A Systematic Review and Meta-Analysis of the Associations Between Motor Milestone Timing and Motor Development in Neurodevelopmental Conditions.

Early motor skills may be important early markers of neurodevelopmental conditions or predictors of their later onset. To explore this, we conducted a systematic review and meta-analysis of infant motor skill assessments in those who go on to gain a clinical diagnosis of autism, attention deficit hyperactivity disorder (ADHD), schizophrenia, language conditions, tic disorders, or developmental coordination disorder (DCD). In total, 65 articles met inclusion criteria. Three three-level meta-analyses were run. Meta-analysis of milestone achievement in N=21354 individuals revealed gross motor milestones were significantly delayed compared to controls (g= 0.53, p< 0.001). Subgroup analyses revealed autism (g= 0.63) and DCD (g= 0.53) had the highest magnitude delays. Specific delays were revealed for holding the head up (g= 0.21), sitting (g= 0.28), standing (g= 0.35), crawling (g=0.19), and walking (g= 0.71). Meta-analyses of standardised motor skill measurements in N=1976 individuals revealed reduced performance compared to controls in autism and language conditions (g= -0.54, p< 0.001). Together, these findings demonstrate delayed milestone attainment and motor impairments in early childhood in neurodevelopmental conditions.

Disentangling the relationship between sensory processing, alexithymia and broad autism spectrum: A study in parents' of children with autism spectrum disorders and sensory processing disorders.

BACKGROUND: Autistic features and sensory processing difficulties and their phenotypic co-expression with alexithymia share a transdiagnostic vulnerability. In this work, we explored whether the current concept of broad autism phenotype rather translates altered sensory processing (non-specific to autism), meaning that the characteristics of altered sensory processing should be overexpressed among individuals with heightened vulnerability to sensory processing atypicalities (parents of children with sensorial processing disorder, or SPD parents) and individuals with heightened vulnerability to autistic traits (parents of children with autism spectrum disorders, or ASD parents). In addition, the association between altered sensory processing and alexithymia was inspected. METHOD: The Adolescent/Adult Sensory Profile, Autism Spectrum Quotient, and Toronto Alexithymia Scale were completed by 31 parents of children with ASD, 32 parents of children with SPD, and 52 parents of typically developed (TD) children. RESULTS: Extreme sensory patterns were overexpressed both in parents of children with SPD and parents of children with ASD when compared to parents of TD children. In addition, extreme sensory patterns were significantly associated with alexithymia scores. Specifically, sensory avoidance, low registration, and sensory sensitivity were positively correlated with alexithymia. No significant differences were found regarding the proportion of autistic traits and alexithymia between ASD and SPD groups of parents. CONCLUSIONS: These results challenge the specificity of broad autism phenotype and suggest a neurodevelopmental atypicity with roots in altered sensory and emotional processing.

Proteomics insights into fragile X syndrome: Unraveling molecular mechanisms and therapeutic avenues.

Fragile X Syndrome (FXS) is a neurodevelopment disorder characterized by cognitive impairment, behavioral challenges, and synaptic abnormalities, with a genetic basis linked to a mutation in the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene that results in a deficiency or absence of its protein product, Fragile X Messenger Ribonucleoprotein (FMRP). In recent years, mass spectrometry (MS) - based proteomics has emerged as a powerful tool to uncover the complex molecular landscape underlying FXS. This review provides a comprehensive overview of the proteomics studies focused on FXS, summarizing key findings with an emphasis on dysregulated proteins associated with FXS. These proteins span a wide range of cellular functions including, but not limited to, synaptic plasticity, RNA translation, and mitochondrial function. The work conducted in these proteomic studies provides a more holistic understanding to the molecular pathways involved in FXS and considerably enhances our knowledge into the synaptic dysfunction seen in FXS.

Neurodevelopmental Outcomes of Pregnancies Resulting from Assisted Reproduction: A Review of the Literature.

The term infertility is defined as the lack of conception within 1 year of unprotected intercourse. It affects more than 80 million individuals worldwide. It is estimated that 10-15% of couples of reproductive age are challenged by reproductive issues. Assisted reproduction techniques (ART) are responsible for more than 4% of live births. Our aim is to review the research on neurodevelopmental outcomes of newborns born after the implementation of assisted reproduction methods compared to those conceived naturally. We conducted a comprehensive search of the PubMed, Crossref and Google Scholar electronic databases for related articles up to June 2022 using the PRISMA guidelines. Our research revealed a large number of long term follow-up studies between 2 and 18 years of age, with comparable developmental outcomes. Many studies compared the effects of different infertility treatments against natural conception. The review of the literature revealed that ART is safe, as the majority of studies showed no effect on the neurodevelopmental outcomes of the offspring. In most cases when such an effect was observed, it could be attributed to confounding factors such as subfertility, multiple pregnancies and gestational age at delivery. Finally, the increase in the prevalence of neurodevelopmental disorders after ART, as described in studies with statistically significant results, is predominantly marginal, and given the low incidence of neurodevelopmental disorders in the general population, its clinical significance is debatable.

Phenotypic Spectrum and Molecular Findings in 17 ATR-X Syndrome Italian Patients: Some New Insights.

ATR-X syndrome is a rare X-linked congenital disorder caused by hypomorphic mutations in the ATRX gene. A typical phenotype is well defined, with cognitive impairment, characteristic facial dysmorphism, hypotonia, gastrointestinal, skeletal, urogenital, and hematological anomalies as characteristic features. With a few notable exceptions, general phenotypic differences related to specific ATRX protein domains are not well established and should not be used, at least at the present time, for prognostic purposes. The phenotypic spectrum and genotypic correlations are gradually broadening, mainly due to rapidly increasing accessibility to NGS. In this scenario, it is important to continue describing new patients, illustrating the mode and age of onset of the typical and non-typical features, the classical ones and those tentatively added more recently. This report of well-characterized and mostly unreported patients expands the ATR-X clinical spectrum and emphasizes the importance of better clinical delineation of the condition. We compare our findings to those of the largest ATR-X series reported so far, discussing possible explanations for the different drawn conclusions.

Trastorno por Déficit de Atención con Hiperactividad: Ritmo Circanual en el Mes de Nacimiento / Attention Deficit Hyperactivity Disorder: Circannual Rhythm in the Month of Birth

Estudiamos la existencia de ritmo circanual en el mes de nacimiento en participantes con trastorno de déficit de atención e hiperactividad (TDAH)y analizamos la asociación entre meses de nacimiento y TDAH. La muestra incluye 10978 participantes (1778 TDAH / 9200 no TDAH), entre 3 y18 años, reclutados mediante muestreo consecutivo de primeras consultas atendidas en salud mental entre 1992 y 2021. Los participantes conTDAH presentan un ritmo circanual significativo en los meses de nacimiento, con una acrofase en octubre. Nacer en el último cuatrimestre del añoincrementa significativamente la probabilidad de ser diagnosticado TDAH, controlando el efecto de sexo y edad. Con el transcurso de los meses delaño, existe una tendencia lineal creciente significativa de ser diagnosticado de TDAH, no observada en población general, ni en casos sin TDAH.Es necesario tener precaución en el diagnóstico y tratamiento de los niños nacidos en los últimos meses del año, que, por su mayor inmadurez encomparación con los demás niños de la clase, pudieran ser diagnosticados y tratados erróneamente como TDAH. (AU)

We studied the existence of circanual rhythm in the month of birthin participants with attention deficit hyperactivity disorder (ADHD) and analyzed the association between months of birth and ADHD. We analyzed10,978 participants (1,778 ADHD/9,200 non-ADHD), aged 3 to 18 years. A consecutive sample of first visits to mental health between 1992 and2021 is used. Participants with ADHD exhibit a significant circannual rhythm in the months of birth, with an acrophase in October. Being born in thelast quarter of the year significantly increases the probability of being diagnosed with ADHD, controlling for the effect of sex and age. As the monthsof the year go by, there is a significant increasing linear trend of being diagnosed with ADHD, which is not observed neither in general populationnor in cases without ADHD. Caution is necessary in diagnosis and treatment of children born in the last months of year, who, due to their greaterimmaturity compared to the other children in class, could be misdiagnosed and treated as ADHD. (AU)

Impact of assisted reproduction techniques on the neuro-psycho-motor outcome of newborns: a critical appraisal.

Subfertility and infertility are common problems among couples of reproductive age, and they increasingly require the use of assisted reproductive techniques (ART). Understandably, doubts about the safety of such methods are increasing among future parents. The purpose of this review is to analyse the real impact of ART, such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), on the health of the unborn baby; in particular, this work is focussed on the problems related to the neuro-psycho-motor area. Twenty-four studies were reviewed and outcomes investigated were: risk of the onset of neurodevelopmental diseases, worsening of school cognitive performance and risk of developing infantile cerebral palsy (CP) or neurological sequelae. For the first two outcomes, we did not find a correlation with ART; nevertheless, the results of the included studies about risk of CP are discordant and influenced by various confounding factors, such as pre-term birth and multiple pregnancies.IMPACT STATEMENTWhat is already known on this subject? Assisted reproductive techniques (ART) are the main answer for achieving pregnancy in infertile couples. However, a wide number of studies have tried to focus on possible different outcomes in terms of maternal and foetal/new-born health. Regarding this scenario, a peculiar importance is given to diseases affecting the neuro-psycho-motor area of the new-born. Since this group of detrimental pathologies could heavily affect the new-born's quality of life and require costly social facilities, different studies have tried to focus on possible outcomes after ART.What do the results of this study add? This manuscript provides a review of the literature regarding ART procedures and neuro-psycho-motor implication. A review is strongly required due to the importance of collecting evidence from studies with different methodologies.What are the implications of these findings for clinical practice and/or further research? This manuscript provides evidence about the need for wider and more congruent studies regarding neurodevelopment disorders in new-borns after ART procedures. Data are prone to suggest a slight correlation, but several confounding factors can heavily hamper the possibility to draw a firm conclusion about the topic.

Musical Performance in Adolescents with ADHD, ADD and Dyslexia-Behavioral and Neurophysiological Aspects.

Research has shown that dyslexia and attention deficit (hyperactivity) disorder (AD(H)D) are characterized by specific neuroanatomical and neurofunctional differences in the auditory cortex. These neurofunctional characteristics in children with ADHD, ADD and dyslexia are linked to distinct differences in music perception. Group-specific differences in the musical performance of patients with ADHD, ADD and dyslexia have not been investigated in detail so far. We investigated the musical performance and neurophysiological correlates of 21 adolescents with dyslexia, 19 with ADHD, 28 with ADD and 28 age-matched, unaffected controls using a music performance assessment scale and magnetoencephalography (MEG). Musical experts independently assessed pitch and rhythmic accuracy, intonation, improvisation skills and musical expression. Compared to dyslexic adolescents, controls as well as adolescents with ADHD and ADD performed better in rhythmic reproduction, rhythmic improvisation and musical expression. Controls were significantly better in rhythmic reproduction than adolescents with ADD and scored higher in rhythmic and pitch improvisation than adolescents with ADHD. Adolescents with ADD and controls scored better in pitch reproduction than dyslexic adolescents. In pitch improvisation, the ADD group performed better than the ADHD group, and controls scored better than dyslexic adolescents. Discriminant analysis revealed that rhythmic improvisation and musical expression discriminate the dyslexic group from controls and adolescents with ADHD and ADD. A second discriminant analysis based on MEG variables showed that absolute P1 latency asynchrony |R-L| distinguishes the control group from the disorder groups best, while P1 and N1 latencies averaged across hemispheres separate the control, ADD and ADHD groups from the dyslexic group. Furthermore, rhythmic improvisation was negatively correlated with auditory-evoked P1 and N1 latencies, pointing in the following direction: the earlier the P1 and N1 latencies (mean), the better the rhythmic improvisation. These findings provide novel insight into the differences between music processing and performance in adolescents with and without neurodevelopmental disorders. A better understanding of these differences may help to develop tailored preventions or therapeutic interventions.

Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets.

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.

The effects of persistent sleep disturbances during early childhood over adolescent ADHD, and the mediating effect of attention-related executive functions: Data from the 2004 Pelotas Birth Cohort.

OBJECTIVE: Investigate effects of persistent sleep disturbances during early childhood over ADHD during the adolescence, and the potential attention-related executive functions mediating this effect. METHODS: We used data from the 2004 Pelotas Birth Cohort. Children's Sleep disturbances were reported by their mothers at 12, 24, and 48 months of age, whereas the Test-of-Everyday-Attention-for-Children (TEA-Ch) and the Development and Well Being Assessment (DAWBA) were applied at 11 years of age to evaluate attention-related executive functions and ADHD, respectively. Persistent sleep problems were defined as reporting have two or more points of difficulty to sleep, nightmares, restless sleeps, and/or <10h/24h sleep duration. Logistic regression and mediation models were used, adjusting for maternal and child sociodemographic, behavior and health related variables. RESULTS: The highest prevalence of adolescent ADHD (15.4%) was on the group who reported having nightmares at 2,4 and 6 years. In adjusted models, we observed an odd of ADHD in the adolescence 2.26 higher in those who reported persistent nightmares (CI95% 1.33, 4.01) compared to those reported transitory or no nightmares. Persistent difficulty to sleep (OR=1.74 CI95% 1.13, 2.66) and restless sleep (OR=1.80, CI95% 1.23, 2.64) during childhood also increased ADHD odds at 11 years. No indirect effect through attention related executive functions was found using mediating models. DISCUSSION: Persistent early sleep disturbances may increase odds of ADHD among adolescents and could be consider as early marker of such disorder, specially nightmares problems. These effects were not mediated by attention-related executive functions. Nevertheless, we had 75% of cohort inception response.

Pediatric care for children with developmental coordination disorder, can we do better?

This paper adopts a method of narrative critical review based on a non-systematic search of the literature to provide insights into the trends of developmental coordination disorder (DCD) treatment and to point out some future alternative approaches to prevent secondary health implications in children with DCD. The cause of DCD is unknown, but evidence suggests that these children have atypical brain structure and function. Interventions to help children cope with their activity limitations are effective in improving motor competence and motor skill related fitness in the short term. Although activity-orientated interventions can improve motor outcomes in children with DCD, high quality intervention trials and evaluation of long-term effects are urgently needed. Importantly, motor coordination problems associated with DCD extend to exercise-related activities leading to reduced participation in play and sports, which causes secondary problems in muscular fitness and body composition. Hence, treatment goals should not be limited to the improvement of motor skills (in ADL), but should also focus on health-related quality of life. We therefore propose when noticing motor problems in a child, already before enrolling but also during intervention, to explore ways to adapt everyday physical activities to optimally match the child's skill level. Hence, such activities will not only train the skills and improve physical fitness but will lead to positive engagement, thereby preventing the child from opting out of active play and sports. This provides the child with chances for exercise-dependent learning and will also positively impact social-emotional well-being.

Early-Onset Dementia Associated with a Heterozygous, Nonsense, and de novo Variant in the MBD5 Gene.

The haploinsufficiency of the methyl-binding domain protein 5 (MBD5) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5-neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients with atypical early-onset dementia.

Neurodevelopmental and psychiatric disorders in pediatric bladder and bowel dysfunction.

BACKGROUND: Bladder and bowel dysfunction (BBD) is a common pediatric problem that describes a constellation of lower urinary tract symptoms associated with constipation and/or encopresis. Its association with neurodevelopmental and psychiatric (NDP) problems is not well understood. OBJECTIVES: Our primary aim was to identify pre-existing NDP disorders in children with BBD. Secondarily, we aimed to screen for new behavioral problems and evaluate the association between bladder or bowel symptoms and behaviors symptoms. METHODS: A cross sectional study was conducted in urology clinics. New patients referred for BBD between 4 and 17 years old were recruited and completed: a demographics survey, Dysfunctional Voiding Score System questionnaire, assessment of bowel movements with the Bristol Stool Scale, and Strength and Difficulties questionnaire (SDQ). Those with known spinal dysraphism were excluded. SDQ scores were evaluated for abnormal screens in different subscales and total difficulties scores. Pearson correlation analyses were conducted for association. RESULTS: We included 61 participants (age 9.5 ± 4.1 years), including 33 females and 28 males. One or more pre-existing NDP disorder(s) was reported in 14 (23%) children; most commonly being learning disability (43%) and attention deficit hyperactivity disorder (29%). This cohort had more severe BBD symptoms as reflected in DVSS scores. SDQ scores demonstrated that 12 patients without pre-existing NDP diagnoses scored in the clinical range, with hyperactivity as the most common difficulty (6/12; 50%). CONCLUSIONS: A significant proportion of children with BBD have a comorbid NDP disorder and present with more severe symptomatology. The SDQ can be used as a behavioral screening tool this population for the identification of children who may benefit from formal developmental pediatrics assessment.

Developmental and epileptic encephalopathies: what we do and do not know.

Developmental encephalopathies, including intellectual disability and autistic spectrum disorder, are frequently associated with infant epilepsy. Epileptic encephalopathy is used to describe an assumed causal relationship between epilepsy and developmental delay. Developmental encephalopathies pathogenesis more independent from epilepsy is supported by the identification of several gene variants associated with both developmental encephalopathies and epilepsy, the possibility for gene-associated developmental encephalopathies without epilepsy, and the continued development of developmental encephalopathies even when seizures are controlled. Hence, 'developmental and epileptic encephalopathy' may be a more appropriate term than epileptic encephalopathy. This update considers the best studied 'developmental and epileptic encephalopathy' gene variants for illustrative support for 'developmental and epileptic encephalopathy' over epileptic encephalopathy. Moreover, the interaction between epilepsy and developmental encephalopathies is considered with respect to influence on treatment decisions. Continued research in genetic testing will increase access to clinical tests, earlier diagnosis, better application of current treatments, and potentially provide new molecular-investigated treatments.

THE DEVELOPING BRAIN REVEALED DURING SLEEP.

Given the prevalence of sleep in early development, any satisfactory account of infant brain activity must consider what happens during sleep. Only recently, however, has it become possible to record sleep-related brain activity in newborn rodents. Using such methods in rat pups, it is now clear that sleep, more so than wake, provides a critical context for the processing of sensory input and the expression of functional connectivity throughout the sensorimotor system. In addition, sleep uniquely reveals functional activity in the developing primary motor cortex, which establishes a somatosensory map long before its role in motor control emerges. These findings will inform our understanding of the developmental processes that contribute to the nascent sense of embodiment in human infants.

The thalamic reticular nucleus: A common nucleus of neuropsychiatric diseases and deep brain stimulation.

This review focuses on the studies that have been reviewed to determine the influence of the thalamic reticular nucleus on neuropsychiatric diseases and deep brain stimulation. The literature reviewed to date describes how alterations in the thalamic reticular nucleus affect several functions that regulated brain rhythms and provokes symptoms of many disorders. The observations as the basis for the renewed interest in the thalamic reticular nucleus in experimental models and testing its effectiveness in patients with resistant neuropsychiatric disorders. The preclinical studies showed that deep brain stimulation in the thalamic reticular nucleus could have beneficial effects on EEG activity, including synchronization and desynchronization activity of the brain, as well as promoting an alleviate to neuropsychiatric diseases. These observations open up the possibility of studying the role played by neurotransmitters in the pathologic process and the deep brain stimulation in the thalamic reticular nucleus in experimental animal models and offer evidence of its possible action in the human brain.

Deep Learning Techniques for Automatic Detection of Embryonic Neurodevelopmental Disorders.

The increasing rates of neurodevelopmental disorders (NDs) are threatening pregnant women, parents, and clinicians caring for healthy infants and children. NDs can initially start through embryonic development due to several reasons. Up to three in 1000 pregnant women have embryos with brain defects; hence, the primitive detection of embryonic neurodevelopmental disorders (ENDs) is necessary. Related work done for embryonic ND classification is very limited and is based on conventional machine learning (ML) methods for feature extraction and classification processes. Feature extraction of these methods is handcrafted and has several drawbacks. Deep learning methods have the ability to deduce an optimum demonstration from the raw images without image enhancement, segmentation, and feature extraction processes, leading to an effective classification process. This article proposes a new framework based on deep learning methods for the detection of END. To the best of our knowledge, this is the first study that uses deep learning techniques for detecting END. The framework consists of four stages which are transfer learning, deep feature extraction, feature reduction, and classification. The framework depends on feature fusion. The results showed that the proposed framework was capable of identifying END from embryonic MRI images of various gestational ages. To verify the efficiency of the proposed framework, the results were compared with related work that used embryonic images. The performance of the proposed framework was competitive. This means that the proposed framework can be successively used for detecting END.

Chromatin Remodeling Complex NuRD in Neurodevelopment and Neurodevelopmental Disorders.

The nucleosome remodeling and deacetylase (NuRD) complex presents one of the major chromatin remodeling complexes in mammalian cells. Here, we discuss current evidence for NuRD's role as an important epigenetic regulator of gene expression in neural stem cell (NSC) and neural progenitor cell (NPC) fate decisions in brain development. With the formation of the cerebellar and cerebral cortex, NuRD facilitates experience-dependent cerebellar plasticity and regulates additionally cerebral subtype specification and connectivity in postmitotic neurons. Consistent with these properties, genetic variation in NuRD's subunits emerges as important risk factor in common polygenic forms of neurodevelopmental disorders (NDDs) and neurodevelopment-related psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BD). Overall, these findings highlight the critical role of NuRD in chromatin regulation in brain development and in mental health and disease.

Hospital psychosocial interventions for patients with brain functional impairment: A retrospective cohort study.

Psychosocial interventions could improve health and care outcomes, however, little is known about their use for patients with complex needs in the acute hospital care setting. This study aimed to evaluate factors associated with psychosocial intervention use when treating patients with brain functional impairment during their hospital care. The all-inclusive New South Wales (NSW) Admitted Patient Data were employed to identify patients with neurodevelopment disorders, brain degenerative disorders, or traumatic brain injuries admitted to NSW public hospitals for acute care from July 2001 to June 2014. We considered receipt of psychosocial interventions as the primary outcome, and used mixed effect logistic models to quantify factors in relation to outcome. Of important note, psychosocial intervention use was more common in principal hospitals, and amongst those receiving intensive care or having comorbid mental disorders in the study populations. Approximate 70.8% of patients with traumatic brain injuries did not receive psychosocial interventions, despite attempts to target those in need and an overall increasing trend in adoption. Continuing efforts are warranted to improve service delivery and uptake.