J Neurodev Disord [JOURNAL]
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200 papers
Hemispheric transfer and dyslexia: testing the deficit hypothesis for word and symmetry recognition using visual half-field tasks.
Meijer Z, Karlsson EM, Gerrits R … +2 more , Vingerhoets G, Verhelst H
J Neurodev Disord · 2026 Jan · PMID 41612171 · Full text
BACKGROUND: The interhemispheric transfer deficit theory proposes that individuals with dyslexia have impaired interhemispheric transfer, particularly affecting the integration of visual information from the left and rig...
BACKGROUND: The interhemispheric transfer deficit theory proposes that individuals with dyslexia have impaired interhemispheric transfer, particularly affecting the integration of visual information from the left and right visual fields. This study aimed to evaluate this hypothesis by examining interhemispheric transfer in dyslexia using visual half-field tasks targeting both linguistic and visuospatial processing. METHODS: We examined interhemispheric transfer in dyslexia using two visual half-field tasks: a lexical decision task to assess written word processing, and a symmetry decision task to examine visuospatial processing. We compared reaction times and accuracy in 90 Dutch-speaking participants (45 with dyslexia, 45 controls) across left, right, and bilateral stimulus presentations. RESULTS: While both tasks successfully captured expected visual half-field differences in the control group, favoring the right visual field in the lexical decision task and the left visual field in the symmetry detection task, we did not observe that the dyslexia group showed increased differences between the two fields, as predicted by the interhemispheric transfer deficit theory. Furthermore, the dyslexia group benefited just as much as controls from stimuli presented simultaneously to both visual fields. Thus, no evidence of interhemispheric transfer deficits related to dyslexia was found in either task. CONCLUSIONS: These findings challenge the broad applicability of the interhemispheric transfer deficit theory in dyslexia, suggesting that such impairments may be task-dependent rather than domain-general. Future studies should further explore the conditions under which interhemispheric transfer deficits might occur in dyslexia.
Transcranial direct current stimulation on social communication among children and adolescents with autism spectrum disorder: a systematic review and meta-analysis.
Alabbad M, Nuhmani S, Ahmed R … +3 more , Bashir S, Khan MA, Abualait T
J Neurodev Disord · 2026 Jan · PMID 41555221 · Full text
BACKGROUND: Transcranial direct current stimulation (tDCS) has gained attention as a potential intervention to improve social cognition in children with autism spectrum disorder (ASD). However, its effects across social...
BACKGROUND: Transcranial direct current stimulation (tDCS) has gained attention as a potential intervention to improve social cognition in children with autism spectrum disorder (ASD). However, its effects across social domains and the influence of stimulation parameters remain unclear. This systematic review and meta-analysis evaluate the effectiveness of tDCS in enhancing social functioning in children with ASD, focusing on emotion recognition, theory of mind (ToM), and social responsiveness. METHODS: A comprehensive search identified randomized controlled trials (RCTs) investigating tDCS effects on social cognition in children with ASD. Studies were assessed for effect sizes and statistical significance. A meta-analysis pooled results, and moderators of tDCS effectiveness were examined. RESULTS: Screening 14 studies revealed that anodal tDCS applied to the left dorsolateral prefrontal cortex (DLPFC) produced the most consistent improvements in emotion recognition, ToM, and social responsiveness. However, results varied, with some studies reporting improvements, while others showed no substantial effects. Dual-stimulation or cathodal stimulation yielded mixed outcomes. Evidence was limited by small sample sizes, risk of bias, and variability in stimulation parameters. CONCLUSIONS: Anodal tDCS over the left DLPFC shows promise for improving social cognition in ASD. Larger controlled trials are needed to determine the effectiveness of combining tDCS with social skills training.
Extra-axial cerebrospinal fluid volumes from 6 to 24 months of age are associated with poorer executive function at school-age in children with and without autism.
Zhang Y, Rutsohn J, Kim SH … +15 more , Pandey J, Schultz RT, Zwaigenbaum L, Burrows C, Dager SR, John TS, Estes AM, McKinstry RC, Marrus N, Pruett JR, Styner M, Hazlett HC, Piven J, Shen MD, Garic D
J Neurodev Disord · 2026 Jan · PMID 41540340 · Full text
BACKGROUND: Abnormally increased extra-axial cerebrospinal fluid (EA-CSF) volume is present as early as 6 months in infants later diagnosed with autism and is associated with symptom severity at the age of diagnosis, but...
BACKGROUND: Abnormally increased extra-axial cerebrospinal fluid (EA-CSF) volume is present as early as 6 months in infants later diagnosed with autism and is associated with symptom severity at the age of diagnosis, but it is unknown whether early EA-CSF enlargement has long-term impacts on other clinical domains. Executive function (EF) deficits are frequently observed in children with autism and are linked with worse academic outcomes, higher anxiety, and lower adaptive functioning. The current study examines the association between EA-CSF volume at infancy and EF at school age in a longitudinally phenotyped cohort of children with either high (HL) or low (LL) familial likelihood for autism. METHODS: In this prospective study, 239 infants underwent MRI scans during natural sleep at 6, 12, and 24 months of age. HL was defined as having an older sibling with autism. The sample was divided into three diagnostic groups: HL infants who were diagnosed with autism at 24 months (HL+, n = 34), HL infants not diagnosed with autism (HL-, n = 131), and LL infants without autism (LL-, n = 74). Two parent-rating scales of EF were collected at the school-age follow-up (Mage= 10.4 years ± 1.34): the Behavior Rating Inventory of Executive Function (BRIEF) and Conners Parent Short Form. ANOVA was used to test for diagnostic group differences in EF. Longitudinal mixed-effects models utilized EA-CSF volumes in infancy to predict EF at school-age, while controlling for IQ, sex, total cerebral volume, and diagnostic group. RESULTS: Consistent with previous literature, HL + participants had greater EF deficits than both HL- and LL- on the BRIEF (F = 18.46, p < .0001) and greater EF deficits than LL- on the Conners (F = 8.55, p < .001). Further, higher EA-CSF volumes during infancy were associated with poorer executive function eight years later on both BRIEF (ß=0.18, p < .001) and Conners (ß=0.18, p < .001). This association between EA-CSF and executive function was observed across familial likelihood and diagnostic groups. CONCLUSIONS: Our study indicates that elevations in EA-CSF volumes during infancy, even in those who do not have autism, have long-term associations beyond autism symptomatology. These findings underscore the potential link between infant CSF physiology and future behavioral domains such as executive function at school age.
An assessment of autistic and parkinsonian movement profiles to inform selective classification algorithms.
Hickman LJ, Fraser DS, Galea JM … +2 more , Happé F, Cook JL
J Neurodev Disord · 2026 Jan · PMID 41514394 · Full text
BACKGROUND: Movement differences in autism have attracted growing attention in recent years. Anecdotally, autistic movement has been likened to that of Parkinson's Disease (PD). Given that PD assessments are primarily mo...
BACKGROUND: Movement differences in autism have attracted growing attention in recent years. Anecdotally, autistic movement has been likened to that of Parkinson's Disease (PD). Given that PD assessments are primarily movement-based, it is important to ensure that autistic individuals are not scoring highly on PD diagnostic criteria due to autism-related movement differences. Quantifying overlap in movement profiles and identifying distinguishing features is essential, particularly given increased PD diagnosis rates in the autistic population. METHODS: We conducted the first direct comparison study of autistic and parkinsonian movement. Autistic individuals (N = 31), individuals with PD (N = 32) and control participants (N = 31) completed a Shapes Tracing Task and a Reaction Time Task. Kinematic features were compared between groups and classification algorithms were run to distinguish between groups. RESULTS: Groups were distinguishable based on kinematic features. The autistic group differed from both PD and control groups in speed modulation and sub-movements, and from the PD group in reaction time. Classification algorithms for clinical (autism and PD) versus non-clinical groups, and for autism versus PD, were most accurate when combining kinematic and questionnaire data. There were no kinematic similarities between autism and PD that were also distinct from controls. CONCLUSIONS: Whilst kinematic features did not appear similar between autism and PD, they were informative for group classification. This proof-of-concept study highlights that movement-based metrics may aid in identifying whether someone belongs to a clinical group, and which one - suggesting potential for refining diagnostic approaches for both autism and PD.
Longitudinal Rett syndrome behaviour questionnaire scores and their associations with genotype and trajectories of mobility, weight and seizure frequency status.
Downs J, Wong K, Doshi D … +1 more , Leonard H
J Neurodev Disord · 2026 Jan · PMID 41501636 · Full text
INTRODUCTION: The Rett Syndrome Behaviour Questionnaire (RSBQ) describes behavioural and emotional features. This study investigated total RSBQ score trajectories and their clustering, and for trajectory groups, relation...
INTRODUCTION: The Rett Syndrome Behaviour Questionnaire (RSBQ) describes behavioural and emotional features. This study investigated total RSBQ score trajectories and their clustering, and for trajectory groups, relationships with genotype and mobility, weight-for-age z scores, and seizure frequency. METHODS: Females in the Australian Rett Syndrome Database who were genetically confirmed with RSBQ data collected between 2000 and 2019 were included. The age trend was modelled with mixed-effects linear regression. Unique trajectory classes for total RSBQ scores and time-varying predictors (mobility, weight-for-age z scores, seizure frequency) were identified with group-based trajectory modelling. Associations between genotype, time-varying predictors and RSBQ total score class memberships were assessed with multinomial logistic regression. RESULTS: There were 1,034 questionnaires collected from 298 individuals (age range 1.7-37.9 years) with a median of 3 (range 1-7) per person. For individuals aged 5 to 20 years at first RSBQ response, the mean (95% CI) scores were 43.9 (40.7, 47.1) at age 5 and 42.0 (39.9, 44.2) at age 20. Total score trajectories clustered into low and middle groups where scores decreased steadily, and a high group which decreased after age 20. Compared to independent walking, assisted walking increased the probability of being in the high-scoring RSBQ group. Very low weight (<-6 z score) increased the probability of being in the medium or high-scoring group. Weak associations were found with seizure frequency and genotype. CONCLUSION: RSBQ total scores declined with increasing age suggesting improvement in the behavioural and emotional phenotype with age and time. There were few relationships between RSBQ scores and indicators of clinical severity. These natural history data form a baseline for comparison as new treatments become available.
Exploring sleep challenges in CDKL5 Deficiency Disorder.
Leonard H, Szepe E, Junaid M … +3 more , Wong K, Saldaris J, Downs J
J Neurodev Disord · 2026 Jan · PMID 41484992 · Full text
BACKGROUND: Sleep disturbance is a common and significant issue for individuals with CDKL5 Deficiency Disorder (CDD) and their families. The study aimed to investigate experiences of sleep disturbance in CDD and associat...
BACKGROUND: Sleep disturbance is a common and significant issue for individuals with CDKL5 Deficiency Disorder (CDD) and their families. The study aimed to investigate experiences of sleep disturbance in CDD and associated factors. METHODS: Data were sourced from the baseline and follow-up questionnaires completed by caregivers of 258 individuals in the International CDKL5 Disorder Database. Outcome variables were scaled scores for selected domains of the Sleep Disturbance Scale for Children: Disorders of Maintaining Sleep (DIMS), Disorders of Excessive Somnolence (DOES), Sleep Breathing Disorders (SBD), and Sleep-Wake Transition Disorders (SWTD). For DIMS and SBD, t scores were calculated and dichotomised into high (≥ 70) and low (< 70) groups. Through univariable and multivariable Poisson and logistic regression analyses, the relationships between the sleep disturbance domains and covariates, including sex, age group, genetic variant, motor skills, seizure frequency and patterns, medication use and side effects, constipation, and emotional behaviours, were examined. Caregivers also provided qualitative data on their children’s sleep abnormalities. Content analysis assessed caregivers’ responses to the prompt, “Is there anything about your child’s sleeping that you consider unusual or problematic?”. RESULTS: Individuals ≥18 years old had an adjusted mean DIMS scaled score 6.49 (95% CI -12.44,-0.55) points lower than those aged 3–5 years. Daily seizures were associated with lower DIMS (-6.65, 95% CI -11.52,-1.78) and higher SBD (7.09, 95% CI 2.39,11.79) scores. Those whose parents reported constipation had more than twice the odds of a high DIMS t score (2.39, 95% CI 1.24,4.62). The mean DOES-mod score was 6.92 (95% CI 0.40,13.44) points higher in those able to sit and walk than in those unable to sit and walk, and was higher in adolescents and adults. Occurrence of seizures during night-time sleep was associated with higher SWTD-mod scores (4.09, 95% CI -0.15,8.32). Caregivers reported insomnia (sleep initiation and maintenance), “night parties” (possibly reflecting disrupted circadian rhythms), and daytime somnolence affecting functioning as major concerns, with seizure timing and frequency, gastrointestinal symptoms, and medication use identified as contributing factors. CONCLUSIONS: Functional abilities and comorbidities influenced sleep. Reducing the impacts of constipation and side-effects of anti-seizure medications on sleep could improve sleep and enhance child and family wellbeing.
GABAergic regulation of Locus coeruleus activity in necdin-deficient mice, an animal model of Prader-Willi syndrome.
Tsai LP, Chan H, Hung WC … +5 more , Min MY, Cheng SJ, Yang CE, Yu CH, Wong SB
J Neurodev Disord · 2025 Dec · PMID 41469939 · Full text
BACKGROUND: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of paternally expressed genes on chromosome 15q11-13, including NDN, which encodes necdin. Necdin deficiency has been linked to impa...
BACKGROUND: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of paternally expressed genes on chromosome 15q11-13, including NDN, which encodes necdin. Necdin deficiency has been linked to impaired visuospatial memory, social recognition, and stress regulation-features also seen in PWS. Previous work showed that necdin-deficient (Ndn + m/-p) mice exhibit reduced activity of noradrenergic neurons in the locus coeruleus (LC), a nucleus essential for arousal and stress responses. However, the mechanisms underlying LC hypoactivity remain unclear. Because GABAergic signaling is critical for LC excitability, this study examined the role of GABA and GABA receptor-mediated inhibition in Ndn + m/-p mice. METHODS: Electrophysiological recordings from brainstem slices of wild-type (WT) and Ndn + m/-p mice were used to measure spontaneous firing rates (SFRs) of LC noradrenergic neurons. The effects of bicuculline (GABA antagonist) and CGP54626 (GABA antagonist) were tested. Whole-cell patch-clamp recordings assessed receptor-mediated currents. Western blotting quantified receptor subunit expression in peri-LC tissue. Immunocytochemistry and ELISA examined GABA receptor expression and GABA release in cultured astrocytes. RESULTS: LC-NE neurons in Ndn + m/-p mice exhibited significantly reduced baseline SFR compared with WT. Bicuculline did not alter firing in either genotype, whereas CGP54626 significantly increased SFR in WT but not in Ndn + m/-p neurons, indicating impaired GABA receptor-mediated tonic inhibition. Whole-cell patch-clamp experiments confirmed intact GABA receptor-mediated inward currents in both genotypes, while no GABA receptor-mediated phasic currents were detected. Western blot analysis revealed comparable expression of GABA receptor α2 subunit and GABAR1 in peri-LC tissue between WT and Ndn + m/-p mice, suggesting functional rather than expression-level deficits. GFAP-positive cell density in the LC region was unchanged in vivo; however, in astrocyte cultures, Ndn + m/-p astrocytes exhibited greater proliferation by DIV 19 and consistently secreted higher levels of GABA, with significant elevations at later culture stages. CONCLUSION: Necdin deficiency selectively disrupts GABA receptor-mediated tonic inhibition of LC-NE neurons while preserving GABA receptor function. Elevated astrocytic proliferation and GABA release may further enhance ambient inhibition, contributing to LC hypoactivity and the neurobehavioral phenotypes of PWS. These findings identify GABA receptor dysfunction and astrocytic dysregulation as potential mechanistic targets for therapeutic intervention in PWS.
Dysfunctional neural dynamics associated with sensory phenotypes in Fragile X syndrome: insights from mouse models.
Goel A, Razak KA, Chubykin AA … +1 more , Antoine MW
J Neurodev Disord · 2025 Dec · PMID 41469555 · Full text
Fragile X Syndrome (FXS), the leading known inherited cause of atypical behaviors associated with autism spectrum disorders (ASD), arises due to the reduced expression or absence of the Fragile X Messenger Ribonucleoprot...
Fragile X Syndrome (FXS), the leading known inherited cause of atypical behaviors associated with autism spectrum disorders (ASD), arises due to the reduced expression or absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP). Individuals with ASD and FXS often experience atypical sensory processing across modalities such as touch, hearing, and/or vision. The consequences of altered sensory processing can be debilitating, leading to impairments in sensory discrimination and an inability to filter out irrelevant sensory stimuli such as innocuous sounds, smells, sights, or touches. Currently, there is a significant knowledge gap in the field of FXS regarding the circuit mechanisms that drive atypical sensory processing and how these contribute to hypersensitivity and secondary effects, such as learning impairments and increased anxiety. Animal models of FXS mirror many of the sensory hypersensitivity issues observed in humans, exhibiting heightened anxiety, as well as learning and social impairments. Here, we discuss the dysfunctional neural dynamics underlying atypical sensory processing across modalities in FXS, potential therapeutic interventions targeting specific ion channels, receptors, and circuits, and propose future research directions that could pave the way for circuit-targeted therapies.
MRI patterns and clinical outcomes in cerebral palsy: insights from a large MRICS-based cohort.
Yuan J, Cao K, Li D … +6 more , Hu J, Wang X, Xin W, Zhang L, Xu Y, Zhu C
J Neurodev Disord · 2025 Dec · PMID 41469542 · Full text
BACKGROUND: To classify MRI patterns in children with cerebral palsy (CP) using the MRI Classification System (MRICS) and examine their associations with perinatal risk factors and clinical outcomes. METHODS: This retros...
BACKGROUND: To classify MRI patterns in children with cerebral palsy (CP) using the MRI Classification System (MRICS) and examine their associations with perinatal risk factors and clinical outcomes. METHODS: This retrospective cohort study included 1,403 children with CP who underwent post-neonatal cranial MRI between 2011 and 2020. MRI patterns were categorized using MRICS. We analyzed the associations between MRI findings and perinatal risk factors (e.g., gestational age, birth weight, sex, perinatal adversity, plurality) using univariate and multivariable multinomial logistic regression. Clinical outcomes-including CP subtype, gross motor function, intellectual disability, epilepsy, and composite impairment index-were assessed using chi-square, Kruskal-Wallis tests, and correspondence analysis. RESULTS: MRI abnormalities were observed in 86.5% of children, with predominant white matter injury (PWMI) being most common (46.5%). Preterm birth and perinatal adversity significantly increased the risk of PWMI and PGMI. PWMI was linked with spastic CP, better motor outcomes, and lower rates of intellectual disability. In contrast, PGMI and maldevelopments were associated with epilepsy, hearing loss, and severe impairment. Importantly, a subset of children with normal MRI findings still exhibited substantial functional impairments, emphasizing the limitations of structural imaging alone. CONCLUSIONS: MRI patterns, as classified by MRICS, provide critical insight into the neurodevelopmental heterogeneity of CP. Normal MRI findings do not preclude significant clinical impairment, underscoring the need for integrated neuroimaging and clinical-genetic assessment in CP management.
Clinical and neuropsychological characterization of Jacobsen syndrome (del11q).
Garriz-Luis A, Rodríguez-Toscano E, Burdeus-Olavarrieta M … +3 more , Arango C, Parellada M, Díaz-Caneja CM
J Neurodev Disord · 2025 Dec · PMID 41419787 · Full text
BACKGROUND: Jacobsen Syndrome (JS), also known as 11q Deletion Syndrome (del11q), is a rare genetic disorder affecting approximately 1 in 100,000 births that presents with varied clinical manifestations and severities in...
BACKGROUND: Jacobsen Syndrome (JS), also known as 11q Deletion Syndrome (del11q), is a rare genetic disorder affecting approximately 1 in 100,000 births that presents with varied clinical manifestations and severities including intellectual disability, psychomotor delays, and distinctive physical traits. This study offers a detailed analysis of the clinical and cognitive profiles of individuals with JS and examines how these characteristics are related to each other and to genetic variables. METHODS: Twenty-nine participants with JS (20 female, mean age 12.48 years, SD = 9.13) underwent standardized assessments assessing cognitive functioning, adaptive behavior, autistic traits, and general psychopathology. A CGH array was used to assess genetic deletions. We employed descriptive and inferential statistical analyses to explore the association between clinical and cognitive characteristics and deletion size. RESULTS: Sixty percent of participants had verbal language. Mean intelligence quotient was 50.18, the range of adaptive functioning was very broad, and 43% showed behaviors exceeding the ADOS-2 cutoff for autism spectrum classification. A higher cognitive performance was associated with better adaptive skills, including more advanced language skills and with more depressive symptoms or a diagnosis of depression. Larger deletions were associated with more delays in developmental milestones and poorer cognitive functioning. No significant association was found between haploinsufficiency of the KIRREL3 and ARHGAP32 genes and cognitive functioning or autistic characteristics. CONCLUSIONS: Our findings provide deeper insights into the complex relationship between genetic factors and clinical attributes in individuals with JS, revealing notable clinical variability within the JS population. This information may help predict developmental difficulties as genetic findings emerge.
Distinct clinical phenotypes of pediatric Obsessive-Compulsive Disorder with and without neurodevelopmental disorders: evidence for a neurodevelopmental continuum.
D'Aiello B, Pontillo M, Demaria F … +6 more , Di Luzio M, Di Vincenzo C, Bertoncini I, Villani V, Menghini D, Vicari S
J Neurodev Disord · 2025 Dec · PMID 41408159 · Full text
This study aimed to investigate clinical, demographic, and psychopathological differences between pediatric patients with obsessive-compulsive disorder (OCD) with and without comorbid neurodevelopmental disorders (NDDs),...
This study aimed to investigate clinical, demographic, and psychopathological differences between pediatric patients with obsessive-compulsive disorder (OCD) with and without comorbid neurodevelopmental disorders (NDDs), focusing on symptom presentation, comorbidities, and functional outcomes. A total of 121 drug-naïve children and adolescents with recent-onset OCD (66 with comorbid NDDs and 55 without) were assessed at the Child and Adolescent Neuropsychiatry Unit of Bambino Gesù Children’s Hospital. Participants underwent multidisciplinary clinical evaluations, including structured diagnostic interviews (Schedule for Affective Disorders and Schizophrenia for School-Aged Children – Present and Lifetime Version for DSM-5 K-SADS-PL DSM-5), symptom-specific scales (Children’s Yale-Brown Obsessive Compulsive Scale [CY-BOCS], Children’s Depression Inventory 2 [CDI-2], Multidimensional Anxiety Scale for Children 2 [MASC-2]), and adaptive functioning assessments (Children’s Global Assessment Scale [CGAS]). The OCD + NDDs group was significantly younger, had lower IQ, and showed a male predominance, but did not differ in global functioning. No significant differences were found in anxiety or depressive symptoms across groups. However, distinct OCD symptom profiles emerged: sexual and forbidden thought obsessions as derived by CY-BOCS were more frequent in the OCD-NDDs group, while hoarding compulsions were more common in OCD + NDDs. Comorbid tics and ADHD were significantly more prevalent in the OCD + NDDs group, whereas PTSD was more frequent in OCD-NDDs. Findings support the presence of distinct phenotypic and comorbidity profiles in pediatric OCD with and without NDDs, emphasizing the need for tailored diagnostic and therapeutic approaches. While internalizing symptoms may remain comparable, the variation in obsessional content and neurodevelopmental burden highlights the clinical importance of early, individualized assessment strategies.
Clinical, translational and developmental biomarkers associated with intellectual and developmental disabilities across the lifespan.
Opendak M, Dichter GS, Nordahl CW
J Neurodev Disord · 2025 Dec · PMID 41408146 · Full text
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Correction: Functional connectivity patterns differ as a function of co-occurring attentional problems in preschoolers with autism.
Boxberger A, Chen B, Olson L … +5 more , Cordova M, Mahmalji J, Rios A, Linke AC, Fishman I
J Neurodev Disord · 2025 Dec · PMID 41390539 · Full text
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Emotion regulation in autistic adolescents: a mixed methods systematic review.
Micheel J, Zapf H, Hohmann S … +2 more , Bindt C, Boettcher J
J Neurodev Disord · 2025 Dec · PMID 41366290 · Full text
BACKGROUND: Emotion regulation (ER) difficulties are common in autistic individuals and may contribute to co-occurring psychopathology during adolescence. However, age-group heterogeneity in existing research limits unde...
BACKGROUND: Emotion regulation (ER) difficulties are common in autistic individuals and may contribute to co-occurring psychopathology during adolescence. However, age-group heterogeneity in existing research limits understanding of ER processes in autistic adolescents. Therefore, this mixed methods systematic review synthesizes current knowledge on ER in autistic adolescents aged 10-24 years. METHODS: We systematically searched MEDLINE, PsycINFO, Web of Science, and Scopus for empirical studies on ER in autistic adolescents. 32 studies (including two qualitative) met inclusion criteria and were synthesized using a convergent integrated approach. RESULTS: Autistic adolescents consistently exhibited more ER difficulties than non-autistic peers, which were associated with internalizing and externalizing symptoms. Greater autism symptom severity, lower theory of mind, and social challenges were frequently linked to lower ER, while no consistent associations with age, gender, or IQ were found. Few studies examined physiological or neurobiological factors, but evidence suggested associations between ER difficulties, lower heart rate variability, and atypical neural responses. Cognitive-behavioral and mindfulness-based interventions generally led to improvements in ER, though results varied and discrepancies between self- and proxy-reports were common. CONCLUSION: ER challenges are pronounced in autistic adolescents and are closely associated with mental health symptoms. While interventions show promise, future research should address measurement heterogeneity, examine neurobiological underpinnings, and include more longitudinal and ecologically valid designs. TRIAL REGISTRATION: CRD42024529184 (registered April 06, 2024).
The importance of intrafamilial cognitive phenotyping by the case of 22q11.2 deletion, 15q11.2 deletion, and families with inherited copy number variants of unknown significance.
Pelgrims E, Hannes L, Noens I … +7 more , Peeters Y, Peeters H, Fiksinski AM, Heung T, Bassett AS, Breckpot J, Swillen A
J Neurodev Disord · 2025 Nov · PMID 41310454 · Full text
BACKGROUND: Rare copy number variants (CNVs) are known to be important contributors to the genetic cause of developmental differences (DD). Parental cognitive phenotyping could assist with interpreting inherited variants...
BACKGROUND: Rare copy number variants (CNVs) are known to be important contributors to the genetic cause of developmental differences (DD). Parental cognitive phenotyping could assist with interpreting inherited variants of uncertain significance (VUS), and could help to assess phenotypic variability and improve genetic counseling. However, no methodological framework exists for the intergenerational correlation of cognitive abilities. We introduce an approach to assess intrafamilial concordance of cognitive abilities and apply it to three trio cohorts: adults with de novo 22q11.2 microdeletion (n = 50) acting as a high penetrance control for the method, probands with inherited 15q11.2 BP1-BP2 deletions (n = 10) which is associated with a low penetrance of DD, and probands with DD and a rare CNV classified as VUS (CNVUS) and inherited from a parent with seemingly typical development (n = 21). METHODS: For each cohort, cognitive phenotyping of probands and both parents was performed using standardized, validated, and age-appropriate IQ tests (Wechsler scales). Siblings were tested when available. Intrafamilial concordance of cognitive abilities was assessed based on an overlap of 95% confidence intervals for full-scale IQ (FSIQ) and cognitive subdomains. Trio whole genome sequencing with variant analysis of known DD-related genes was performed in the CNVUS cohort to identify additional (likely) pathogenic variants associated with DD. RESULTS: For the de novo 22q11.2 microdeletion cohort, there was FSIQ discordance in most (42/50; 84%) proband-parent trios, a greater intrafamilial difference between proband and biparental FSIQ for probands with lower FSIQ (r = -0.684, p < 0.001), and evidence that the deletion has a more pronounced effect on performance than on verbal domains. In families with an inherited 15q11.2 deletion, there was evidence of assortative mating (proband's FSIQ aligned exclusively with that of the carrier parent in only two families), and intrafamilial variable expression. In the CNVUS cohort, 10 of 21 parents assessed were found to have borderline to mild ID, although considered within typical range at inclusion, and only five families (24%) showed concordance between proband and transmitting parent FSIQ. Reclassification of CNVUS, limited by small family size and assortative mating, was possible for two families to a likely pathogenic CNV, and for seven families to a likely benign CNV. WGS identified pathogenic variants contributing to the DD in two probands. CONCLUSION: The results suggest that our approach for determining intrafamilial IQ correlation effectively captured the impact of de novo 22q11.2 microdeletion and additive parental background effect on cognitive impairment, consistent with the modest but detectable effect of 15q11.2 deletions. Parental cognitive data could assist with classifying inherited CNVs of unknown significance.
Autistic eye contact? A hermeneutic phenomenological multicenter study of the similarities and differences in eye-contact experiences between adults with and without autism.
Boer J, Boonstra N, Kronenberg L … +3 more , Kuipers S, Vuijk R, Sizoo B
J Neurodev Disord · 2025 Nov · PMID 41291454 · Full text
Eye contact is one of the most important forms of interpersonal communication. Nonetheless, research has shown that there is no gold standard for how eye contact should occur. Atypicalities in eye contact are one of the...
Eye contact is one of the most important forms of interpersonal communication. Nonetheless, research has shown that there is no gold standard for how eye contact should occur. Atypicalities in eye contact are one of the core features of autism spectrum disorder (ASD), but there is still no consensus on what constitutes atypical eye contact in ASD. The current research explores both the breadth and depth of experiences with eye contact in adults with and without ASD. We used a hermeneutic phenomenological multicenter design in which 15 adults with ASD and 15 adults without ASD were interviewed. Analyses using Multisite Qualitative Analysis (MSQA) and the PRICE model for saturation identified four themes: opinion on eye contact, experience of eye contact, approach toward eye contact, and needs regarding eye contact. Adults with and without ASD appeared to have overlapping and distinct experiences. This study provides the first insights into similarities and differences in experiences with eye contact in adults with and without ASD. The results provide guidance for future research and for the development of interventions to reduce problems arising from eye contact in ASD.
Neurodevelopmental delays in children born after medically assisted reproduction: a national population cohort study.
Choe SA, Gwak E, Lee J … +4 more , Byeon JH, Shin JY, Han S, Kim JH
J Neurodev Disord · 2025 Nov · PMID 41286597 · Full text
BACKGROUND: Importance: The neurodevelopmental outcomes of children born after medically assisted reproduction remain incompletely characterized on a population level. We were to assess the incidence and relative risk of...
BACKGROUND: Importance: The neurodevelopmental outcomes of children born after medically assisted reproduction remain incompletely characterized on a population level. We were to assess the incidence and relative risk of neurodevelopmental delay in the children of infertile women born after unassisted conception, intrauterine insemination (IUI), and in vitro fertilization (IVF). METHOD: We conducted a retrospective cohort study using the National Health Insurance Service database of South Korea from October 2017 through December 2023. The study included 115 839 singleton, full-term, non-low-birthweight children born to women aged 20-49 years with a diagnosis of female infertility. The exposure was mode of conception-spontaneous, IUI, or IVF-balanced by propensity score matching on preconceptional maternal factors. Outcome measure was neurodevelopmental delay, defined as scoring below the cutoff in any of six functional domains on the Korean Developmental Screening Test across six consecutive rounds. Crude incidence rate ratios (IRRs) and adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models. RESULTS: Among 115 839 children, 6 575 (5.7%) exhibited delay in at least one domain. Crude IRRs for any delay were 1.19 (95% confidence interval [CI]: 1.07, 1.61) for IUI and 1.10 (95% CI: 1.03, 1.17) for IVF versus unassisted conception. In the survival models, higher risks persisted for both IUI (aHR = 1.19; 95% CI: 1.06, 1.34) and IVF (1.09, 95% CI: 1.02, 1.06) compared with unassisted conception. When comparing IVF and IUI, IVF conferred a lower risk of fine motor delay than IUI (0.84, 95% CI: 0.72, 0.99). Among IVF births, risk of developmental delay was similar across all six domains for frozen and fresh embryo transfers. CONCLUSIONS: Children conceived via IUI or IVF demonstrated a modest but significant increase in screen-positive neurodevelopmental delay compared with those conceived spontaneously. These findings highlight the need for neurodevelopmental monitoring in this population.
A neural substrate for sensory over-responsivity defined by exogenous and endogenous brain systems.
Choi HL, Lazerwitz MC, Powers R … +10 more , Rowe M, Wren-Jarvis J, Sadikov A, Cai LT, Chu R, Rullan L, Trimarchi KJ, Garcia RD, Marco EJ, Mukherjee P
J Neurodev Disord · 2025 Nov · PMID 41266974 · Full text
BACKGROUND: Exogenous (outward-directed) and endogenous (inward-directed) neural systems are essential for cognition and behavior. However, how they are altered in neurodiverse (ND) children remains unanswered in part du...
BACKGROUND: Exogenous (outward-directed) and endogenous (inward-directed) neural systems are essential for cognition and behavior. However, how they are altered in neurodiverse (ND) children remains unanswered in part due to heterogeneity. Sensory over-responsivity (SOR), the most prevalent form of sensory processing disorder (SPD), serves as a quintessential paradigm for investigating the interaction between exogenous and endogenous brain networks given that both basic and higher-order sensory processing are substantially implicated in this condition. METHODS: Neurodiverse children ages 8–12 years old (n = 83; 30 females and 53 males) were directly assessed for SOR using a structured clinical evaluation, the Sensory Processing 3 Dimensions Assessment (SP3D:A), and underwent 3 Tesla MRI. 39 ND children presented with SOR (ND/SOR) and 44 ND children presented without SOR (ND/NO-SOR). Exogenous and endogenous functional connectivity networks (FCNs) were generated through independent component analysis and investigated with two local functional connectivity (FC) measures, fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo), as well as a long-range FC measure, dual regression (DR). Moreover, we examined FC in the context of behavioral regulation as assessed through the Behavioral Assessment System for Children, 3rd edition (BASC-3), categorizing children as “resilient” or “dysregulated” through latent profile analysis. RESULTS: In general, ND/SOR children exhibit reduced long-range exogenous FC. However, in terms of local FC, we find that ND/SOR children have reduced exogenous and elevated endogenous FC which is diametrically opposed to ND/NO-SOR children. Furthermore, this double dissociation is specific to ND children who are behaviorally resilient, while emotionally dysregulated ND children possess a distinct pattern. CONCLUSION: Achieving optimal brain system connectivity—a balanced contrast—is influenced by sensory over-responsivity and essential for resilience.
Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.
Berry-Kravis E, Hagerman R, Cohen J … +12 more , Budimirovic D, Buchanan CB, Silove N, Tich N, Thibodeau A, Dobbins T, Sebree T, O'Quinn S, Albers DS, Bzdek KG, Nomikos G, Budur K
J Neurodev Disord · 2025 Nov · PMID 41254489 · Full text
BACKGROUND: Dysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannab...
BACKGROUND: Dysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannabidiol that has been uniquely formulated as a gel for transdermal delivery and is currently under investigation for the treatment of behavioral symptoms associated with FXS. DESIGN: ZYN2-CL-017 is an ongoing, long-term, open-label extension (OLE) safety trial of ZYN002 in patients with FXS. We are enrolling patients from past and current ZYN002 clinical trials to evaluate the safety and tolerability of ZYN002 in patients with FXS. METHODS: Primary safety assessments were conducted in patients who enrolled into the OLE from 2 completed ZYN002 trials. Secondary analyses, conducted in a subgroup enrolled from a completed placebo-controlled trial of ZYN002, included the FXS-specific Aberrant Behavior Checklist-Community Social Avoidance and Irritability subscales (ABC-C SA and ABC-C Irr, examined change from baseline of the randomized study) and the Caregiver Global Impression of Change (CaGI-C, examined change from baseline of the OLE), in which caregivers were asked to rate the change in their child's overall behavior. RESULTS: At the time of this interim analysis data cut (January 31, 2024), 240 patients had been enrolled from 2 completed ZYN002 trials. Mean age at entry to the OLE was 9.7 years (range 3-17 years), and the majority were male (76.3%) and White (80.4%). Mean exposure to ZYN002 during the initial trials and OLE was 28 months. Treatment-related adverse events (AEs) were reported in 12.9% of patients; the most common (6.7% of patients) was short-term application site pain. The highest degree of skin irritation reported by investigators was moderate erythema in 7 patients (2.9%). In the secondary analysis cohort (n=196 evaluable patients), patients demonstrated clinically meaningful changes in ABC-C SA, ABC-C Irr, and CaGI-C scores. CONCLUSIONS: Interim analysis results of the ongoing OLE in children, adolescents, and young adults with FXS demonstrated that ZYN002 has a favorable long-term safety profile and is generally well tolerated. Clinically meaningful changes in behaviors from baseline continued to be observed during the OLE. These findings support further study of ZYN002 in patients with FXS. TRIAL REGISTRATION: ZYN2-CL-017 is registered on Clinicaltrials.gov (NCT03802799) on December 26, 2018.
Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease.
Ding Y, Feng J, Prifti V … +6 more , Rico GA, Solorzano AG, Chang HE, Freedman EG, Foxe JJ, Wang KH
J Neurodev Disord · 2025 Nov · PMID 41199165 · Full text
BACKGROUND: CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofusc...
BACKGROUND: CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofuscinoses (NCLs), a group of lysosomal storage disorders that impair brain function. Clinical features include progressive vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates the neurological assessment of cognitive dysfunction, while the rarity of CLN3 cases limits the study of sex-specific disease trajectories in humans. Therefore, there is a critical need for objective, translational biomarkers to monitor disease progression and support therapeutic development in preclinical animal models. METHODS: Building on our recent studies in individuals with CLN3 disease, we developed a parallel experimental paradigm using high-density electroencephalography (EEG) in Cln3 knockout (Cln3-/-) mice to longitudinally assess auditory neurophysiological changes. We applied a duration-based mismatch negativity (MMN) paradigm, similar to that used in our human studies, to evaluate automatic detection of auditory pattern changes in male and female mice between 3 and 9 months of age. RESULTS: Wild-type (WT) mice of both sexes showed robust and stable duration MMN responses across this age range. In contrast, Cln3-/- mice showed marked sex- and age-dependent deficits: female mutants displayed persistent MMN deficits, whereas male mutants exhibited early MMN abnormalities that unexpectedly improved with age. Auditory brainstem responses confirmed intact peripheral hearing in Cln3-/- mice, indicating a central origin for the observed abnormalities. Further analyses revealed that MMN impairments were driven by age- and sex-specific alterations in auditory evoked potentials to both standard and deviant stimuli. CONCLUSIONS: These findings demonstrate sex- and age-dependent disruptions in central auditory processing in Cln3-/- mice and support auditory duration MMN as a sensitive, translational biomarker of brain dysfunction in CLN3 disease. This approach offers a functional, cross-species measure for tracking disease progression and evaluating therapeutic interventions in Batten disease.
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