Editorial: No short-cuts - translating neurobiological knowledge to clinical practice requires moving away from stand-alone biomarkers to an integrative biopsychosocial approach.

Although decades of research have shown the importance of neurobiological factors in the development of mental health problems in children and adolescents, the translation of this knowledge to use in clinical practice has proven difficult. One of the pitfalls is the false assumption that biological factors are so fundamental that they overrule all other factors and can be used as stand-alone biomarkers or tests for diagnostic purposes and treatment decisions. This assumption is false because all neurodevelopmental disorders result from complex interactions between biology and environment. Therefore, neurobiological assessments should never be used as a shortcut for diagnostic assessments that include the environment, including family, peers, and society at large. Instead, they should be integrated in the diagnostic process. This calls for empirically supported guidance on how to weigh information from neurobiological and psychosocial assessments in the diagnostic and treatment decision process.

The effectiveness of a dialogical family guidance intervention regarding child treatment response in families with a child with neurodevelopmental disorders.

BACKGROUND: Children with neurodevelopmental disorders (NDD) can have emotional and behavioral symptoms affecting not only the child, but the whole family. Since family members have a strong impact on each other, studies highlight the need to offer effective family interventions to strengthen the wellbeing of the family. The aim of the current study is to clarify whether there is a difference between parents` opinions regarding their child`s emotional and behavioral condition immediately after Dialogical Family Guidance (DFG) has ended and after a three and six month follow-up. METHOD: Fifty families with a child with NDD were randomized into two groups. Group 1 received DFG with an immediate starting point, and Group 2 received DFG after a three-month waiting period. Parent experiences of treatment response regarding their children`s emotional and behavioral symptoms were estimated before and after DFG using the parent version of the Strengths and Difficulties Questionnaire (SDQ-p) at baseline, and after three and six months. Additionally, comparisons between boys and girls, and the age of the child were analyzed. RESULTS: The total difficulties score between Group 1 and Group 2 showed no difference immediately after DFG, or after three months. Regarding subdomains boys had more peer problems than girls, and at baseline, children between 3 and 6 years appeared to have more conduct problems than children between 7 and 13 years. Subdomain prosocial behavior increased statistically significantly during the study period in Group 1. Other SDQ-p subdomains remained constant in both groups between baseline and three and six month follow-up. CONCLUSIONS: The result does not show any differences between parents` opinions regarding their child immediately after or three months after DFG regarding SDQ-p total difficulties scores in either group. The difference between younger and older children regarding conduct problems at baseline, and the difference between boys and girls regarding peer problems is worth paying attention to in the clinical setting. Because of the small sample, it is not possible to draw relevant conclusions regarding the intervention`s effect regarding the child`s mental health dimensions, gender, or age. Nevertheless, Dialogical family Guidance represents one intervention that can be used. TRIAL REGISTRATION: ClinicalTrials.gov NCT04892992 (retrospectively registered May 18th 2021).

Childhood disabilities and the cost of developmental therapies: the serviceprovider perspective.

PURPOSE: For children with neurodevelopmental disabilities (CWNDs), early diagnosis that leads to early intervention with regular targeted therapies is critical. In Qatar, private therapy centres that address this demand often have highly exclusive prices restricting families from availing them. This paper examines the challenges faced by families with CWNDs, as well as various financial and systemic obstacles, from the vantage point of these centres, all of which culminate in an extraordinarily high disability price tag for disability families in Qatar. METHODS: This study is based on qualitative, semi-structured, and in-depth interviews with private therapy centres and developmental paediatricians. RESULTS: Therapy centre representatives expressed common struggles in lengthy and cumbersome administration and licencing procedures, difficulty in hiring and retaining high quality staff, and expenses that need to be paid to the state. From their experience, families largely struggle with delayed diagnoses that significantly slow down intervention plans and therapies as well as staggeringly high financial costs with a dearth of funding options. CONCLUSIONS: We recommend sincere engagement, dialogue, and cooperation between multiple stakeholders; a supportive ecosystem to balance and distribute the demand that includes schools and parents; as well more efficient administrative procedures and recruitment strategies.

Health Care for Youth With Neurodevelopmental Disabilities: A Consensus Statement.

Individuals with a neurodevelopmental disability (NDD) face significant health care barriers, disparities in health outcomes, and high rates of foregone and adverse health care experiences. The Supporting Access for Everyone (SAFE) Initiative was developed to establish principles of health care to improve equity for youth with NDDs through an evidence-informed and consensus-derived process. With the Developmental Behavioral Pediatric Research Network, the SAFE cochairs convened a consensus panel composed of diverse professionals, caregivers, and adults with NDDs who contributed their varied expertise related to SAFE care delivery. A 2-day public forum (attended by consensus panel members) was convened where professionals, community advocates, and adults with NDDs and/or caregivers of individuals with NDDs presented research, clinical strategies, and personal experiences. After this, a 2-day consensus conference was held. Using nominal group technique, the panel derived a consensus statement (CS) on SAFE care, an NDD Health Care Bill of Rights, and Transition Considerations. Ten CSs across 5 topical domains were established: (1) training, (2) communication, (3) access and planning, (4) diversity, equity, inclusion, belonging, and anti-ableism, and (5) policy and structural change. Relevant and representative citations were added when available to support the derived statements. The final CS was approved by all consensus panel members and the Developmental Behavioral Pediatric Research Network steering committee. At the heart of this CS is an affirmation that all people are entitled to health care that is accessible, humane, and effective.

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.

Mitochondria are critical for brain development and homeostasis. Therefore, pathogenic variation in the mitochondrial or nuclear genome which disrupts mitochondrial function frequently results in developmental disorders and neurodegeneration at the organismal level. Large-scale application of genome-wide technologies to individuals with mitochondrial diseases has dramatically accelerated identification of mitochondrial disease-gene associations in humans. Multi-omic and high-throughput studies involving transcriptomics, proteomics, metabolomics, and saturation genome editing are providing deeper insights into the functional consequence of mitochondrial genomic variation. Integration of deep phenotypic and genomic data through allelic series continues to uncover novel mitochondrial functions and permit mitochondrial gene function dissection on an unprecedented scale. Finally, mitochondrial disease-gene associations illuminate disease mechanisms and thereby direct therapeutic strategies involving small molecules and RNA-DNA therapeutics. This review summarizes progress in functional genomics and small molecule therapeutics in mitochondrial neurodevelopmental disorders.

Improving care for rare genetic neurodevelopmental disorders: A systematic review and critical appraisal of clinical practice guidelines using AGREE II.

PURPOSE: Rare genetic neurodevelopmental disorders associated with intellectual disability require lifelong multidisciplinary care. Clinical practice guidelines may support healthcare professionals in their daily practice, but guideline development for rare conditions can be challenging. In this systematic review, the characteristics and methodological quality of internationally published recommendations for this population are described to provide an overview of current guidelines and inform future efforts of European Reference Network ITHACA (Intellectual disability, TeleHealth, Autism, and Congenital Anomalies). METHODS: MEDLINE, Embase, and Orphanet were systematically searched to identify guidelines for conditions classified as "rare genetic intellectual disability" (ORPHA:183757). Methodological quality was assessed using the Appraisal of Guidelines, Research, and Evaluation II tool. RESULTS: Seventy internationally published guidelines, addressing the diagnosis and/or management of 28 conditions, were included. The methodological rigor of development was highly variable with limited reporting of literature searches and consensus methods. Stakeholder involvement and editorial independence varied as well. Implementation was rarely addressed. CONCLUSION: Comprehensive, high-quality guidelines are lacking for many rare genetic neurodevelopmental disorders. Use and transparent reporting of sound development methodologies, active involvement of affected individuals and families, robust conflict of interest procedures, and attention to implementation are vital for enhancing the impact of clinical practice recommendations.

Addressing the Gap in Research Training in Child Psychiatry and Neurodevelopment.

Psychiatric and neurodevelopmental conditions in children are common, often co-occur, and can be highly impairing. Moreover, psychiatric disorders that typically do not fully manifest until adulthood, such as schizophrenia, have their roots in early development, with atypical brain and behavioral patterns arising well before a clinical diagnosis is made. The relevance of brain development to improving outcomes of psychiatric and neurodevelopmental conditions underscores the need to cultivate a pipeline of investigators with the necessary training to conduct rigorous, developmentally focused research.

Friendship interventions for children with neurodevelopmental needs: A systematic review and meta-analysis.

RATIONALE: Children with neurodevelopmental disorders such as attention-deficit hyperactivity disorder (ADHD), autism, developmental language disorder (DLD), intellectual disability (ID), and social (pragmatic) communication disorder (SPCD) experience difficulties with social functioning due to differences in their social, emotional and cognitive skills. Previous systematic reviews have focussed on specific aspects of social functioning rather than broader peer functioning and friendships. OBJECTIVE: To systematically review and methodologically appraise the quality and effectiveness of existing intervention studies that measured friendship outcomes for children with ADHD, autism, DLD, ID, and SPCD. METHOD: Following PRISMA guidelines, we searched five electronic databases: CINAHL, Embase, Eric, PsycINFO, and PubMed. Two independent researchers screened all abstracts and disagreements were discussed with a third researcher to reach consensus. The methodological quality of studies was assessed using the Cochrane Risk of Bias Tool for Randomised Trials. RESULTS: Twelve studies involving 15 interventions were included. Studies included 683 children with a neurodevelopmental disorder and 190 typically-developing children and diagnosed with either autism or ADHD. Within-group meta-analysis showed that the pooled intervention effects for friendship across all interventions were small to moderate (z = 2.761, p = 0.006, g = 0.485). The pooled intervention effect between intervention and comparison groups was not significant (z = 1.206, p = 0.400, g = 0.215). CONCLUSION: Findings provide evidence that some individual interventions are effective in improving social functioning and fostering more meaningful friendships between children with neurodevelopmental disorders and their peers. Effective interventions involved educators, targeted child characteristics known to moderate peer functioning, actively involved peers, and incorporated techniques to facilitate positive peer perceptions and strategies to support peers. Future research should evaluate the effectiveness of friendship interventions for children with DLD, ID and SPCD, more comprehensively assess peer functioning, include child self-report measures of friendship, and longitudinally evaluate downstream effects on friendship.

Pediatric Neurocritical Care: Maximizing Neurodevelopmental Outcomes Through Specialty Care.

The field of pediatric neurocritical care (PNCC) has expanded and evolved over the last three decades. As mortality from pediatric critical care illness has declined, morbidity from neurodevelopmental disorders has expanded. PNCC clinicians have adopted a multidisciplinary approach to rapidly identify neurological injury, implement neuroprotective therapies, minimize secondary neurological insults, and establish transitions of care, all with the goal of improving neurocognitive outcomes for their patients. Although there are many aspects of PNCC and adult neurocritical care (NCC) medicine that are similar, elemental difference between adult and pediatric medicine has contributed to a divergent evolution of the respective fields. The low incidence of pediatric critical care illness, the heterogeneity of neurological insults, and the limited availability of resources all shape the need for a PNCC clinical care model that is distinct from the established paradigm adopted by the adult neurocritical care community at large. Considerations of neurodevelopment are fundamental in pediatrics. When neurological injury occurs in a child, the neurodevelopmental stage at the time of insult alters the impact of the neurological disease. Developmental variables contribute to a range of outcomes for seemingly similar injuries. Despite the relative infancy of the field of PNCC, early reports have shown that implementation of a specialized PNCC service elevates the quality and safety of care, promotes education and communication, and improves outcomes for children with acute neurological injuries. The multidisciplinary approach of PNCC clinicians and researchers also promotes a culture that emphasizes the importance of quality improvement and education initiatives, as well as development of and adherence to evidence-based guidelines and family-focused care models.

Application of non-invasive neuromodulation in children with neurodevelopmental disorders to improve their sleep quality and constipation.

BACKGROUND: Children with neurodevelopmental disorders have a very wide clinical variability. A common prevalent factor is problems with stool and sleep quality. Currently, there are multiple studies related to their evaluation, but not so much related to a specific intervention. The aim was to evaluate the effectiveness and safety of the application of non-invasive neuromodulation as a treatment in children with neurodevelopmental disorders to improve constipation and quality of sleep. METHODS: A total of 23 minors aged between 2 and 16 were included in this cross-sectional study. All participants were applied the microcurrent device for 60 min, 3 times per week for a total of 4 weeks. The technique was based on non-invasive neuromodulation using a surface-applied microcurrent electrostimulation device that administers an external, imperceptible, pulsed electrical stimulation. It is applied to the extremities, in a coordinated manner, using gloves and anklets connected with electrodes to a control console. Sleep latency and microarousals were evaluated through a sleep diary. To assess the evolution and type of defecation, the adapted and validated version in Spanish of the Bristol Stool Form Scale was used. RESULTS: No adverse events occurred during the study and no incidences were registered. Clinically relevant improvements were registered in defecation frequency and type as well as in sleep related parameters. An increase in the hours of sleep was registered, from 7,35 (0,83) to 9,09 (1,35), and sleep interruptions decreased from 3,83 (1,95) to 1,17 (1,11), (p < .001). CONCLUSION: Microcurrents can be used as an effective and safe treatment to improve quality of sleep and constipation in children with neurodevelopmental disorders. More studies are needed in order to obtain statistically significant results. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05265702. FIRST REGISTRATION: 03/03/2022 PROTOCOL: https://clinicaltrials.gov/ct2/show/NCT05265702?term=baez+suarez&draw=2&rank=4.

ICT Framework for Supporting Applied Behavior Analysis in the Social Inclusion of Children with Neurodevelopmental Disorders.

The applied behavior analysis (ABA) model emphasizes observable and measurable behaviors by carrying out decision making using experimental data (behavioral observation assessment strategies). In this framework, information and communication technology (ICT) becomes highly suitable for enhancing the efficiency and effectiveness of the methodology. This paper aims to delve into the potential of ICT in providing innovative solutions to support ABA applications. It focuses on how ICT can contribute to fostering social inclusion with respect to children with neurodevelopmental disorders. ICT offers advanced solutions for continuous and context-aware monitoring, as well as automatic real-time behavior assessments. Wireless sensor systems (wearable perceptual, biomedical, motion, location, and environmental sensors) facilitate real-time behavioral monitoring in various contexts, enabling the collection of behavior-related data that may not be readily evident in traditional observational studies. Moreover, the incorporation of artificial intelligence algorithms that are appropriately trained can further assist therapists throughout the different phases of ABA therapy. These algorithms can provide intervention guidelines and deliver an automatic behavioral analysis that is personalized to the child's unique profile. By leveraging the power of ICT, ABA practitioners can benefit from cutting-edge technological advancements to optimize their therapeutic interventions and outcomes for children with neurodevelopmental disorders, ultimately contributing to their social inclusion and overall wellbeing.

Similitudes en el deterioro cognitivo de pacientes con esquizofrenia de inicio reciente y pacientes crónicos: una consideración sobre la hipótesisdel neurodesarrollo / Similarities in cognitive impairment between recent-onset and chronic schizophrenia patients: a consideration for the neurodevelopmental hypothesis

Se ha descrito la presencia de déficits cognitivos en pacientes con esquizofrenia, dichas alteraciones pueden observarse en fases tempranas y crónicas de la enfermedad.Sin embargo, los hallazgos respecto a los déficits en estas fases aún mantienen el debate sobre si la esquizofrenia es una condición neurodegenerativa que cursa con un deterioro continuo o si los déficits permanecen estables, como sugiere la hipótesis del neurodesarrollo. En el presente estudio se compara el rendimiento cognitivo de pacientes con esquizofrenia de inicio reciente (RO) y pacientes crónicos (CH) con la finalidad de contrastar la hipótesis del neurodesarrollo con la perspectiva neurodegenerativa. Método. Se incluyeron 20 participantes de RO (< 5 años desde el primer episodio psicótico) y 30 pacientes de CH (>5 años desde el primer episodio psicótico). Para la evaluación cognitiva se utilizó la Batería Cognitiva Consensuada MATRICS (MCCB), la Prueba Torre de Londres, la Prueba de Clasificación de Tarjetas de Wisconsin y la Prueba de Stroop. Se utilizó ANCOVA para las comparaciones de grupos. Resultados. No hubo diferencias entre los grupos en la mayoría de las pruebas cognitivas. Se observó una diferencia significativa en la prueba de span espacial del MCCB. Conclusiones. Los déficits cognitivos permanecen estables a lo largo del tiempo; nuestros hallazgos son consistentes con la hipótesis del neurodesarrollo de la esquizofreniamás que con el enfoque neurodegenerativo. (AU)

Impairment in attention, memory, processing speed and executive functions have been described in patients with schizophrenia. Such impairments can be observed in early stages of the disease and in chronic patients; discrepancy in findings regarding the cognitive deficits at different stages of the illness keeps the debate about schizophrenia as a neurodegenerative condition which courses with continuous deterioration, or if deficits remain stable, as the neurodevelopmental hypothesis suggests. The aim of the present study was to compare the cognitive performance of recent-onset (RO) and chronic (CH) schizophrenia patients to contrast the neurodevelopmental hypothesis against the neurodegenerative approach. Methods. Twenty RO participants (< 5 years from first psychotic episode) and 30 CH patients (> 5 years from first psychotic episode) were included in the sample. The MATRICS Consensus Cognitive Battery (MCCB), Tower of London test (ToL), Wisconsin Card Sorting Test (WCST) and Stroop Test were used for cognitive evaluation. ANCOVA analysis was performed for group comparisons. Results. No differences between RO and CH patients were identified on most cognitive tests. However, a significant difference was observed in the visual spatial span test from MCCB. Conclusions. We conclude that cognitive deficits remain stable over the course of the disease. Our findings are consistent with the neurodevelopmental hypothesis of schizophrenia rather than the neurodegenerative approach. (AU)

hnRNPH2 gain-of-function mutations reveal therapeutic strategies and a role for RNA granules in neurodevelopmental disorders.

hnRNPH2-related neurodevelopmental disorder (NDD) is caused by mutations in the HNRNPH2 gene and is associated with substantial challenges, including developmental delay, intellectual disability, growth delay, and epilepsy. There is currently no therapeutic intervention available to those with hnRNPH2-related NDD that addresses its underlying mechanisms. In this issue of the JCI, Korff et al. studied specific gain-of-function mutations associated with hnRNPH2-related NDD, with the help of mouse models that recapitulate key features of the condition in humans. Their work paves the way for therapeutic approaches that aim to reduce the expression of mutant hnRNPH2 and highlights a role for disrupted RNA granules in neurodevelopmental and neurodegenerative disorders.

Caregiver Satisfaction with Emergency Department Care for Pediatric Patients with Neurodevelopmental Disorders.

OBJECTIVE: Children with neurodevelopmental disorders (NDDs) often encounter increased adversity when navigating the health care system. In this study, we explored the pediatric emergency department (PED) experience for patients with NDDs and their caregivers compared with that of patients without NDDs. METHODS: Data for this study were obtained from National Research Corporation patient experience survey questionnaires and electronic medical record (EMR) data for patients presenting to a PED between May 2018 and September 2019. ED satisfaction was determined by the top-box approach; ED ratings of 9/10 or 10/10 were considered to reflect high ED satisfaction. Demographics, Emergency Severity Index, ED length of stay, time from arrival to triage, time to provider assessment, and diagnoses were extracted from the EMR. Patients with NDDs were identified based on International Classification of Diseases, Tenth Revision codes; patients with intellectual disabilities, pervasive and specific developmental disorders, or attention-deficit/hyperactivity disorders were included in the NDD cohort. One-to-one propensity score matching between patients with and without NDDs was performed, and a multivariable logistic regression model was built on the matched cohort. RESULTS: Patients with NDDs represented over 7% of survey respondents. Matching was successful for 1162 patients with NDDs (99.5%), resulting in a matched cohort sample size of 2324. Caregivers of patients with NDDs had 25% lower odds of reporting high ED satisfaction (95% confidence interval [CI], 0.62-0.91, p = 0.004). CONCLUSION: Caregivers of patients with NDDs make up a significant proportion of survey respondents and are more likely to rate the ED poorly than caregivers of patients without NDDs. This suggests an opportunity for targeted interventions in this population to improve patient care and experience.

Serious Games in the new era of digital-health interventions: A narrative review of their therapeutic applications to manage neurobehavior in neurodevelopmental disorders.

Children and adolescents with neurodevelopmental disorders generally show adaptive, cognitive and motor skills impairments associated with behavioral problems, i.e., alterations in attention, anxiety and stress regulation, emotional and social relationships, which strongly limit their quality of life. This narrative review aims at providing a critical overview of the current knowledge in the field of serious games (SGs), known as digital instructional interactive videogames, applied to neurodevelopmental disorders. Indeed, a growing number of studies is drawing attention to SGs as innovative and promising interventions in managing neurobehavioral and cognitive disturbs in children with neurodevelopmental disorders. Accordingly, we provide a literature overview of the current evidence regarding the actions and the effects of SGs. In addition, we describe neurobehavioral alterations occurring in some specific neurodevelopmental disorders for which a possible therapeutic use of SGs has been suggested. Finally, we discuss findings obtained in clinical trials using SGs as digital therapeutics in neurodevelopment disorders and suggest new directions and hypotheses for future studies to bridge the gaps between clinical research and clinical practice.

Common sleep disorders in children: assessment and treatment.

Pediatric sleep disorders are a common, mainly among children with pre-existing disabilities, neurological conditions, and neurodevelopmental disorders. The consequences are variable, and sleep disorders may be associated with deficits in neurocognitive performance and growth failure. Rising awareness about sleep disorders among pediatricians will improve the early diagnosis and management of these disorders. This review describes normal sleep patterns in infants and children and provide a recent update on common sleep disorders that improve the diagnosis and treatment of children with sleep disorders.

Roles of lncRNAs in brain development and pathogenesis: Emerging therapeutic opportunities.

The human genome is pervasively transcribed, producing a majority of short and long noncoding RNAs (lncRNAs) that can influence cellular programs through a variety of transcriptional and post-transcriptional regulatory mechanisms. The brain houses the richest repertoire of long noncoding transcripts, which function at every stage during central nervous system development and homeostasis. An example of functionally relevant lncRNAs is species involved in spatiotemporal organization of gene expression in different brain regions, which play roles at the nuclear level and in transport, translation, and decay of other transcripts in specific neuronal sites. Research in the field has enabled identification of the contributions of specific lncRNAs to certain brain diseases, including Alzheimer's disease, Parkinson's disease, cancer, and neurodevelopmental disorders, resulting in notions of potential therapeutic strategies that target these RNAs to recover the normal phenotype. Here, we summarize the latest mechanistic findings associated with lncRNAs in the brain, focusing on their dysregulation in neurodevelopmental or neurodegenerative disorders, their use as biomarkers for central nervous system (CNS) diseases in vitro and in vivo, and their potential utility for therapeutic strategies.