Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

BACKGROUND: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency.

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Neuropsychological study in 19 French patients with White-Sutton syndrome and POGZ mutations.

White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.

Parental Self-Efficacy for Reducing the Risk of Adolescent Depression and Anxiety: Scale Development and Validation.

Burgeoning research suggests that parents can reduce the risk of anxiety and depression in their adolescents and that parental self-efficacy (PSE) may be related to parental risk and protective factors for these disorders. As there are currently no measures available to assess PSE in relation to parenting behaviors that may reduce adolescent risk for depression and anxiety, we developed and validated a measure of PSE, the Parental Self-Efficacy Scale (PSES). Using a sample of 359 parents and 332 adolescents (aged 12-15), the PSES was found to have high reliability, confirmatory factor analysis supported its validity, and most of the hypothesized relationships between the PSES and other measures of parenting practices and adolescent depressive and anxiety symptoms were supported.

A Tailored Web-Based Intervention to Improve Parenting Risk and Protective Factors for Adolescent Depression and Anxiety Problems: Postintervention Findings From a Randomized Controlled Trial.

BACKGROUND: Depression and anxiety disorders in young people are a global health concern. Parents have an important role in reducing the risk of these disorders, but cost-effective, evidence-based interventions for parents that can be widely disseminated are lacking. OBJECTIVE: This study aimed to examine the postintervention effects of the Partners in Parenting (PiP) program on parenting risk and protective factors for adolescent depression and anxiety, and on adolescent depression and anxiety symptoms. METHODS: A two-arm randomized controlled trial was conducted with 359 parent-adolescent dyads, recruited primarily through schools across Australia. Parents and adolescents were assessed at baseline and 3 months later (postintervention). Parents in the intervention condition received PiP, a tailored Web-based parenting intervention designed following Persuasive Systems Design (PSD) principles to target parenting factors associated with adolescents' risk for depression and anxiety problems. PiP comprises a tailored feedback report highlighting each parent's strengths and areas for improvement, followed by a set of interactive modules (up to nine) that is specifically recommended for the parent based on individually identified areas for improvement. Parents in the active-control condition received a standardized package of five Web-based factsheets about adolescent development and well-being. Parents in both conditions received a 5-min weekly call to encourage progress through their allocated program to completion. Both programs were delivered weekly via the trial website. The primary outcome measure at postintervention was parent-reported changes in parenting risk and protective factors, which were measured using the Parenting to Reduce Adolescent Depression and Anxiety Scale (PRADAS). Secondary outcome measures were the adolescent-report PRADAS, the parent- and child-report Short Mood and Feelings Questionnaire (depressive symptoms), and parent- and child-report Spence Children's Anxiety Scale (anxiety symptoms). RESULTS: Parents in the intervention condition completed a mean of 73.7% of their intended personalized PiP program. A total of 318 parents (88.6%, 318/359) and 308 adolescents (92.8%, 308/332) completed the postintervention assessment. Attrition was handled using mixed model of repeated measures analysis of variance. As hypothesized, we found a significant condition-by-time interaction on the PRADAS, with a medium effect size, Cohen d=0.57, 95% CI 0.34-0.79. No significant differences between conditions were found at postintervention on any of the secondary outcome measures, with adolescent depressive (parent-report only) and anxiety (both parent- and adolescent-report) symptoms decreasing significantly from baseline to postintervention in both conditions. CONCLUSIONS: The fully automated PiP intervention showed promising short-term effects on parenting behaviors that are associated with adolescents' risk for depression and anxiety. Long-term follow-up is required to ascertain whether these effects translate into reduced adolescent depression and anxiety problems. The intervention may be useful as a low-cost universal public health program to increase parenting practices believed to benefit adolescents' mental health. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12615000328572; https://www.anzctr.org.au/ Trial/Registration/TrialReview.aspx? id=368274 (Archived by WebCite at http://www.webcitation.org/6qgsZ3Aqj).

[Severe burned patient rehabilitation]. / Réhabilitation du brûlé grave.

Severe burned patient rehabilitation. The rehabilitation of the severe burn requires multidisciplinary care in a specialized rehabilitation center. We present in this article, the care offered in our service, detailing in particular the psychological aspects. Indeed, some patients with severe burns have a psychiatric history, while others will present a status with post-traumatic stress disease following the burn. The general principles of rehabilitation are the establishment of various ways of compression to fight against hypertrophy, as well as the achievement of postures to limit retractions. The organization of chain care minimizes the functional, aesthetic and psychological consequences of burns, and it accompanies the severe burned patients throughout scarring.

Réhabilitation du brûlé grave. La réhabilitation du brûlé grave nécessite une prise en charge pluridisciplinaire en centre de rééducation spécialisé. Nous présentons dans cet article les soins proposés dans notre service, en détaillant en particulier les aspects psychologiques. En effet, une partie des patients victimes de brûlures graves ont des antécédents psychiatriques, tandis que d'autres vont avoir un état de stress post-traumatique consécutif à la brûlure. Les principes généraux de la rééducation sont la mise en place de différents moyens de compression pour lutter contre l'hypertrophie, ainsi que la réalisation de postures pour limiter les rétractions. L'organisation des soins en filière permet de minimiser les conséquences fonctionnelles, esthétiques et psychologiques à la suite de la brûlure, en accompagnant le brûlé grave tout au long de la maturation cicatricielle.

Gesture encoding in human left precentral gyrus neuronal ensembles.

Understanding the cortical activity patterns driving dexterous upper limb motion has the potential to benefit a broad clinical population living with limited mobility through the development of novel brain-computer interface (BCI) technology. The present study examines the activity of ensembles of motor cortical neurons recorded using microelectrode arrays in the dominant hemisphere of two BrainGate clinical trial participants with cervical spinal cord injury as they attempted to perform a set of 48 different hand gestures. Although each participant displayed a unique organization of their respective neural latent spaces, it was possible to achieve classification accuracies of ~70% for all 48 gestures (and ~90% for sets of 10). Our results show that single unit ensemble activity recorded in a single hemisphere of human precentral gyrus has the potential to generate a wide range of gesture-related signals across both hands, providing an intuitive and diverse set of potential command signals for intracortical BCI use.

BRAND: a platform for closed-loop experiments with deep network models.

Objective.Artificial neural networks (ANNs) are state-of-the-art tools for modeling and decoding neural activity, but deploying them in closed-loop experiments with tight timing constraints is challenging due to their limited support in existing real-time frameworks. Researchers need a platform that fully supports high-level languages for running ANNs (e.g. Python and Julia) while maintaining support for languages that are critical for low-latency data acquisition and processing (e.g. C and C++).Approach.To address these needs, we introduce the Backend for Realtime Asynchronous Neural Decoding (BRAND). BRAND comprises Linux processes, termednodes, which communicate with each other in agraphvia streams of data. Its asynchronous design allows for acquisition, control, and analysis to be executed in parallel on streams of data that may operate at different timescales. BRAND uses Redis, an in-memory database, to send data between nodes, which enables fast inter-process communication and supports 54 different programming languages. Thus, developers can easily deploy existing ANN models in BRAND with minimal implementation changes.Main results.In our tests, BRAND achieved <600 microsecond latency between processes when sending large quantities of data (1024 channels of 30 kHz neural data in 1 ms chunks). BRAND runs a brain-computer interface with a recurrent neural network (RNN) decoder with less than 8 ms of latency from neural data input to decoder prediction. In a real-world demonstration of the system, participant T11 in the BrainGate2 clinical trial (ClinicalTrials.gov Identifier: NCT00912041) performed a standard cursor control task, in which 30 kHz signal processing, RNN decoding, task control, and graphics were all executed in BRAND. This system also supports real-time inference with complex latent variable models like Latent Factor Analysis via Dynamical Systems.Significance.By providing a framework that is fast, modular, and language-agnostic, BRAND lowers the barriers to integrating the latest tools in neuroscience and machine learning into closed-loop experiments.

A mosaic of whole-body representations in human motor cortex.

Understanding how the body is represented in motor cortex is key to understanding how the brain controls movement. The precentral gyrus (PCG) has long been thought to contain largely distinct regions for the arm, leg and face (represented by the "motor homunculus"). However, mounting evidence has begun to reveal a more intermixed, interrelated and broadly tuned motor map. Here, we revisit the motor homunculus using microelectrode array recordings from 20 arrays that broadly sample PCG across 8 individuals, creating a comprehensive map of human motor cortex at single neuron resolution. We found whole-body representations throughout all sampled points of PCG, contradicting traditional leg/arm/face boundaries. We also found two speech-preferential areas with a broadly tuned, orofacial-dominant area in between them, previously unaccounted for by the homunculus. Throughout PCG, movement representations of the four limbs were interlinked, with homologous movements of different limbs (e.g., toe curl and hand close) having correlated representations. Our findings indicate that, while the classic homunculus aligns with each area's preferred body region at a coarse level, at a finer scale, PCG may be better described as a mosaic of functional zones, each with its own whole-body representation.

Pseudo-linear Summation explains Neural Geometry of Multi-finger Movements in Human Premotor Cortex.

How does the motor cortex combine simple movements (such as single finger flexion/extension) into complex movements (such hand gestures or playing piano)? Motor cortical activity was recorded using intracortical multi-electrode arrays in two people with tetraplegia as they attempted single, pairwise and higher order finger movements. Neural activity for simultaneous movements was largely aligned with linear summation of corresponding single finger movement activities, with two violations. First, the neural activity was normalized, preventing a large magnitude with an increasing number of moving fingers. Second, the neural tuning direction of weakly represented fingers (e.g. middle) changed significantly as a result of the movement of other fingers. These deviations from linearity resulted in non-linear methods outperforming linear methods for neural decoding. Overall, simultaneous finger movements are thus represented by the combination of individual finger movements by pseudo-linear summation.