at risk of neurodevelopmental disabilities are discussed.

Motor system development is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal tracts (CST). Clinical evidence suggests that age is crucial for developmental stroke outcome, with early lesions inducing a “maladaptive” strengthening of ipsilateral projections from the healthy hemisphere and worse motor impairment. Here, we investigated in developing rats the relation between lesion timing, motor outcome and CST remodeling pattern. We induced a focal ischemia into forelimb motor cortex (fM1) at two distinct pre-weaning ages: P14 and P21. We compared long-term motor outcome with changes in axonal sprouting of contralesional CST at red nucleus and spinal cord level using anterograde tracing. We found that P14 stroke caused a more severe long-term motor impairment than at P21, and induced a strong and aberrant contralesional CST sprouting onto denervated spinal cord and red nucleus. The mistargeted sprouting of CST, and the worse motor outcome of the P14 stroke rats were reversed by an early skilled motor training, underscoring the potential of early activity-dependent plasticity in modulating lesion outcome. Thus, changes in the mechanisms controlling CST plasticity occurring during the third postnatal week are associated with age-dependent regulation of the motor outcome after stroke.

Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the major animal model for DS, have severe cognitive and synaptic plasticity dysfunctions caused by excessive inhibition in their temporal lobe structures. Here we employed a multidisciplinary approach spanning from the behavioral to the electrophysiological and molecular level to investigate the effects elicited by fluoxetine on cognitive abilities, hippocampal synaptic plasticity and GABA release in adult Ts65Dn mice. We report that a chronic treatment with fluoxetine administered in the drinking water normalizes GABA release and promotes recovery of spatial memory abilities, spatial working memory for alternation, and hippocampal synaptic plasticity in adult Ts65Dn mice. Our findings might encourage new experimental attempts aimed at investigating the potential of fluoxetine for application in the treatment of major functional deficits in adult people with DS.

CareToy system is an innovative tele-rehabilitative tool, useful in providing intensive, individualized, home-based, family-centred Early Intervention (EI) in infants. Our aim was to evaluate, through a Randomized Clinical Trial (RCT) study, the effects of CareToy intervention on early motor and visual development in preterm infants. 41 preterm infants (range age: 3.0-5.9 months of corrected age) were enrolled and randomized into two groups, CareToy and Standard Care. 19 infants randomized in CareToy group performed a 4-week CareToy program, while 22 allocated to control group completed 4 weeks of Standard Care. Infant Motor Profile (IMP) was primary outcome measure, Alberta Infant Motor Scale (AIMS) and Teller Acuity Cards were secondary ones. Assessments were carried out at baseline (T0) and at the end of CareToy training or Standard Care period (T1). T1 was the primary endpoint. After RCT phase, 17 infants from control group carried out a 4-week CareToy program, while 18 infants from the CareToy group continued with Standard Care. At the end of this phase, infants were re-assessed at T2. In RCT phase, delta IMP total score and variation and performance sub-domains were significantly higher (P

Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with an early-onset and a strong genetic component in their pathogenesis. According to genetic and epidemiological data, ASD relatives present personality traits similar to, but not as severe as the defining features of ASD, which have been indicated as the Broader Autism Phenotype (BAP). BAP features seem to be more prevalent in first-degree relatives of individuals with ASD than in the general population. Characterizing brain profiles of relatives of autistic probands may help to understand ASD endophenotype. The aim of this review was to provide an up-to-date overview of research findings on the neurostructural and neurofunctional substrates in parents of individuals with ASD (pASD). The primary hypothesis was that, like for the behavioral profile, the pASD express an intermediate neurobiological pattern between ASD individuals and healthy controls.The 13 reviewed studies evaluated structural magnetic resonance imaging (MRI) brain volumes, chemical signals using magnetic resonance spectroscopy (MRS), task-related functional activation by functional magnetic resonance imaging (fMRI), electroencephalography (EEG), or magnetoencephalography (MEG) in pASD. The studies showed that pASD are generally different from healthy controls at a structural and functional level despite often not behaviorally impaired. More atypicalities in neural patterns of pASD seem to be associated with higher scores at BAP assessment. Some of the observed atypicalities are the same of the ASD probands. In addition, the pattern of neural correlates in pASD resembles that of adult individuals with ASD, or it is specific, possibly due to a compensatory mechanism are the same as those detected in ASD subjects. Future studies should ideally include a group of pASD and HC with their ASD and non-ASD probands respectively. They should subgrouping the pASD according to the BAP scores, considering gender as a possible confounding factor, and correlating these scores to underlying brain structure and function. These types of studies may help to understand the genetic mechanisms involved in the various clinical dimension of ASD.

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and behavioral disturbances, language and speech impairment ( OMIM #300352). CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT−/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and behavioral disturbances, language and speech impairment ( OMIM #300352). CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT−/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.