Journal of Neurodevelopmental Disorders

Differences in looking to and processing of audiovisual speech have been theorized to contribute to heterogeneity in language ability in autistic children. Differential audiovisual speech processing has been indexed by event-related potentials (ERPs), specifically via amplitude suppression in response to audiovisual versus auditory-only speech, and linked with vocabulary in school-aged children. This study used an intact-group comparison and concurrent correlational design in infant siblings of autistic children (Sibs-Autism) and non-autistic children (Sibs-NA) to determine whether amplitude suppression is (a) present in infancy, (b) different in Sibs-Autism versus Sibs-NA, and (c) related to looking to audiovisual speech and language abilities. We collected EEG data from 54 infants aged 12-18 months (29 Sibs-Autism; 25 Sibs-NA) while they viewed videos of audiovisual and auditory-only speech, as well as eye tracking and language data. We found significant amplitude differences at the N2 ERP component in response to audiovisual versus auditory-only speech but no significant group differences in ERP amplitudes. Associations between looking to audiovisual speech, amplitude effects, and language were moderated by group, chronological age, and biological sex. Our findings suggest that differential audiovisual speech processing is present in 12-18-month-olds and may explain heterogeneity in looking to audiovisual speech and emerging language ability.

Individuals with autism spectrum disorder (ASD) often exhibit atypical auditory processing, yet it remains unclear whether and how the integration of simple acoustic features and contextual information is impacted in ASD. One real-world example of this integration is the auditory looming bias, the prioritized processing and perception of approaching auditory stimuli. We designed a paradigm that presents intensity-rising (looming) and intensity-falling (receding) auditory stimuli to 3-4-year-old children with ASD (n = 21), children with sensory processing concerns who do not have ASD (SPC; n = 16) and children with typical development (TD; n = 30). We recorded neural responses using electroencephalography (EEG) and found evidence of looming bias in the SPC and TD groups, as indexed by greater P1 peak amplitude during the looming than receding stimuli (TD: t(64) = 6.87, p < .001; SPC: t(64) = 4.07, p < .001). But this finding was not present in the ASD group (p = .194). Additionally, the ASD group showed reduced differentiation between looming and receding stimuli, as indicated by significantly lower Rise-Fall Difference Score (RFDS) in comparison to the TD group (Z = -3.00, padj = .008). These findings suggested altered context-dependent modulation of sensory input in ASD. Lay SummaryMany children with autism show differences in how they process sounds. Using sound patterns in which loudness gradually increased and decreased over time, like many real-world sounds, we found that children with autism showed less neural differentiation between increasing and decreasing sounds. This finding suggested that the brain may process changes in sound differently in autism, particularly in how it adjusts to sounds as they change over time, which could contribute to the sensory challenges many children with autism experience in daily life.

Background Diagnosis and treatment monitoring of attention-deficit/hyperactivity disorder (ADHD) largely rely on subjective assessments, highlighting the need for objective markers. Voice features and speech embeddings represent promising candidates for such markers, as they may capture alterations in speech production relevant to ADHD. However, it remains unclear which speech features are most informative for distinguishing ADHD and monitoring treatment effects, and which speech tasks most reliably elicit such differences. Methods Twenty-seven children with ADHD and 27 age-matched neurotypical controls completed six speech tasks across two study visits. Children with ADHD were unmedicated at baseline (first visit) and were assessed under prescribed methylphenidate treatment at follow-up, whereas controls underwent repeated assessment without intervention. Established acoustic voice features (eGeMAPS) and high-dimensional speech embeddings (WavLm, Whisper) were extracted and analysed using linear mixed models to examine baseline group differences and group-by-time interaction effects reflecting medication-associated change patterns. Results At baseline, children with ADHD differed significantly from controls in frequency, spectral, and temporal voice features, characterized by lower and more variable pitch, altered spectral properties, and reduced rhythmic stability. Group-by-time interaction effects indicated medication-associated modulation in the ADHD group, including reduced loudness variability and increased precision of vowel articulation at follow-up, changes not observed in controls. Speech embeddings revealed additional baseline and interaction effects beyond established acoustic features. Free speech tasks, particularly picture description, yielded the most robust and consistent effects. Conclusion Children with ADHD differed from neurotypical controls in vocal features at baseline and showed distinct longitudinal change patterns consistent with medication-related change. These findings support further investigation of speech-based measures as candidate digital phenotypes and potential digital biomarkers in ADHD, with picture description emerging as a particularly promising task for future clinical assessment protocols.

Because both monothetic and polythetic diagnostic classification approaches focus on the presence of individual symptom(s) to identify individuals in a clinical population, they may be diagnostically sensitive clinical markers of multidimensional disorders such as developmental language disorder (DLD). DLD researchers have also used likelihood ratios (LHs) to identify possible diagnostic clinical markers of DLD, however the diagnostic sensitivity of LHs varies markedly across studies. A recent multidimensional computational elastic-net regression examined a total of 71 measures of spoken language and cognitive processing from a cohort of 223 children ages 7;0 to 11;0 with and without DLD (DLD = 110; typically developing (TD) controls = 113). All 200 iterations of the model had high discriminative power (87% - 88%) in positively identifying and distinguishing the DLD participants across all thresholds. Notably, the models identified a sparse DLD-specific deficit profile which only included nine of the 71 measures. In this study, we ask if the individual LHs for each of these nine measures are equally sensitive in identifying and discriminating the children with DLD from TD controls or if diagnostic markers of multidimensional disorders such as DLD can only be identified based on computational modeling approaches. The LHs for each of the nine measures were in the moderately high ranged (3.25 - 10). However, at the the highest LH cut points for each measure, there was little to no overlap in the children each measure identified as having DLD. Follow up analysis revealed that the elastic net model-derived predictive scores for each participant were significantly correlated with the participants language ability. The model also identified a subgroup of TD participants as having the same DLD-deficit profile as the DLD participants. This subgroup were younger, predominantly male participants whose standardized language assessment scores were lower as compared to the larger TD cohort. Taken together, the results from this study show that, because multidimensional modeling approaches such as elastic net regression leverage the variability in the deficit profiles across individual members of a diagnostic group and the unique contributions of each of the behavioral features of the phenotype, they may be an effective tool in deriving diagnostically specific deficit profiles for phenotypically complex, multicausal, multidimensional, neurodevelopmental disorders such as DLD. The results also demonstrate the robustness of the derived DLD-specific deficit profile in identifying individuals with "mild" or subclinical DLD, demonstrating the potential utility of this approach in both clinical and research arenas. What this paper adds.O_ST_ABSWhat is already known on this subject.C_ST_ABSThe identification of diagnostic markers for DLD has been a challenge for both clinicians and researchers across multiple decades. Monothetic classification markers such as non-word repetition, optional infinitive, or syntax dependencies have been explored, as well as polythetic classification approaches where a list of diagnostic symptoms is used together. However, each assumes different criteria and symptoms that should be included as diagnostic markers of DLD. What this study adds.Our study assessed the feasibility and effectiveness of monothetic vs. polythetic classification approaches for identifying DLD. Since our prior work, which used elastic net logistic regression computational modeling with strong discriminatory power, consistently selected nine key features as the DLD-deficit profile, in this effort, we calculated each of the nine features likelihood ratios to examine each measures ability to identify children with DLD. The monothetic approach failed to identify a consistent set of children with DLD, and the polythetic classification approach also did not identify participants who were shown to have mild DLD by the elastic net modeling approach. Instead, our analysis showed that a computational modeling approach, such as elastic net regression, that included small but important input from multiple cognitive and linguistic aspects of children, could better capture multifaceted information about the disorder, better account for individual variability, and consistently identify most participants with DLD. Clinical implications of this study.Elastic net logistic regression identifies a small subset of important features for distinguishing DLD and can assign a probability of DLD presence for each participant. Instead of the polythetic and monothetic approaches commonly used in the field, our study shows that integrating advanced computational modeling, such as elastic net regression, with clinician judgment can better refine assessment processes and address prior and ongoing inconsistencies in the DLD literature and diagnostic practices.

PurposeNavigational ability develops throughout childhood alongside the maturation of brain regions supporting egocentric and allocentric processing. In Autism Spectrum Disorder (ASD), atypical hippocampal development may impact flexible spatial memory; however, findings on navigational ability in autistic children remain inconsistent. This study aimed to compare both objective and perceived navigation ability in children with ASD and typically developing (TD) peers. MethodTwenty-six children with high-functioning ASD and twenty-five age- and gender-matched TD children (M_age = 12.04 years, SD = 1.64) completed a battery of navigational tasks from the Spatial Performance Assessment for Cognitive Evaluation (SPACE), including Path Integration, Egocentric Pointing, Mapping, Associative Memory, and Perspective Taking. Perceived navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. ResultsNo significant group differences were observed across any objective navigation tasks. However, children with ASD reported significantly lower perceived navigation ability compared to TD peers. ConclusionThese findings suggest a dissociation between perceived and actual navigational ability in ASD. By early adolescence, objective navigation performance appears intact, potentially reflecting sufficient maturation of underlying neural systems or the presence of compensatory mechanisms. The results underscore the importance of incorporating objective, task-based measures when assessing cognitive abilities in autistic populations.

AimAutistic children have a high but varied prevalence of internalizing and externalizing problems. This study aimed to identify the subtypes of internalizing and externalizing problems among autistic preschool children in Japan, examine their temporal stability, and investigate differences in participation in daily life and family outcomes across these subtypes. MethodsA prospective cohort study was conducted with 275 caregivers of autistic children aged 51-75 months. Internalizing and externalizing problems were assessed using the Strengths and Difficulties Questionnaire. ResultsLatent transition analysis identified five subtypes: Low-symptom, High-emotional, Externalizing, Comorbid, and Peer-difficulty groups. Membership in the High-emotional and Externalizing groups was relatively stable over time, whereas the Peer-difficulty group showed frequent transitions to subtypes with higher levels of internalizing or externalizing problems. Significant differences in participation in daily life and family outcomes were observed across subtypes, but these patterns were inconsistent with a simple gradient of symptom levels. ConclusionsThe novel findings that the temporal stability of subtype membership varied and that differences in participation in daily life and family outcomes were observed across the subtypes suggest that the heterogeneity of internalizing and externalizing problems may be associated with variations in childrens participation in daily life and family outcomes over time. Plain Language SummaryAutistic preschool children often experience emotional and behavioral difficulties, but the way these difficulties manifest varies widely across individuals. This study aimed to identify the patterns of these difficulties, examine how they change over time, and investigate how participation in daily life and family outcomes differ across autistic preschool children. We conducted a study with 275 caregivers of autistic children aged 4-6 years in Japan. From caregiver reports of childrens emotional and behavioral difficulties, five distinct patterns were identified: a group with mainly emotional difficulties, a group with mainly behavioral difficulties, a group with both types of difficulties, a group with relatively low levels of difficulties, and a group characterized primarily by peer-related difficulties. Our findings suggest that different patterns of emotional and behavioral difficulties are associated with differences in childrens participation in daily life and family outcomes. These differences could not be explained simply by the overall severity of difficulties but rather reflect distinct patterns based on the type of difficulty. The results indicate that autistic children face diverse difficulties that change over time.

BackgroundAutistic individuals experience higher rates of sleep problems throughout their lives, and there is considerable heterogeneity in manifestations of these issues that remains unexplained. Here, we examine associations over time of heterogenous sleep trajectories with autism diagnosis, and behavioural and genetic factors related to autism. MethodWe used data from the Avon Longitudinal Study of Parents and Children (N=13,886, autistic n=150). The primary outcome was parent and self-reported night-time sleep duration, measured on 10 occasions (between 0.5y and 15.5y). The independent variables were autism diagnosis, autism polygenic score (PGS) and four parent-reported autistic traits: repetitive behaviour, social communication, speech coherence, and sociability. Latent class growth analysis was conducted to identify heterogenous classes of sleep trajectories, and these trajectory classes were regressed onto the independent variables. ResultsFour night-time sleep duration trajectory subclasses were identified; shorter (n=512, 4.1%), longer (n=1654, 13.1%), intermediate-shorter (n=3630, 28.8%), and intermediate-longer (used as the reference class; n=6825, 54.1%). An autism diagnosis was associated with a shorter or intermediate-shorter sleep duration trajectory, compared to the reference class. Similarly, higher scores in domains of repetitive behaviour, speech coherence and social communication were associated with shorter sleep duration trajectories. The autism PGS and sociability were not associated with any sleep trajectories compared to the intermediate-longer sleep trajectory (reference group). ConclusionAn autism diagnosis and specific autistic traits were associated with poorer long-term sleep outcomes across childhood and adolescence, highlighting the need for early, sustained sleep interventions, and the potential of trait-specific mechanisms for sleep problems. HighlightsO_LIFour distinct night-time sleep duration trajectories were identified across development C_LIO_LIAutism diagnosis predicted shorter and intermediate-shorter sleep trajectories C_LIO_LISpecific (but not all) autistic traits were linked to shorter sleep trajectories C_LIO_LIAutism PGS did not predict sleep duration trajectories C_LI

Atypical social functioning is a core feature of autism, yet findings remain fragmented across components and development. We aimed to systematically integrate this literature and characterize the organization, development, and moderators of social functioning in autism. We conducted a systematic review and meta-analysis of behavioral studies published between January 1990 and August 2025, identified through PubMed, Web of Science, and prior reviews, including studies with clinically diagnosed autistic individuals and neurotypical controls. A qualitative synthesis and two complementary quantitative meta-analyses were performed, with risk of bias evaluated through study-level characteristics. A total of 2,622 studies (94,114 autistic and 172,847 neurotypical individuals across 32 countries) were included, covering 22 social components that clustered into five domains. Overall group differences were substantial (Hedges g = -0.744, 95% CI [-0.797, -0.690]). Differences emerged earliest in motivation-based processes ([~]6 months), followed by motor, emotion, and inference domains, and showed age-related divergence alongside improvement in some skills. Cross-domain analyses revealed stronger interdependencies in autism and an organizational pattern most consistent with serial relationships among domains. These findings should be interpreted in light of methodological heterogeneity, underpowered samples, and uneven cultural representation. Together, the results provide an integrative framework for understanding the organization and development of social functioning in autism, with implications for precision subtyping, developmentally timed interventions, and neurodiversity-informed research and policy. This study was pre-registered (PROSPERO: CRD42024566141).

The causes of severe neuropsychiatric deteriorations among patients with previously stable autism spectrum disorder (ASD) are poorly understood and present substantial challenges for care. We aimed to characterize the prevalence of autoimmune and inflammatory conditions and markers, as well as musculoskeletal findings, among youth with ASD experiencing a suspected post-infectious neuropsychiatric deterioration. The Stanford Immune Behavioral Health (IBH) Clinic is a specialty program for youth with neuropsychiatric deteriorations that are suspected to be post-infectious (non-psychosocial). We report findings for 43 consecutive patients with ASD (70% male [30 of 43]) evaluated in the IBH Clinic. The average (SD) age at clinical presentation was 12.0 (4.0) years. Juvenile arthritis was diagnosed in 15 patients (35%), predominantly enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Seven patients had ultrasonographic evidence of joint effusions and/or synovitis without meeting juvenile idiopathic arthritis (JIA) criteria. Autoimmune conditions other than arthritis were observed in 9 patients (21%). The mean (SD) age at arthritis and other autoimmune condition diagnoses were 16.2 (5.5) and 12.7 (4.9) years, respectively. We observe markers of immune activation during neuropsychiatric deteriorations in over half of patients (60% [26 of 43]), including markers of autoimmunity (33% [12 of 36]), complement activation (41% [13 of 32]), immune dysregulation/inflammation (11% [4 of 37]), and vasculopathy (30% [13 of 43]). One-third (37% [16 of 43]) demonstrated two or more markers. These data underscore the importance of targeted immune evaluation--including musculoskeletal imaging and inflammatory marker screening--in ASD patients who have had a suspected post-infectious behavioral regression. Lay SummaryIn this cohort study of 43 patients with autism spectrum disorder (ASD) and suspected post-infectious deteriorations, more than half had laboratory markers of immune activation (using a limited panel), one-third had joint inflammation (confirmed by ultrasound), and additional autoimmune conditions were observed in 21%. From this, we conclude that patients with ASD who experience a suspected post-infectious neuropsychiatric deterioration may have underlying inflammation which may contribute to neuropsychiatric and behavioral regressions, highlighting the importance of immunologic and rheumatologic evaluation in clinical assessment.

Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental condition with multifactorial etiology, resulting from complex interactions between genetic susceptibility and environmental exposures. Although numerous studies have identified individual perinatal risk factors for ASD, most have examined these exposures in isolation, limiting understanding of how perinatal complications cluster and jointly influence neurodevelopment. Evidence from Latin America also remains scarce. This study aimed to identify multivariate perinatal risk patterns associated with ASD in a Chilean population, addressing gaps in regional representation and methodological approaches. We conducted a population-based analysis of mothers of children with and without ASD in Chile. A broad set of medical and psychosocial perinatal variables was jointly analyzed using multiple correspondence analysis (MCA) to characterize interrelated risk structures. MCA revealed a clear separation between ASD and non-ASD groups along the first dimension, suggesting that ASD diagnosis is embedded within structured perinatal patterns rather than isolated exposures. MCA-derived, stepwise, and LASSO-penalized logistic regression models were then compared. The most parsimonious model identified maternal vaginal bleeding during pregnancy, prenatal maternal stress or anxiety, and negative pregnancy intention or perception as the strongest factors jointly associated with increased odds of ASD, with a dose-response pattern observed for maternal stress. An unexpected inverse association with neonatal cyanosis may reflect enhanced medical surveillance and warrants cautious interpretation. These findings underscore the importance of integrated perinatal care addressing both obstetric and maternal mental health, and demonstrate the value of multivariate approaches for elucidating complex developmental risk pathways.

Abstract Parental depression and early child neurodevelopment are closely interconnected, yet few population-based studies have examined both maternal and paternal depression in relation to early neurodevelopmental risk. This study aimed to examine the association between child neurodevelopmental risk and parental depression in the French national birth cohort Etude Longitudinale Francaise depuis l'Enfance (ELFE). We conducted a cross-sectional analysis of 12,953 children and their parents who participated in the 2-year follow-up. Child neurodevelopmental risk was assessed at age 2 years using the Modified Checklist for Autism in Toddlers and categorized as low, intermediate, or high risk. Parental depression was assessed using the Kessler Psychological Distress Scale and defined as maternal depression, paternal depression, or depression in at least one parent. Multivariable logistic regression models were adjusted for sociodemographic, pregnancy-related, and child characteristics. Compared with low child neurodevelopmental risk, intermediate risk was associated with higher odds of maternal depression and depression in at least one parent. High child neurodevelopmental risk was associated with substantially higher odds of maternal depression and depression in at least one parent. Associations with paternal depression were weaker and were no longer statistically significant after adjustment. These findings suggest that parental depression, particularly maternal depression, is associated with early child neurodevelopmental risk from the stage of initial developmental concerns. They support an integrated, family-centred approach combining early identification of child developmental vulnerability with attention to parental mental health.

I ntroduction: Prospective memory (PM) deficits in children with attention-deficit/hyperactivity disorder (ADHD) significantly impact academic and daily functioning. Through two experiments, this study investigated how cognitive load and encoding strategies modulate PM performance. Methods: Experiment 1 included 43 children (21 ADHD, 22 typically developing) who completed an n-back task under high and low cognitive load. Experiment 2 included 44 children with ADHD who were randomly assigned to either a standard encoding group or an implementation intention encoding group, also completing the n-back task under both load conditions. Results: Experiment 1 showed that children with ADHD had significantly lower PM accuracy than typically developing peers. Signal detection analysis revealed that this deficit stemmed from a more conservative response bias rather than impaired perceptual sensitivity. Unexpectedly, PM accuracy and perceptual sensitivity were higher under high cognitive load than low load for both groups. Experiment 2 demonstrated that implementation intention encoding significantly enhanced PM accuracy and perceptual sensitivity in children with ADHD, with stable effects across load conditions and no interference with ongoing task performance. Discussion: These findings indicate that PM deficits in children with ADHD reflect a conservative response strategy rather than an inability to detect target cues. Implementation intention encoding provides an effective, load-independent cognitive strategy for enhancing PM performance. These results offer novel insights into the cognitive mechanisms underlying PM deficits in ADHD and provide evidence-based guidance for targeted interventions.

Background and Objectives In ADHD, a heterogeneous neurodevelopmental condition, behavioral and motor manifestations may reflect multiple inefficient or perturbed inhibitory systems. To evaluate Transcranial Magnetic Stimulation (TMS) evoked cortical silent period (CSP) duration, an indicator of GABA(B) receptor-mediated inhibition in motor cortex, as a potential biomarker of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Method We retrospectively analyzed TMS data, obtained using both round and figure-of-8 coils, from three cross-sectional studies conducted in 8- to 12-year-old children with ADHD (n=79; 10.7 +/- 1.5 years old) and age-and-sex-matched typically developing controls (n=96; 10.5 +/- 1.4 years old). Results Median CSP was 32% shorter in ADHD (p=0.02). Regression analysis demonstrated a relationship between shorter CSP and both lower active motor thresholds (p < 0.0001) and more severe hyperactivity symptom rating (p = 0.026). Test-retest CSP measures in 83 children showed moderate reliability (intraclass correlation 0.77 [ADHD], 0.75 [controls]). Conclusion TMS-evoked CSP may be a useful biomarker in future investigations of ADHD subtypes, domains of impaired function, or treatment outcomes.

Attention-deficit/hyperactivity disorder (ADHD) is associated with impairments in sustained attention and inhibitory control. Neurofeedback (NFB) is a widely used non-pharmacological treatment for ADHD and is generally well tolerated, but evidence for its efficacy remains mixed. Here we report results from secondary analysis of a randomized controlled trial of NFB training for adult ADHD, analysing behaviour and neural data from attention testing in both test-retest and treatment-vs-waiting list control group contrasts. We used electroencephalography (EEG) to investigate event-related cortical dynamics during the Test of Variables of Attention (TOVA), administered before and after NFB treatment. 44 adults with ADHD (NFB treatment, ADHD-T: n = 23; waitlist control, ADHD-W: n = 21) completed the TOVA before and after the NFB training period, while 128-channel EEG was recorded. Treatment-related change was examined through analyses based on behavioural TOVA performance, power spectral density, and event-related potentials, analysed with Bayesian linear mixed models. We found no meaningful evidence for NFB-specific improvements in TOVA behavioural performance over time, and no evidence that NFB modulated ERP or spectral indices relative to the ADHD-W group. Overall, we found no evidence that NFB treatment meaningfully benefited sustained attention or inhibitory control in adults with ADHD.

Autism spectrum disorder (ASD) is associated with deficits in synaptic plasticity across brain regions. While striatal dysfunction is observed in various mouse models of ASD, the effect of ASD-associated genes on striatal plasticity has not been well characterised. We previously showed that overexpression of the SFARI ASD risk gene eIF4E in transgenic (eIF4E-TG) mice produces ASD-like behaviours and impairs dorsal striatal dopamine release. Here, we examined whether eIF4E overexpression alters striatal synaptic transmission and plasticity. Using microscopy, whole-cell electrophysiology, optogenetics and fast-scan cyclic voltammetry, we assessed dendritic morphology and excitatory synaptic properties of spiny projection neurons (SPNs). The eIF4E-TG mice exhibited higher dendritic spine density, elevated AMPA and NMDA receptor-mediated mEPSC frequency, and reduced AMPA mEPSC amplitude. We also observed an increased induction rate and magnitude of long-term potentiation (LTP) in SPNs, which is NMDA receptor-dependent but is not prevented by pharmacological D1 or D2 receptor antagonism under the conditions tested. Finally, we found that somatic and dendritic Ca2+ signals evoked by brief depolarisation are altered in SPNs from eIF4E-TG mice. Together, these findings are consistent with eIF4E overexpression promoting an NMDA receptor-dependent form of striatal LTP that is not prevented by D1/D2 receptor antagonism.

Genetic counselling outcome measures are increasingly adapted for diverse clinical contexts. While the Genetic Counselling Outcome Scale (GCOS-24) is available in Swedish, no autism-specific version has been developed. Therefore, we adapted the Swedish GCOS-24 using the English version of the modified GCOS-24 (mGCSOS-24) to create a Swedish autism-specific mGCOS-24. Thereafter, we evaluated both the Swedish autism mGCOS-24 and the Swedish general GCOS-24 using Rasch analysis to assess their psychometric properties. Both instruments exhibited structural challenges, including multidimensionality, disordered thresholds, local item dependence, and invariance issues. For the Swedish autism mGCOS-24, we were able to identify subscales with acceptable measurement properties. However, applying the same structure to the Swedish general GCOS-24 did not resolve its broader limitations. This study introduces the first Swedish autism-specific mGCOS-24 and represents the first Rasch-based evaluation of any GCOS-24 or mGCOS-24 in Swedish. Our findings highlight important opportunities for measure refinement but also indicate that new or more substantially adapted tools may be needed to capture outcomes of genetic counselling in autistic populations.

Neuroligin-3 (NLGN3) was first identified as a risk gene associated with autism spectrum disorder (ASD). The initial variant, p.R451C, associating NLGN3 with ASD has been heavily investigated, yet little is known about the functional consequences of other NLGN3 variants. Furthermore, while most of the identified variants are present in males with maternally inherited variants from unaffected mothers, several de novo variants were observed in females, suggesting a possible functional difference between de novo and maternally inherited variants. To address the functional consequences of NLGN3 variants in vivo, we generated transgenic Drosophila models corresponding to one de novo variant (p.R175W) identified in one female proband, and two maternally inherited variants (p.R451C and p.R597W) identified in male probands. In Drosophila, loss of the fly homolog, Nlg3, altered sleep patterns, synaptic architecture, and vesicle dynamics, which were rescued by the expression of the human NLGN3Ref allele. When comparing the variants, the de novo p.R175W variant and the maternally inherited p.R451C variant altered synapse morphology and sleep patterns, with minimal effects on vesicle dynamics, and the p.R597W variant altered sleep and vesicle dynamics with minimal impact on synapse morphology. Using overexpression models, human NLGN3Ref altered sleep patterns and synaptic morphology. Moreover, the p.R175W variant exacerbated sleep phenotypes, and the p.R175W and p.R451C variants exacerbated synapse morphology phenotypes. Together, our findings suggest that de novo NLGN3 variants identified in females are likely gain-of-function, while maternally inherited variants have mixed loss-and gain-of-function effects. Moreover, the location of the variants may contribute to the distinct functional differences we observed. Some NLGN3 variants disrupt synaptic development, while other variants alter synaptic function, suggesting that NLGN3 variants have differential effects. These functional differences may provide insight into the heterogeneity of individuals with ASD. Author SummaryAutism spectrum disorder (ASD) is a common neurodevelopmental disorder. Mutations in the Neuroligin-3 (NLGN3) gene are associated with ASD but very few of these mutations have been characterized in animal models. Most of these mutations affect male individuals who maternally inherited their genetic mutation; however, more rarely female individuals may present with a genetic mutation that was not identified in either of the parents. Here, we utilized the fruit fly model to investigate how three different mutations, one mutation identified in a female and two mutations identified in males, affect the flys behavior and synapse development. We identified altered sleep patterns in some of our mutants which is consistent with sleep disturbances being highly comorbid with ASD. Additionally, we identified alterations in synapse development and function which is consistent with the role of NLGN3 in synapse formation and maturation. Together, our findings support that NLGN3 is important for regulating the synapse and mutations in this gene can alter its function. However, different mutations can have differential effects. This demonstrates the need to assess multiple variants simultaneously because each variant may have distinct functional significances.

Adult ADHD is increasingly recognized across the lifespan, yet the psychometric equivalence of the Adult ADHD Self-Report Scale (ASRS) remains unverified for older populations. This study examined age-related Differential Item Functioning (DIF) in 600 adults (n = 100 per decade, ages 20-80) who completed the 18-item ASRS. Using a bi-factor Graded Response Model, we extracted latent ADHD trait scores ({omega}H = .895) and assessed DIF via ordinal logistic regression with adaptive age modeling. Five of 18 items exhibited significant uniform DIF. At equivalent latent severity, older adults were less likely to endorse hyperactivity symptoms in Part A (fidgeting, feeling "driven by a motor") but more likely to endorse specific symptoms in Part B (careless mistakes, misplacing items, interrupting). From ages 20 to 80, expected Part A scores decreased by 1.36 points (~0.27 per decade), while Part B scores increased by 1.15 points (~0.23 per decade). These findings indicate a phenotypic redistribution of ADHD symptoms as individuals age. Because the 6-item Part A screener serves as the primary clinical gatekeeper, its concentration of negative DIF suggests standard screening practice may systematically underestimate ADHD severity in older adults. We recommend using the full 18-item ASRS when screening older populations and suggest that developing age-adjusted norms would improve diagnostic accuracy.

Aim: To determine whether the neural phenotype (whole-brain resting-state functional connectivity pattern) of attention deficit hyperactivity disorder associated with prenatal alcohol exposure (ADHD+PAE) differs from that in unexposed children with ADHD of probable familial origin (ADHD-PAE). Method: Resting-state functional MRI was acquired from 26 children with ADHD+PAE, 25 with ADHD-PAE, and 25 typically developing (TD) children, all aged 8-13 years. Mean connectivity matrices based on the Cole-Anticevic Brainwide Network Parcellation of the brain were compared between the groups. Results: Within the frontoparietal network (FPN), children with ADHD+PAE showed widespread lower group-mean connectivity than children with ADHD-PAE; effects were concentrated primarily in cerebellar-cerebral cortical and cerebral cortical-cerebral cortical connections. Children with ADHD-PAE showed widespread hyperconnectivity relative to TD children. Children with ADHD+PAE showed mixed hyper- and hypoconnectivity relative to TD. Interpretation: These results are consistent with other MRI findings indicating that ADHD+PAE is neurally distinct from ADHD-PAE; PAE may be associated with broadly reduced connectivity, especially across cerebellar-cerebral cortical systems.

Self-determination has been assessed as an internal psychological construct. External factors may also affect self-determination, but opportunities to make choices and decisions remain understudied. We developed and evaluated the AASPIRE-Choices and Decisions Scale (AASPIRE-CDS), a new measure of autistic adults opportunities to make choices and decisions, using a community-based participatory approach. We created and refined the AASPIRE-CDS through an iterative process. Data, from the AASPIRE Outcomes Project, included 839 autistic adults participating through direct report, supported direct report, and caregiver report (CR). Exploratory and confirmatory analyses supported a unidimensional structure. Measurement invariance analyses supported configural, metric, and partial scalar invariance across report type without CR, and across living status, with and without CR. The AASPIRE-CDS showed high internal consistency, test-retest reliability, and responsiveness to change over time. Convergent validity analyses showed that higher AASPIRE-CDS scores were associated with greater self-determination and communication fluency, more independent living, and fewer support needs. The AASPIRE-CDS showed weaker (albeit significant) associations with quality of life, overall health, and employment satisfaction than the self-determination measure showed with these variables. This pattern suggests that opportunities for choice-making are related to, but distinct from, commonly used measures of self-determination. Findings support the AASPIRE-CDS as a valid and reliable measure of choice-making opportunities in autistic adults across support needs but suggest caution interpreting CR. They underscore the importance of supporting autistic adults choice-making and evaluating opportunities for choice alongside internal self-determination. Future research should use larger CR samples to examine the validity of caregiver-reported choice-making opportunities.