Neurodevelopmental Disorders

Neurogenetic disorders with distinct genetic etiologies and known psychiatric phenotypes present a compelling model to study the links between genotype and phenotype. In recent years, the study of quantitative endophenotypes has become increasingly relevant in garnering a comprehensive understanding of psychiatric dysfunction. Neurofibromatosis Type 1 (NF1) and 22q11.2 Deletion Syndrome (22q11DS) are two compelling examples of neurogenetic disorders that are highly penetrant for neuropsychiatric phenotypes, and are also characterized by prefrontal cognitive dysfunction. We investigated endophenotypes of executive control in these populations, using a reverse-genetic approach. In Chapter 2, we measured risk-taking behavior using a child-friendly gambling task in patients with NF1 and controls (N=29 NF1, 23 controls). We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. Behaviorally, patients with NF1 iii tended to made fewer risky decisions than controls. Neuroimaging analyses revealed significant hypoactivation of multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls, in both decision-making and outcome phases of the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1. In Chapter 3, we reviewed recent literature on the utility of studying endophenotypes of psychiatric illness in 22q11DS. We provided an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder's heterogeneous presentation were reviewed. We discussed the use of how animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system. In Chapter 4, we investigated executive function and its relationship with structural neuroanatomy in patients with 22q11DS and matched controls (N=43 22q11DS, 43 controls), along with cognitive measures that tap behavioral regulation and metacognitive aspects of executive function. Behaviorally, patients with 22q11DS were impaired on multiple executive function measures. Right orbitofrontal cortical thickness showed a differential relationship between real-world executive function in patients with 22q11DS and controls. We also observed a group difference in the relationship between behavioral regulation and metacognition measures iv with thickness of ventral and dorsolateral prefrontal regions, respectively. Findings suggest that executive dysfunction characteristic of 22q11DS is underscored by altered prefrontal cortical structure. In Chapter 5, we investigated gene expression levels and behavioral correlates in patients with 22q11DS and matched controls (N=56 22q11DS, 48 controls). Using real-time quantitative polymerase chain reaction (RT-qPCR), we measured gene expression levels of three genes that are hemizygous in 22q11DS (COMT, DGCR8, and ZDHHC8). We found decreased expression of all three genes in patients with 22q11DS. We found a positive relationship between age and COMT expression in patients with 22q11DS, but not in controls. We also investigated the relationship between gene expression levels and relevant cognitive measures related to executive function, and found interaction effects between group and IQ for DGCR8 and ZDHHC8. Lastly, we found a relationship between working memory and COMT expression in patients with 22q11DS, but not in controls. Results suggest that the relationships between gene expression and cognitive function may differ between patients with 22q11DS and controls. Overall, the collected work provides insight into the use of endophenotypes of executive control in neurogenetic disorders. In clinical psychiatry, current methods for diagnosing psychiatric illness rely on clinical symptoms. Our research is in line with the NIMH RDoC framework, which supports the notion of studying intermediate endophenotypes in order to better diagnose and treat patients with psychiatric illness. Having a comprehensive understanding of the building blocks of psychiatric disease can lead not only to better methods of diagnosis, but also to better treatment strategies. v The dissertation of Rachel Karen Jonas is approved.

BackgroundTriple X syndrome (47,XXX) is a relatively common sex chromosomal aneuploidy characterized by the presence of a supernumerary X chromosome in females and has been associated with a variable cognitive, behavioural and psychiatric phenotype. 47,XXX may serve as a suitable model for studying the effect of genetic architecture on brain morphology. Previous studies have shown alterations in brain structure in 47,XXX particularly in childhood and adolescence. In this study, we examined subcortical and cortical brain morphology in adult women with 47,XXX using ultra-high field 7T MRI. Given previous evidence of impaired social functioning and emotion recognition in adults with 47,XXX, we also investigated the relationship of these functions with brain morphology.MethodsTwenty-one adult women with 47,XXX and 22 age- and sex-matched healthy controls were included. Structural T1-weighted images were acquired using a 7-Tesla magnetic resonance scanner. Measures of subcortical brain v...

dix). The p.V326F variant in S21 was inherited from her reportedly unaffected father, whereas the p.A449V variant in S26 was inherited from her mother, who was diagnosed with intellectual disability (Supplemental Table and Supplemental Clinical Appendix). The detailed clinical information we were able to gather (see Supplemental Clinical Appendix and Supplemental Table

Arka Plan: İnme, dünya çapında 15 milyon kişiyi etkileyen ve 5 milyon kişinin ölümüne neden olan ciddi bir sağlık sorunudur. İnme sonrası uzun dönem bakım ihtiyaçları karmaşık olup, sosyal hizmet müdahaleleri bu süreçte kritik rol oynamaktadır. Gereç ve Yöntem: Bu çalışmada, inme sonrası uzun dönem bakımda sosyal hizmet müdahalelerini değerlendiren araştırmalar sistematik olarak incelenmiştir. Semantic Scholar veri tabanından 50 makale seçilmiş, belirlenen kriterlere uygun 10 çalışma analize dahil edilmiştir. İncelenen 10 çalışma arasında 2 gözlemsel çalışma, 2 randomize kontrollü çalışma (1 küme randomize kontrollü çalışma dahil), 5 sistematik inceleme veya meta-analiz ve 2 literatür taraması yer almaktadır. Bulgular: İnceleme sonucunda, sosyal hizmet değerlendirmelerinin inme hastalarının %40'ında karşılanmamış ihtiyaçları ortaya koyduğu, bakım koordinasyonunun sağlık hizmeti kullanımını artırarak maliyetleri düşürdüğü ve psiko-eğitsel müdahalelerin aile işlevselliğinde sınırlı ama anlamlı gelişmeler sağladığı belirlenmiştir. Sonuçlar: Sosyal hizmet müdahaleleri, inme sonrası uzun dönem bakımda sosyal ve ailesel destek eksikliklerini azaltmada etkilidir, ancak müdahale türü ve uygulama ortamına göre sonuçlar değişkenlik göstermektedir. Holistik bakım yaklaşımları ve sürekli destek sistemleri geliştirilmesi önemlidir.

The aim of the present study was to determine whether monitoring measures are differentially disturbed in dysexecutive patients after frontal lesions. Twelve dysexecutive patients and 12 healthy controls were administered a paired-associates learning task. Their performances on recall prediction, judgment-of-learning (JOL), and feeling-of-knowing judgment (FOK) were then compared. The results revealed that the two groups differed only on accuracy measures of the FOK paradigm. The study of the overall correlations between the three measures of metamemory revealed a significant relation between recall prediction and accuracy measures of the JOL. We failed to find any significant correlation with the accuracy measures of the FOK. Taken together, our data confirm that metamemory experience is not a unitary construct but rather a group of distinct and quite independent mechanisms.

Objective Early communication skills, which emerge during the prelinguistic period, form the essential foundation for later language development in typically developing (TD) children and in children with communication disorders. Children with autism spectrum disorder (ASD) often exhibit significant deficits in these skills. This study aimed to investigate early communication skills in minimally verbal or nonverbal Persian-speaking children with ASD compared to their TD peers. Materials & Methods This cross-sectional study included two groups of Persian-speaking children, 70 with ASD, divided into three age groups (3, 4, and 5 years), and 132 TD children divided into four age groups (9, 10, 11, and 12 months). Children with ASD had a maximum of 3 to 5 spontaneous expressive words based on the MacArthur-Bates communicative development inventories (CDI-1). The communication skills were evaluated using the communication skills checklist (CSC) and were compared between age groups and between the two study groups. Results No significant differences were observed between children with ASD aged 3-5 years and TD children aged 9-11 months in the CSC domains (P>0.05). However, significant differences were found between ASD children and TD children aged 12 months in all CSC domains and between ASD children and TD children aged 9-11 months in the communication domain (assessing gesture use, eye contact and communicative function), with the ASD group scoring lower (P<0.001). One-way ANOVA results revealed no significant differences in the CSC scores among age groups of the ASD children (P>0.05), but significant differences among TD children's age groups were reported, with older children having higher scores (P<0.001). Conclusion Despite being older, children with ASD have notable delays in all early communication skills compared to 12-month-old TD children. These underscore the need for early screening and intervention targeting early communication skills in children with ASD to support language and communication development in these children.

Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourin...

(1)  Do Nootropics and Promnestics Enhance Human Cognition and Creative Thought?
(2)  Origins of Human Cognition and Creative Thought
(3) Neurodevelopmental and Neurodegenerative Motor and Movement Disorders
(4) Psychological Persuasion and the Mass/Social Media

ADHD is often associated with difficulty sustaining attention, impulsivity, and distractibility. Yet, paradoxically, many individuals with ADHD report episodes of "Hyperfocus", where they become intensely absorbed in a task for extended periods, sometimes to the exclusion of basic needs like eating or sleeping. This phenomenon raises intriguing questions about the nature of attention, motivation, and executive function in ADHD. Why can someone with ADHD struggle to focus on daily responsibilities yet become completely absorbed in specific tasks? This study investigates the cognitive, behavioral, and emotional factors that contribute to hyperfocus and its implications in daily functioning.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confi...

Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by difficulties in communication, social interaction, and repetitive behavior patterns. Research is needed on new therapeutic approaches that take into account its potential multicausal origin and multisystem involvement. The theory of complex systems applied to health suggests that for an intervention to be effective, it must be multidimensional. Case presentation: In December 2022, a 4-year-old girl was evaluated for symptoms consistent with ASD and sensory, communicative, and socioemotional alterations. The diagnosis of moderate-severe autism was confirmed through standardized interviews, and a low developmental profile was documented in several neurodevelopmental domains. Intervention: The Katia Dolle Method® programs for ASD (a complex naturopathic intervention) were implemented from March 2023 to November 2024 in a personalized manner. These included: 1. Nutrition; 2. Naturopathic supplementation; 3. Parent school and parental coaching; 4. Structured neurostimulation; 5. Monitoring and follow-up. Results: The progress reported by the parents through continuous observation was corroborated by temporal comparisons of scores on three standardized instruments: ATEC (autism severity improved from severe to mild), DP-3 (general developmental index improved from very low to average), and SENA (all problem indicators decreased while capacity indicators increased). Conclusions: Through a complex naturopathic intervention (Katia Dolle Method®) combined with parental coaching applied over 21 months, a 4-year-old girl significantly improved the severity of her ASD and the symptomatology associated with the disorder (ATEC-85.7%), exceeding the outcomes expected with other types of therapies documented in the scientific literature. The general DP-3 index rose from 62 to 91 in the last 12 months of intervention, representing a 29-point gain (~2.4 SD). This increase (+46.8%) goes beyond what is expected from maturation, and the "catch-up effect" reflects an accelerated developmental trajectory that substantially reduced the gap with her neurotypical peers. Convergent improvements in socioemotional domains (SENA) support the clinical robustness of the observed change.

Background: 22q11.2 deletion syndrome (22q11DS) is caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk to develop psychosis. The gene coding for catechol-O-methyl-transferase (COMT) is located at the deleted region, resulting in disrupted dopaminergic neurotransmission in 22q11DS, which may contribute to the increased vulnerability for psychosis. A dysfunctional motivational reward system is considered one of the salient features in psychosis and thought to be related to abnormal dopaminergic neurotransmission. The functional anatomy of the brain reward circuitry has not yet been investigated in 22q11DS. Methods: This study aims to investigate neural activity during anticipation of reward and loss in adult patients with 22q11DS. We measured blood-oxygen-level dependent (BOLD) activity in 16 patients with 22q11DS and 12 healthy controls during a monetary incentive delay task using a 3T Philips Intera MRI system. Data were analysed using SPM8. Results: During anticipation of reward, the 22q11DS group alone displayed significant activation in bilateral middle frontal and temporal brain regions. Compared to healthy controls, significantly less activation in bilateral cingulate gyrus extending to premotor, primary motor and somatosensory areas was found. During anticipation of loss, the 22q11DS group displayed activity in the left middle frontal gyrus and anterior cingulate cortex, and relative to controls, they showed reduced brain activation in bilateral (pre)cuneus and left posterior cingulate. Within the 22q11DS group, COMT Val hemizygotes displayed more activation compared to Met hemizygotes in right posterior cingulate and bilateral parietal regions during anticipation of reward. During anticipation of loss, COMT Met hemizygotes compared to Val hemizygotes showed more activation in bilateral insula, striatum and left anterior cingulate. Conclusions: This is the first study to investigate reward processing in 22q11DS. Our preliminary results suggest that people with 22q11DS engage a fronto-temporal neural network. Compared to healthy controls, people with 22q11DS primarily displayed reduced activity in medial frontal regions during reward anticipation. COMT hemizygosity affects responsivity of the reward system in this condition. Alterations in reward processing partly underlain by the dopamine system may play a role in susceptibility for psychosis in 22q11DS.

The present study was conducted on parents of children with neurodevelopmental disorder (autism spectrum disorder, cerebral palsy and intellectual disability) for measuring the level of anxiety, depression and stress among urban and rural area. The total sample consisted 120 parents, in which 60 urban residents (30 male and 30 female) and 60 rural residents (30 male and 30 female). For this purpose of investigation, adopted scale of ADS scale developed by Bhatnagar et al. (2012) was administrated. 2×2 factorial design was used. The obtained data was analyzed by using ‘t’ test and person correlation. The result shows that the parents of children with neurodevelopmental disorders living in urban areas face a significantly greater psychological issues than their rural counterparts, particularly in terms of anxiety, depression, and stress.
     
Keywords: Stress, Anxiety, Depression, Neurodevelopmental, disability

We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism.

Purpose: The burden of disease associated with tuberous sclerosis complex (TSC) places significant strain on both individuals with the condition and their families. Research has primarily focused on patients, with limited attention to caregiver experiences. This review aims to summarize current knowledge, identify key burden factors, and highlight the unmet needs of caregivers in TSC.
Methods: This review was conducted following PRISMA guidelines. A comprehensive search of electronic databases was carried out to identify original research articles. Two reviewers independently screened the studies for eligibility. The quality of the included studies was assessed using the AXIS tool. Relevant data were extracted, and a narrative synthesis was performed to collate and interpret the findings.
Results: Nine studies involving a total of 982 informal caregivers of both children and adults with TSC were included in the review. All included studies were carried out in Europe and the United States. Five primary factors, namely the care recipient's age, caregivers' characteristics, disease-related features, caregivers' compromised mental health, and disrupted family dynamics, were identified as central themes in shaping caregivers' experiences. Caregivers consistently reported a range of unmet needs, including inadequate access to psychological support, insufficient information about TSC management, and a lack of coordinated healthcare services.
Conclusion: Caregivers of individuals with TSC face significant challenges, yet meaningful support is limited. More research is needed to understand their burden, while developing tailored support, better resource access, and coordinated care are essential to improve their well-being and care quality.

IMPORTANCE Low-income minority children living in urban neighborhoods are at high risk for mental health problems and underachievement. ParentCorps, a family-centered, school-based intervention in prekindergarten, improves parenting and school readiness (ie, self-regulation and preacademic skills) in 2 randomized clinical trials. The longer-term effect on child mental health and academic performance is not known. OBJECTIVE To examine whether ParentCorps delivered as an enhancement to prekindergarten programs in high-poverty urban schools leads to fewer mental health problems and increased academic performance in the early elementary school years. DESIGN, SETTING, AND PARTICIPANTS This is a 3-year follow-up study of a cluster randomized clinical trial of ParentCorps in public schools with prekindergarten programs in New York City. Ten elementary schools serving a primarily low-income, black student population were randomized in 2005, and 4 consecutive cohorts of prekindergarten students were enrolled from September 12, 2005, through December 31, 2008. We report follow-up for the 3 cohorts enrolled after the initial year of implementation. Data analysis was performed from September 1, 2014, to December 31, 2015. INTERVENTIONS ParentCorps included professional development for prekindergarten and kindergarten teachers and a program for parents and prekindergarten students (13 two-hour group sessions delivered after school by teachers and mental health professionals). Annual teacher ratings of mental health problems and academic performance and standardized tests of academic achievement in kindergarten and second grade by testers masked to the intervention or control group randomization. RESULTS A total of 1050 children (4 years old; 518 boys [49.3%] and 532 girls [50.7%]) in 99 prekindergarten classrooms participated in the trial (88.1% of the prekindergarten population), with 792 students enrolled from 2006 to 2008. Most families in the follow-up study (421 [69.6%]) were low income; 680 (85.9%) identified as non-Latino black, 78 (9.8%) as Latino, and 34 (4.3%) as other. Relative to their peers in prekindergarten programs, children in ParentCorps-enhanced prekindergarten programs had lower levels of mental health problems (Cohen d=0.44; 95% CI, 0.08-0.81) and higher teacher-rated academic performance (Cohen d = 0.21; 95% CI, 0.02-0.39) in second grade. CONCLUSIONS AND RELEVANCE Intervention in prekindergarten led to better mental health and academic performance 3 years later. Family-centered early intervention has the potential to prevent problems and reduce disparities for low-income minority children.

‘The Moan Zone’ is a novel intervention that draws inspiration from ‘Worry Time’ - a CBT intervention commonly used to provide relief from excessive anxiety by creating a schedule  that sets aside dedicated time for worrying.
Instead of focusing on and managing anxiety as an individual experience, ‘The Moan Zone’ provides a framework for creating intentional, fulfilling and highly structured interactions between loved ones.

This systematic review explores the complex intersection of disability and juvenile offending, highlighting the systemic barriers that disproportionately affect disabled youth within the juvenile justice system. How inadequate support mechanisms, societal stigma, and misidentification of behavioral issues contribute to the over-representation of individuals with disabilities among juvenile offenders is addressed. Objectives: The primary objective of this review is to consolidate existing literature on the prevalence of disabilities among juvenile offenders and their impact on delinquent behavior. Specifically, it aims to identify risk factors associated with juvenile offending in disabled youth, evaluate the effectiveness of current intervention programs, and highlight gaps in research that inform policy and practice. Method: A comprehensive literature search was conducted using databases such as PubMed, Scopus, and PsycINFO, focusing on studies that examine the relationship between disability and juvenile offending. The review employed a systematic approach, following PRISMA guidelines, to assess the quality of existing research and synthesize findings thematically. Results: The findings reveal that disabled youth face significant challenges, including limited access to mental health services, educational disruptions, and societal stigma, all of which exacerbate the risk of delinquency and recidivism. The review underscores the necessity of tailored interventions that address both behavioral concerns and the unique needs stemming from disabilities. It also identifies a lack of effective training for law enforcement and judicial personnel regarding disability awareness. Conclusion: This review advocates for a shift from punitive measures to rehabilitative approaches that empower disabled youth and promote their psychosocial well-being. It emphasizes the need for collaborative policy reform and the implementation of rights-based frameworks that enhance support for disabled juvenile offenders. By addressing these intersecting trajectories, stakeholders can foster a more inclusive and equitable juvenile justice system, ultimately reducing recidivism and improving outcomes for disabled youth.

Background Many children with developmental language disorders (DLD) have well-documented weaknesses in vocabulary. In recent years, investigators have explored the nature of these weaknesses through the use of novel word learning paradigms. These studies have begun to uncover specific areas of difficulty and have provided hints about possible intervention strategies that might help these children learn words more accurately and efficiently. Among the studies of this type are those that incorporate repeated spaced retrieval activities in the learning procedures. Methods In this study, we examined the data from four of these studies that employed the same types of participants (4- and 5-year-old children with DLD and same-age children with typical language development), research design, and outcome measures. The studies differed primarily in the type of learning condition that was being compared to a spaced retrieval condition. A mixed-effects modeling framework was used, enabling th...

Background: Autism Spectrum Disorder (ASD) is associated with significantly elevated rates ofpsychiatric comorbidities, with anxiety disorders representing the most prevalent co-occurring
conditions. Despite growing recognition of this comorbidity, a concise synthesis of prevalencerates, underlying mechanisms, and effective interventions for Generalised Anxiety Disorder(GAD) in autistic adolescents remains needed.

Neural Plasticity of milliseconds or less. A single neuron can be part of different processes at different times. It remains unclear how fast a neuron can switch its functional properties. If such switching can be made on a ms time scale, fast and efficient computations can be made. We show that the temporal precision of cortical neurons can be better than 1 ms.

PurposeTo elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.MethodsA combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.ResultsAll five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.ConclusionLINGO1 is a transmembrane receptor, ...

Phosphatidylcholine (PC) is the predominant phospholipid in mammalian membranes, representing 40-50% of total phospholipid content and serving as the only proven essential phospholipid for very-low-density lipoprotein (VLDL) assembly and triglyceride export.
Beyond its role as a bioavailable choline donor, PC contributes to membrane architecture, neurotransmitter acetylcholine synthesis, and methylation metabolism.

Clinical and nutritional evidence consistently highlights global inadequacy of choline intake, with fewer than 10% of women and pregnant individuals meeting Adequate Intake (AI) levels.

PC supplementation is uniquely positioned to address this gap with superior bioavailability, lower TMAO formation risk compared to free choline salts, and addition al lipid-stabilizing functions.
PC supports hepatic health by reversing fatty liver and reducing elevated liver enzymes through VLDL-mediated lipid clearance.

It enhances neurological function by stabilizing neuronal membranes, supporting

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social communication and social interaction across multiple contexts and restricted/repetitive behaviors (Takumi et al., 2020). Although the DSM-5 and ICD-11 clearly define clinical phenotypes of ASD, behavioral symptoms among patients are heterogeneous (Muhle et al., 2018). Some behavioral phenotypes are overlapped with other major psychiatric disorders (Hossain et al., 2020). Moreover, patients with ASD often show comorbid symptoms such as anxiety, depression, gastrointestinal symptoms, epilepsy, sleep disturbance, sensory abnormalities,

Background: Gene-environment interactions (GEI) are involved in the pathogenesis of mental diseases. We evaluated interaction between mutant human disrupted-in-schizophrenia 1 (mhDISC1) and maternal immune activation implicated in schizophrenia and mood disorders. Methods: Pregnant mice were treated with saline or polyinosinic:polycytidylic acid at gestation day 9. Levels of inflammatory cytokines were measured in fetal and adult brains; expression of mhDISC1, endogenous DISC1, lissencephaly type 1, nuclear distribution protein nudE-like 1, glycoprotein 130, growth factor receptor-bound protein 2, and glycogen synthase kinase-3beta were assessed in cortical samples of newborn mice. Tissue content of monoamines, volumetric brain abnormalities, dendritic spine density in the hippocampus, and various domains of the mouse behavior repertoire were evaluated in adult male mice. Results: Prenatal interaction produced anxiety, depression-like responses, and altered social behavior that were accompanied by decreased reactivity of the hypothalamic-pituitary-adrenal axis, attenuated serotonin neurotransmission in the hippocampus, reduced enlargement of lateral ventricles, decreased volumes of amygdala and periaqueductal gray matter and density of spines on dendrites of granule cells of the hippocampus. Prenatal interaction modulated secretion of inflammatory cytokines in fetal brains, levels of mhDISC1, endogenous mouse DISC1, and glycogen synthase kinase-3beta. The behavioral effects of GEI were observed only if mhDISC1 was expressed throughout the life span. Conclusions: Prenatal immune activation interacted with mhDISC1 to produce the neurobehavioral phenotypes that were not seen in untreated mhDISC1 mice and that resemble aspects of major mental illnesses. Our DISC1 mouse model is a valuable system to study GEI relevant to mental illnesses.

Elucidating the molecular basis of complex human psychiatric disorders is challenging due to the multitude of factors that underpin these disorders. Genetic and chromosomal changes are two factors that have been suggested to be involved in psychiatric disorders. Indeed, numerous risk loci have been identified in autism spectrum disorders, schizophrenia, and related psychiatric disorders. Here, we introduce genetic animal models that disturb excitatory-inhibitory balance in the brain and animal models mirroring human chromosomal abnormalities, both of which may be implicated in autism spectrum disorder pathophysiology. In addition, we discuss recent unique translational research using rodent models, such as Cntnap2 knockout mouse, Mecp2 mutant mouse, Pick1 knockout mouse, and neonatal ventral hippocampal lesion rat. By using these models, several types of drugs are administered during the developmental period to see the effect on psychotic symptoms and neural activities in adults. The accumulating evidence from recent animal studies provides an informative intervention strategy as a translational research.

Introducción: los neonatos de mediano riesgo suelen presentar alteraciones del neurodesarrollo, sutiles o inaparentes, que pueden evidenciarse a mediano y a largo plazos; es por ello que se les considera niños de riesgo neurológico. La identificación de los factores de riesgo asociados con los problemas del neurodesarrollo es un primer paso para prevenir o reducir sus efectos. Objetivo: con esta revisión cualitativa de la literatura especializada pretendemos describir las características de un grupo de neonatos denominados colectivamente recién nacidos de mediano riesgo neonatal y que, al nacer, no presentan compromiso evidente del desarrollo neurológico. Indagamos, también sobre los factores etiológicos asociados con esta condición. Materiales y métodos: realizamos una búsqueda bibliográfica en las bases Scientific Electronic Library Online (SciELO), Literatura Latinoamericana y del Caribe en Ciencias de la Salud (LILACS), la Biblioteca Nacional de Medicina de Estados Unidos de Nor...

Objectives Moderate-risk neonates (MRNs) are newborns who usually remain hospitalized in neonatal intensive care units (NICU) after birth. Although they have low rates of mortality, morbidity burden may be significant and involve neurological risk. The aim of this study was to estimate the prevalence of neurodevelopmental disorders and the influence of biological and socio-environmental factors on the neurodevelopment of MRN. Methods A cross-sectional study was performed on a sample of 162 MRNs aged 2-24 months, who remained in NICU ≥ 72 h after birth, with gestational age (GA) ≥ 34 weeks, birth weight ≥ 1500 g, and normal neurological and clinical examinations by the time of hospital discharge. Four neurodevelopmental areas were assessed using the Argentinian test PRUNAPE: language (LG), fine and gross motor skills (FM and GM), and personal-social skills (PS). Data from biological (gestational, perinatal and postnatal) and socio-environmental factors were collected through parental questionnaires. Results Thirty-four percent of infants failed the test. Gross motor was the most affected area (14.2%), followed by LG (11.7%), FM (7.4%), and PS (4.3%). Among gestational factors global failure was associated with drugs and alcohol consumption (p ≤ 0.029). Language was associated with maternal smoking (p = 0.007; OR 3.5), FM (p = 0.009; OR 13.0), and GM (p = 0.002; OR 10.6) with drug use, and both LG (p = 0.000; OR 22.6) and GM (p = 0.007; OR 16.2) with alcohol consumption during pregnancy. Infants born by cesarean had a higher risk of failure than those born by vaginal delivery (p = 0.049; OR: 2.2), as well as infants with pathological complementary diagnosis (p = 0.001; OR 2.7). Mechanical ventilation was associated with FM disorders (p = 0.025; OR 4.2). Children with siblings had a higher risk of failing the test than only children (p = 0.041; OR 2.0). Conclusions Rate of neurodevelopmental disorders in MRN exceeds widely that of the general population. GM was the most affected area. Maternal addictions, cesarean birth, pathological complementary studies, MV, and having siblings are factors associated with failure in the screening.

Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioural outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oro-motor control difficulties and expressive language impairment. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient and local efficiency across cortical region...

Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. Groups did not differ in age, global cognitive impairment, adaptive fun...

Highlights • Next-generation chromosome engineering using genome-editing technique was developed • A library of mouse ESC models with CNVs seen in autism was developed • ESC models with CNVs correlated with autism showed abnormal translation

Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers.

Autistic adults lead challenging economic lives. We explore a sample composed of both autistic and non-autistic individuals to evaluate determinants of financial risk tolerance in the two groups, and whether risk attitudes are associated with selected economic outcomes. We measure risk preference through different tools: an assessment of participants' decisions when faced with hypothetical scenarios, two psychometric measures of individuals' self-assessment of their risk tolerance, and one measure of observed actual risky behavior. Results indicate that autistic individuals are more risk averse across most financial risk preference measures even when we control for other co-existing conditions such as psychological disorders and learning disabilities. They lack understanding of the concept of risk diversification. Although autistic individuals are less likely to be employed or to make financial investments, higher-risk propensities increase the likelihood of such and other economic outcomes across both groups of individuals. Financial and economic curricula addressing financial risk must be tailored for individuals with developmental disabilities.

Children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) and prescribed pharmacotherapy require ongoing regular follow-up for many years. Recent literature outlining the role of primary care in the ongoing medication monitoring of children and young people with ADHD is reviewed. We propose that a General Practitioner with a Specialist Interest (GPwSI) model could be developed in relation to ADHD to ensure that shared care arrangements between CAMHS and primary care for children with ADHD are in place. Clinical materials to support GPs in this new role are described.

On average, language and communication characteristics of individuals with Down syndrome (the most common genetic cause of intellectual disability) follow a consistent profile. Despite considerable individual variability, receptive language is typically stronger than expressive language, with particular challenges in phonology and syntax. We review the literature on language and literacy skills of individuals with Down syndrome, with emphasis on the areas of phonology, vocabulary, syntax, and pragmatics. We begin by describing the hearing, oral-motor, cognitive, social, and prelinguistic and early nonverbal communication characteristics of individuals with Down syndrome. We conclude with a discussion of clinical implications and research directions.

Since hundreds of years ago, metals have been recognized as impacting our body’s physiology. As a result, they have been studied as a potential cure for many ailments as well as a cause of acute or chronic poisoning. However, the link between aberrant metal levels and neuropsychiatric illnesses such as schizophrenia and neurodevelopmental disorders, such as autism spectrum disorders (ASDs), is a relatively new finding, despite some evident ASD-related consequences of shortage or excess of specific metals. In this review, we will summarize past and current results explaining the pathomechanisms of toxic metals at the cellular and molecular levels that are still not fully understood. While toxic metals may interfere with dozens of physiological processes concurrently, we will focus on ASD-relevant activity such as inflammation/immune activation, mitochondrial malfunction, increased oxidative stress, impairment of axonal myelination, and synapse formation and function. In particular, w...

BackgroundNeurotypical individuals categorize items even during ultra-rapid presentations (20 ms; see Thorpe et al. Nature 381: 520, 1996). In cognitively able autistic adults, these semantic categorization processes may be impaired and/or may require additional time, specifically for the categorization of atypical compared to typical items. Here, we investigated how typicality structures influence ultra-rapid categorization in cognitively able autistic and neurotypical male adults.MethodsImages representing typical or atypical exemplars of two different categories (food/animals) were presented for 23.5 vs. 82.3 ms (short/long). We analyzed detection rates, reaction times, and the event-related potential components dN150, N1, P2, N2, and P3 for each group.ResultsBehavioral results suggest slower and less correct responses to atypical compared to typical images. This typicality effect was larger for the category with less distinct boundaries (food) and observed in both groups. Howeve...

Prenatal alcohol exposure affects the cardiovascular health of the offspring. Epigallocatechin-3-gallate (EGCG) may be a protective agent against it, but no data are available regarding its impact on cardiac dysfunction. We investigated the presence of cardiac alterations in mice prenatally exposed to alcohol and the effect of postnatal EGCG treatment on cardiac function and related biochemical pathways. C57BL/6J pregnant mice received 1.5 g/kg/day (Mediterranean pattern), 4.5 g/kg/day (binge pattern) of ethanol, or maltodextrin until Day 19 of pregnancy. Post-delivery, treatment groups received EGCG-supplemented water. At post-natal Day 60, functional echocardiographies were performed. Heart biomarkers of apoptosis, oxidative stress, and cardiac damage were analyzed by Western blot. BNP and Hif1α increased and Nrf2 decreased in mice prenatally exposed to the Mediterranean alcohol pattern. Bcl-2 was downregulated in the binge PAE drinking pattern. Troponin I, glutathione peroxidase,...

Neurodevelopmental or cognitive disorders in children pose significant challenges to family functioning. The present study investigates the challenges faced by parents of children at risk of specific learning disabilities (SLD). Methods: This study, based on qualitative research and a phenomenological approach, explored and deeply recognized the lived experiences of parents facing challenges related to children referred for specialized testing. Parents' perspectives were examined using a purposeful sampling method and semi-structured interviews. Data saturation was reached after 23 interviews, ensuring comprehensive data collection. The data were organized and analyzed based on the Colaizzi (1987) method. Qualitative research criteria, such as participant validation, independent coding, and evaluator reliability, were applied to ensure data validity. Results: The findings highlighted six fundamental challenges as follows: "Feeling helpless," "neglect of individual needs," "fear of the future," "feeling defenseless," "feeling guilty," and "lack of competence." Meanwhile, the two following themes emerged: "Weakness in parenting skills" and "emotional dysregulation," which are considered potential underlying factors contributing to these challenges. Conclusion: The challenges faced by the participating parents are largely due to contextual factors. Many parents feel overwhelmed and isolated due to their lack of awareness of parenting strategies and emotional management during critical situations. These underlying factors, functioning as a vicious cycle, lead to negative consequences and additional psychological issues within the family, contributing to the development of disorders in children. Therefore, the development of structured and specialized training for parents of children at risk of neurodevelopmental disorders appears to be essential.

Rejection Sensitive Dysphoria (RSD) is commonly described as an acute emotional reaction to perceived rejection or criticism, particularly in individuals with Attention Deficit Hyperactivity Disorder (ADHD). While often framed as emotional hypersensitivity, this paper proposes an alternative model: that RSD may stem from the cognitive phenomenon of hyperfocus a well-documented ADHD trait when directed inward toward ambiguous or unresolved social cues. This inward-facing hyperfocus traps the individual in a cognitively demanding simulation loop, lacking the dopamine reinforcement typical of external task-based focus, and instead provoking stress responses. This paper outlines the neurocognitive mechanisms behind this phenomenon and offers a framework for understanding RSD as a problem-solving loop in the absence of actionable input. Implications for therapy, self-management, and further empirical research are discussed.

Kabuki syndrome (KS) is a rare multisystem disorder, characterized by intellectual disability, growth delay, and distinctive craniofacial features. It is mostly caused by de novo mutations of KMT2D, which is responsible for histone H3lysine 4 mono-methylation (H3K4me1) that marks active and poised enhancers. We assessed the impact of KMT2D mutations on chromatin and transcriptional regulation in a cohort of multiple KS1 tissues, including primary patient samples and disease-relevant lineages, namely cortical neurons (iN), neural crest stem cells (NCSC), and mesenchymal cells (MC). In parallel, we generated an isogenic line derived from human embryonic stem cells (hESC) for the stepwise characterization of neural precursors and mature neurons. We found that transcriptional dysregulation was particularly pronounced in cortical neurons and widely affected synapse activity pathways. This was consistent with highly specific alterations of spontaneous network-bursts patterns evidenced by ...

Adult ADHD is a disorder which is characterized primarily by a poor attention span, distractibiity, forgetfulness, impulsivity, and difficulty completing daily tasks. Adult ADHD may be diagnosed during the young adult or middle adult years, or it may have been diagnosed during childhood or adolescence. People with adult ADHD tend to seek help after becoming overwhelmed with academic or work responsibilities or due to problems with relationships. While much has been learned during the past 20 years about medications for adult ADHD and the frustrating cognitive effects, the negative social and emotional effects of adult ADHD have been largely overlooked. In this post, I am explaining how adult ADHD can impact a person's overall sense of identity and can cause low self-esteem, insecurity in relationships, and shame and doubt in a person's academic and career performance. If you experience the symptoms of adult ADHD, you will relate to the situations described in this post. If you do not have adult ADHD, I hope that this post helps you to increase understanding about how this disorder can affect more aspects of a person's life than just attention and memory. The following sections describe how you may think, feel, and behave while dealing with adult ADHD.

Background: Autism spectrum disorder (ASD) is characterized by atypical behaviors in social environments and in reaction to changing events. While this dyad of symptoms is at the core of the pathology along with atypical sensory behaviors, most studies have investigated only one dimension. A focus on the sameness dimension has shown that intolerance to change is related to an atypical pre-attentional detection of irregularity. In the present study, we addressed the same process in response to emotional change in order to evaluate the interplay between alterations of change detection and socio-emotional processing in children and adults with autism. Methods: Brain responses to neutral and emotional prosodic deviancies (mismatch negativity (MMN) and P3a, reflecting change detection and orientation of attention toward change, respectively) were recorded in children and adults with autism and in controls. Comparison of neutral and emotional conditions allowed distinguishing between general deviancy and emotional deviancy effects. Moreover, brain responses to the same neutral and emotional stimuli were recorded when they were not deviants to evaluate the sensory processing of these vocal stimuli. Results: In controls, change detection was modulated by prosody: in children, this was characterized by a lateralization of emotional MMN to the right hemisphere, and in adults, by an earlier MMN for emotional deviancy than for neutral deviancy. In ASD, an overall atypical change detection was observed with an earlier MMN and a larger P3a compared to controls suggesting an unusual pre-attentional orientation toward any changes in the auditory environment. Moreover, in children with autism, deviancy detection depicted reduced MMN amplitude. In addition in children with autism, contrary to adults with autism, no modulation of the MMN by prosody was present and sensory processing of both neutral and emotional vocal stimuli appeared atypical. Conclusions: Overall, change detection remains altered in people with autism. However, differences between children and adults with ASD evidence a trend toward normalization of vocal processing and of the automatic detection of emotion deviancy with age.

Very preterm birth is associated with academic difficulties, but the underlying neurocognitive mechanisms of these difficulties remain largely unclear. The present study aimed to assess the role of working memory (WM), attentional processes, and processing speed in academic difficulties of very preterm born adolescents at 13 years. Participants included 55 very preterm and 61 full-term adolescents. Academic performance, visuospatial WM, alerting, orienting, executive attention, sustained attention, and processing speed (simple and choice reaction time [RT]) were compared between groups. Mediation analyses with multiple, parallel mediators were performed to examine whether these functions mediate the relation between very preterm birth and academic performance. Very preterm born adolescents showed poorer reading comprehension, arithmetic, visuospatial WM, alerting, sustained attention, and choice RT than full-term controls. The relationship between very preterm birth and arithmetic was mediated by visuospatial WM, sustained attention, and choice RT. The relationship between very preterm birth and reading comprehension was mediated by visuospatial WM and choice RT. The findings indicate that very preterm birth affects arithmetic and reading comprehension through its negative effect on visuospatial WM, sustained attention, and processing speed. These neurocognitive processes may identify very preterm born children at risk for academic difficulties and could serve as targets for interventions.

Very preterm birth is associated with neurodevelopmental impairments and outcomes have not improved over the last decades. Insight in learning processes is important for the development of effective interventions. Implicit learning is of particular interest because of its independence from working memory processes that are affected by preterm birth. This study examined implicit learning abilities in 49 very preterm and 61 full-term 13year-old adolescents. The degree of implicit learning was not different between groups. This indicates intact implicit learning abilities in adolescents born very preterm. Implicit learning strategies may be beneficial for skill learning in very preterm born children.

BackgroundAdvances in neonatal healthcare have resulted in decreased mortality after preterm birth but have not led to parallel decreases in morbidity. Academic performance provides insight in the outcomes and specific difficulties and needs of preterm children.ObjectiveTo study academic performance in preterm children born in the antenatal steroids and surfactant era and possible moderating effects of perinatal and demographic factors.DesignPubMed, Web of Science and PsycINFO were searched for peer-reviewed articles. Cohort studies with a full-term control group reporting standardised academic performance scores of preterm children (&lt;37 weeks of gestation) at age 5 years or older and born in the antenatal steroids and surfactant era were included. Academic test scores and special educational needs of preterm and full-term children were analysed using random effects meta-analysis. Random effects meta-regressions were performed to explore the predictive role of perinatal and demog...