J Neurodev Disord [JOURNAL]
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200 papers
Visual feedback and motor memory contributions to sustained motor control deficits in autism spectrum disorder across childhood and into adulthood.
Shafer RL, Bartolotti J, Driggers A … +3 more , Bojanek E, Wang Z, Mosconi MW
J Neurodev Disord · 2025 May · PMID 40380091 · Full text
BACKGROUND: Autistic individuals show deficits in sustained fine motor control which are associated with an over-reliance on visual feedback. Motor memory deficits also have been reported during sustained fine motor cont...
BACKGROUND: Autistic individuals show deficits in sustained fine motor control which are associated with an over-reliance on visual feedback. Motor memory deficits also have been reported during sustained fine motor control in autism spectrum disorders (ASD). The development of motor memory and visuomotor feedback processes contributing to sustained motor control issues in ASD are not known. The present study aimed to characterize age-related changes in visual feedback and motor memory processes contributing to sustained fine motor control issues in ASD. METHODS: Fifty-four autistic participants and 31 neurotypical (NT) controls ages 10-25 years completed visually guided and memory guided sustained precision gripping tests by pressing on force sensors with their dominant hand index finger and thumb. For visually guided trials, participants viewed a stationary target bar and a force bar that moved upwards with increased force for 15s. During memory guided trials, the force bar was visible for 3s, after which participants attempted to maintain their force output without visual feedback for another 12s. To assess visual feedback processing, force accuracy, variability (standard deviation), and regularity (sample entropy) were examined. To assess motor memory, force decay latency, slope, and magnitude were examined during epochs without visual feedback. RESULTS: Relative to NT controls, autistic individuals showed a greater magnitude and a trend for a steeper slope of force decay during memory guided trials. Across conditions, the ASD group showed reduced force accuracy (β = 0.41, R = 0.043, t=2.36, p = .021) and greater force variability (β=-2.16, R = 0.143, t=-4.04, p = .0001) and regularity (β=-0.52, R = 0.021, t=-2.21, p = .030) relative to NT controls at younger ages, but these differences normalized by adolescence (age x group interactions). Lower force accuracy and greater force variability during visually guided trials and steeper decay slope during memory guided trials were associated with overall autism severity. CONCLUSIONS: Our findings that autistic individuals show a greater magnitude and tendency for a greater rate of force decay than NT individuals following the removal of visual feedback indicate that motor memory deficits contribute to fine motor control issues in ASD. Findings that sensorimotor differences in ASD were specific to younger ages suggest delayed development across multiple motor control processes.
Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns.
Silver H, Greenberg R, Siper PM … +11 more , Zweifach J, Soufer R, Sahin M, Berry-Kravis E, Soorya LV, Thurm A, Bernstein JA, Kolevzon A, Grice DE, Buxbaum JD, Levy T
J Neurodev Disord · 2025 Apr · PMID 40307697 · Full text
BACKGROUND: SHANK2 disorder is a rare neurodevelopmental disorder caused by a deletion or pathogenic sequence variant of the SHANK2 gene and is associated with autism spectrum disorder (ASD), intellectual disability (ID)...
BACKGROUND: SHANK2 disorder is a rare neurodevelopmental disorder caused by a deletion or pathogenic sequence variant of the SHANK2 gene and is associated with autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay. To date, research in SHANK2 has focused on laboratory-based in vivo and in vitro studies with few prospective clinical studies in humans. METHODS: A remote assessment battery was comprised of caregiver interviews with a psychiatrist, psychologists, and a genetic counselor, caregiver-reports, and review of records. Results from this cohort were reported using descriptive statistics. An age-matched sample of participants with SHANK3 haploinsufficiency (Phelan-McDermid syndrome, PMS) was used to compare adaptive behavior between the two groups. RESULTS: All ten participants demonstrated delays in adaptive behavior, with most motor skills preserved and a weakness in communication. According to parent report, 90% of participants carried a formal diagnosis of ASD, 50% of participants carried a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and mild-to-moderate developmental delays were noted. Sensory hyperreactivity and seeking behaviors were more pronounced than sensory hyporeactivity. Medical features included hypotonia, recurrent ear infections, and gastrointestinal abnormalities. No similar facial dysmorphic features were observed. Compared to PMS participants, individuals with SHANK2 disorder had significantly higher adaptive functioning. CONCLUSIONS: Consistent with previous studies of SHANK2 disorder, these results indicate mild to moderate developmental impairment. Overall, SHANK2 disorder is associated with developmental and adaptive functioning delays, high rates of autism, including sensory symptoms and repetitive behaviors, and ADHD. This study was limited by its remote nature, diverse age range, and the homogeneous racial and ethnic sample. Future studies should examine larger, diverse cohorts, add cognitive testing, capture longitudinal data, and include in-person assessments.
Automated extraction of functional biomarkers of verbal and ambulatory ability from multi-institutional clinical notes using large language models.
Kaster L, Hillis E, Oh IY … +7 more , Aravamuthan BR, Lanzotti VC, Vickstrom CR, Brain Gene Registry Consortium, Gurnett CA, Payne PRO, Gupta A
J Neurodev Disord · 2025 Apr · PMID 40307685 · Full text
BACKGROUND: Functional biomarkers in neurodevelopmental disorders, such as verbal and ambulatory abilities, are essential for clinical care and research activities. Treatment planning, intervention monitoring, and identi...
BACKGROUND: Functional biomarkers in neurodevelopmental disorders, such as verbal and ambulatory abilities, are essential for clinical care and research activities. Treatment planning, intervention monitoring, and identifying comorbid conditions in individuals with intellectual and developmental disabilities (IDDs) rely on standardized assessments of these abilities. However, traditional assessments impose a burden on patients and providers, often leading to longitudinal inconsistencies and inequities due to evolving guidelines and associated time-cost. Therefore, this study aimed to develop an automated approach to classify verbal and ambulatory abilities from EHR data of IDD and cerebral palsy (CP) patients. Application of large language models (LLMs) to clinical notes, which are rich in longitudinal data, may provide a low-burden pipeline for extracting functional biomarkers efficiently and accurately. METHODS: Data from the multi-institutional National Brain Gene Registry (BGR) and a CP clinic cohort were utilized, comprising 3,245 notes from 125 individuals and 5,462 clinical notes from 260 individuals, respectively. Employing three LLMs-GPT-3.5 Turbo, GPT-4 Turbo, and GPT-4 Omni-we provided the models with a clinical note and utilized a detailed conversational format to prompt the models to answer: "Does the individual use any words?" and "Can the individual walk without aid?" These responses were evaluated against ground-truth abilities, which were established using neurobehavioral assessments collected for each dataset. RESULTS: LLM pipelines demonstrated high accuracy (weighted-F1 scores > .90) in predicting ambulatory ability for both cohorts, likely due to the consistent use of Gross Motor Functional Classification System (GMFCS) as a consistent ground-truth standard. However, verbal ability predictions were more accurate in the BGR cohort, likely due to higher adherence between the prompt and ground-truth assessment questions. While LLMs can be computationally expensive, analysis of our protocol affirmed the cost effectiveness when applied to select notes from the EHR. CONCLUSIONS: LLMs are effective at extracting functional biomarkers from EHR data and broadly generalizable across variable note-taking practices and institutions. Individual verbal and ambulatory ability were accurately extracted, supporting the method's ability to streamline workflows by offering automated, efficient data extraction for patient care and research. Future studies are needed to extend this methodology to additional populations and to demonstrate more granular functional data classification.
Functional connectivity between the visual and salience networks and autistic social features at school-age.
Girault JB, Nishino T, Talović M … +24 more , Nebel MB, Reynolds M, Burrows CA, Elison JT, Lee CM, Snyder AZ, Shen MD, Shen AM, Botteron KN, Estes AM, Dager SR, Gerig G, Hazlett HC, Marrus N, McKinstry RC, Pandey J, Schultz RT, John TS, Styner MA, Zwaigenbaum L, Todorov AA, Piven J, Pruett JR, IBIS Network
J Neurodev Disord · 2025 Apr · PMID 40295911 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is highly heritable and phenotypically variable. Neuroimaging markers reflecting variation in behavior will provide insights into circuitry subserving core features. We examined...
BACKGROUND: Autism spectrum disorder (ASD) is highly heritable and phenotypically variable. Neuroimaging markers reflecting variation in behavior will provide insights into circuitry subserving core features. We examined functional correlates of ASD symptomology at school-age, while accounting for associated behavioral and cognitive domains, in a longitudinal sample followed from infancy and enriched for those with a genetic liability for ASD. METHODS: Resting state functional connectivity MRIs (fcMRI) and behavioral data were analyzed from 97 school-age children (8.1-12.0 years, 55 males, 15 ASD) with (n = 63) or without (n = 34) a family history of ASD. fcMRI enrichment analysis (EA) was used to screen for associations between network-level functional connectivity and six behaviors of interest in a data-driven manner: social affect, restricted and repetitive behavior (RRB), generalized anxiety, inattention, motor coordination, and matrix reasoning. RESULTS: Functional connectivity between the visual and salience networks was significantly associated with social affect symptoms at school-age after accounting for all other behaviors. Results indicated that stronger connectivity was associated with higher social affect scores. No other behaviors were robustly associated with functional connectivity, though trends were observed between visual-salience connectivity and RRBs. CONCLUSIONS: Connectivity between the visual and salience networks may play an important role in social affect symptom variability among children with ASD and those with genetic liability for ASD. These findings align with and extend earlier reports in this sample of the central role of the visual system during infancy in ASD.
Transcriptomic profiling of unmethylated full mutation carriers implicates TET3 in FMR1 CGG repeat expansion methylation dynamics in fragile X syndrome.
Farmiloe G, Bejczy V, Tabolacci E … +2 more , Willemsen R, Jacobs F
J Neurodev Disord · 2025 Apr · PMID 40287634 · Full text
BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the expansion of a CGG repeat in the 5'UTR of the FMR1 (fragile X messenger ribonucleoprotein 1) gene. Healthy individuals possess a repeat...
BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the expansion of a CGG repeat in the 5'UTR of the FMR1 (fragile X messenger ribonucleoprotein 1) gene. Healthy individuals possess a repeat 30-55 CGG units in length. Once the CGG repeat exceeds 200 copies it triggers methylation at the locus. This methylation covers the FMR1 promoter region and silences expression of the gene and the production of FMRP (fragile X messenger ribonucleoprotein). The loss of FMRP is responsible for a number of pathologies including neurodevelopmental delay and autism spectrum disorder. Methylation of the expanded repeat in the FMR1 locus is the causal factor for FXS, however it is not known why the expanded repeat triggers this epigenetic change or how exactly DNA methylation is established. Intriguingly, genetic engineering of expanded CGG repeats of over 300 copies in the FMR1 locus in mice remains unmethylated. Also in humans, in very rare cases, individuals can have an FMR1 CGG expansion > 200 copies but the locus remains unmethylated. These unmethylated full mutation (UFM) individuals give us a rare opportunity to investigate the mechanism of FMR1 promoter methylation. METHODS: Fibroblasts were obtained from a healthy control, an FXS patient and two unmethylated full expansion carriers. RNA was extracted and comparative transcriptomic analysis was performed on all samples. Whole genome sequencing was carried out on DNA from the two UFM carriers and the results analysed to investigate DNA variants that could explain the observed differences in gene expression. RESULTS: Our analyses focused on genes involved in epigenetic modification. We show that Tet methylcytosine dioxygenase 3 (TET3), a gene involved in DNA methylation, is significantly downregulated in UFM carriers compared to healthy controls or FXS patient derived cells. Genomic analyses reveal a number of rare variants present in the TET3 locus in UFM carriers when compared to the reference genome. However, no clear modifying TET3 variants were identified. CONCLUSION: Our results suggest that TET3 is a candidate factor responsible for the lack of methylation of the expanded FMR1 locus. Further analyses are needed to further elucidate this relationship, however given its potential to directly interact with CGG repeats and its ambiguous role in 5-hydroxy-methylation of CG containing sequences, TET3 is a strong candidate for further exploration.
Psychopharmacology in children with genetic disorders of epigenetic and chromatin regulation.
Lenz S, Sivaloganathan A, Goodman SJ … +4 more , Cytrynbaum C, Rapley J, Canning E, Baribeau D
J Neurodev Disord · 2025 Apr · PMID 40275179 · Full text
OBJECTIVE: Hundreds of rare genetic variants associated with autism or intellectual disability have been identified, and many impact genes known to have a primary epigenetic/chromatin regulatory function. The objective o...
OBJECTIVE: Hundreds of rare genetic variants associated with autism or intellectual disability have been identified, and many impact genes known to have a primary epigenetic/chromatin regulatory function. The objective of this study was to examine and compare behavioural profiles and longitudinal psychotropic treatment patterns in children with epigenetic/chromatin variants, other rare variants impacting neurodevelopment, or no known genetic condition. METHODS: Using electronic medical records from a pediatric psychopharmacology program for children with autism or intellectual disability, we compared clinical characteristics, longitudinal psychotropic medication profiles and side effects between those with and without a rare genetic variant, and by variant subtype [epigenetic/chromatin regulation or other variant]. RESULTS: A total of 331 children attended 2724 unique medical visits between 2019 and 2022, with a mean of 8 follow-up visits over 3.4 years. Nine children (3%) had variants in epigenetic/chromatin regulatory genes (EC), twenty-three children (7%) had other rare genetic variants (OTH), and the rest had no reported variant (NR, n = 299, 90%). Those with a rare genetic variant (EC or OTH) were more likely to have an intellectual disability and had a greater number of co-occurring physical health conditions (p < 0.01). Overall, 66% of psychotropic medications were continued for ≥ 3 visits, while 26% were discontinued. Rates of psychotropic polypharmacy, medication patterns, behavioural challenges, and co-occurring developmental diagnoses were similar between genetic groups. Analyses uncorrected for multiple comparisons suggested those with genetic variants were more likely to experience drowsiness/sedation as a side effect (EC 33%, OTH 35%, NR 16%, p < 0.05); weight gain as a side effect was also higher in the epigenetic/chromatin group (EC 50% vs OTH 11%). CONCLUSION: Genetic classification of neurodevelopmental disorders (NDDs) may help anticipate treatment tolerability; additional prescribing considerations may be needed for those with rare variants. Current psychotropic prescribing practices do not differ across rare genetic NDD subgroups.
Serotonin dysfunction in ADHD.
Jackson EF, Riley TB, Overton PG
J Neurodev Disord · 2025 Apr · PMID 40264019 · Full text
It is well accepted that attention deficit hyperactivity disorder (ADHD) is in part driven by dysfunction in the monoaminergic neurotransmitter system, but both the extent of dysfunction and possible therapeutic avenues...
It is well accepted that attention deficit hyperactivity disorder (ADHD) is in part driven by dysfunction in the monoaminergic neurotransmitter system, but both the extent of dysfunction and possible therapeutic avenues presented by serotonergic neurotransmission is frequently overlooked. As such, we present key evidence for dysfunction in serotonergic transmission, as seen from biochemical, genetic and pharmacological perspectives. An overall deficit in serotonin availability is a common theme throughout the literature, thus this review aims to explore possible dysfunctions in the serotonin synthesis pathway which result in this reduced bioavailability, and investigate whether such dysfunctions could be loci of change in ADHD. We have identified several steps in transmission, namely the conversion of tryptophan to 5-hydroxytryptophan and its use of cofactor tetrahydrobiopterin, which could present promising avenues for development of novel clinical interventions for ADHD.
Behavioral and psychological symptoms of dementia and Alzheimer's disease progression in Down syndrome.
Jenkins MR, Peven JC, Kubic L … +22 more , Handen BL, Krinsky-McHale SJ, Hom CL, Lee A, Tudorascu DL, McLachlan M, Zammit M, Minhas D, Luo W, Laymon C, Lee JH, Lott I, Cohen A, Ances BM, Rosas HD, Lai F, Zaman SH, Head E, Mapstone M, Christian BT, Hartley SL, Alzheimer Biomarker Consortium - Down syndrome
J Neurodev Disord · 2025 Apr · PMID 40217501 · Full text
BACKGROUND: Adults with Down syndrome (DS) have a 90% lifetime risk for Alzheimer's disease (AD), with neurobiological pathology present decades prior to dementia onset. The profile and timing of cognitive decline in DS...
BACKGROUND: Adults with Down syndrome (DS) have a 90% lifetime risk for Alzheimer's disease (AD), with neurobiological pathology present decades prior to dementia onset. The profile and timing of cognitive decline in DS is well-documented. However, there is a small body of research on whether Behavioral and Psychological Symptoms of Dementia (BPSD) occur early on in the progression of AD in DS and are associated with early AD pathology (i.e., amyloid-beta [Aβ] and neurofibrillary tau tangles [NFT]). METHODS: Data were analyzed from 337 adults with DS (M = 45.13 years, SD = 9.53 years) enrolled in a large cohort study. The Reiss Screen for Maladaptive Behavior (RSMB) measured common behaviors reported in BPSD across up to four study cycles (spaced approximately 16 months apart). Linear mixed models estimated change in BPSD as predicted by baseline (a) dementia status (i.e., cognitively stable, mild cognitive impairment [MCI], or dementia), (b) Aβ positron emission tomography (PET) tracer [C] PiB, and (c) NFT PET tracer [F]AV-1451. Models controlled for chronological age, sex, study site, premorbid intellectual disability level, APOE e4 allele carrier status, psychiatric diagnoses, and psychiatric medication use. RESULTS: Compared to cognitively stable participants, participants whose status was MCI or dementia, had significantly higher baseline RSMB subdomain scores. Increases in RSMB Depression-Behavioral, Depression-Physical, and Psychosis were observed for participants with MCI. Higher baseline Aβ and NFT were associated with higher RSMB Avoidant at baseline, and increases in RSMB Depression-Physical and Psychosis over time. CONCLUSIONS: BPSD are an important part of AD in DS, particularly during the prodromal stage. Elevated Aβ and NFT predict higher initial avoidance and change in physical depression behaviors and may indicate MCI in adults with DS. Broader increases in BPSD are observed as adults with DS progress from early to late-stage dementia. Clinicians should rule out other possible causes of BPSD when screening for AD, such as stressful life experiences or co-occurring medical conditions. Caregivers of adults with DS should have resources on BPSD management and self-care strategies.
Brain structure in triple X syndrome: regional gray matter volume and cortical thickness in adult women with 47,XXX karyotype.
Domes G, Croyé MA, Freilinger P … +3 more , Bohlscheid A, Willinek WA, Meyer J
J Neurodev Disord · 2025 Apr · PMID 40170168 · Full text
BACKGROUND: Changes in the brain structure of women with Triple X syndrome (karyotype 47,XXX) have been described in a few studies to date, including reduced total brain volume and regional reductions in gray substance i...
BACKGROUND: Changes in the brain structure of women with Triple X syndrome (karyotype 47,XXX) have been described in a few studies to date, including reduced total brain volume and regional reductions in gray substance in cortical and subcortical areas. However, the empirical evidence from adults is very limited and group comparison on a voxel-wise basis for gray matter volume and cortical thickness is still missing. METHODS: Using voxel-based morphometry (VBM) and surface-based morphometry (SBM), we investigated regional gray matter changes in a sample of n = 20 adult women (aged 18-49 years) with 47,XXX karyotype using T1-weighted 3T MRI scans. RESULTS: Compared to an age- and education-matched control group (and controlled for differences in total intracranial volume), the VBM revealed decreased regional gray matter volumes in the hippocampus, amygdala, parts of the basal ganglia, insula, prefrontal areas and cerebellum. To a lesser extent, we also noted specific reductions in cortical thickness in a smaller part of those regions. CONCLUSION: The observed network is significantly involved in the processing of cognitive, affective, and social stimuli and might be a potential neuronal correlate of the autism-like social-cognitive problems described in 47,XXX in the literature.
Disrupted fetal carbohydrate metabolism in children with autism spectrum disorder.
Gumusoglu SB, Schickling BM, Santillan DA … +2 more , Teesch LM, Santillan MK
J Neurodev Disord · 2025 Mar · PMID 40158086 · Full text
BACKGROUND: Despite the power and promise of early detection and treatment in autism spectrum disorder (ASD), early-life biomarkers are limited. An early-life risk biosignature would advance the field's understanding of...
BACKGROUND: Despite the power and promise of early detection and treatment in autism spectrum disorder (ASD), early-life biomarkers are limited. An early-life risk biosignature would advance the field's understanding of ASD pathogenies and targets for early diagnosis and intervention. We therefore sought to add to the growing ASD biomarker literature and evaluate whether fetal metabolomics are altered in idiopathic ASD. METHODS: Banked cord blood plasma samples (N = 36 control, 16 ASD) were analyzed via gas chromatography and mass spectrometry (GC-MS). Samples were from babies later diagnosed with idiopathic ASD (non-familial, non-syndromic) or matched, neurotypical controls. Metabolite set enrichment analysis (MSEA) and biomarker prediction were performed (MetaboAnalyst). RESULTS: We detected 76 metabolites in all samples. Of these, 20 metabolites differed significantly between groups: 10 increased and 10 decreased in ASD samples relative to neurotypical controls (p < 0.05). MSEA revealed significant changes in metabolic pathways related to carbohydrate metabolism and glycemic control. Untargeted principle components analysis of all metabolites did not reveal group differences, while targeted biomarker assessment (using only Fructose 6-phosphate, D-Mannose, and D-Fructose) by a Random Forest algorithm generated an area under the curve (AUC) = 0.766 (95% CI: 0.612-0.896) for ASD prediction. CONCLUSIONS: Despite a high and increasing prevalence, ASD has no definitive biomarkers or available treatments for its core symptoms. ASD's earliest developmental antecedents remain unclear. We find that fetal plasma metabolomics differ with child ASD status, in particular invoking altered carbohydrate metabolism. While prior clinical and preclinical work has linked carbohydrate metabolism to ASD, no prior fetal studies have reported these disruptions in neonates or fetuses who go on to be diagnosed with ASD. Future work will investigate concordance with maternal metabolomics to determine maternal-fetal mechanisms.
Verbal narrative ability and episodic autobiographical memory in adolescents and young adults with 22q11.2 deletion syndrome.
Mayor C, Husmann J, Benaghmouch S … +3 more , Eliez S, Feller C, Schneider M
J Neurodev Disord · 2025 Mar · PMID 40158074 · Full text
BACKGROUND: Poor episodic autobiographical future thinking has recently been reported in 22q11.2 carriers. However, whether these impairments are due to poor language skills or indicate a true episodic autobiographical m...
BACKGROUND: Poor episodic autobiographical future thinking has recently been reported in 22q11.2 carriers. However, whether these impairments are due to poor language skills or indicate a true episodic autobiographical memory deficit remains unclear. Language impairments are the hallmark of the neuropsychological profile of young children with 22q11DS, but language outcomes in adolescence and young adulthood, especially high-level linguistic skills such as narrative, remain largely unexplored. The aims of this study are first to precisely characterize the narrative abilities of a group of adolescents and young adults with a 22q11DS and normal verbal intellectual functioning, in comparison to a control group. Second, to assess their (past) autobiographical episodic memory and their future episodic thinking abilities. Third, to examine the relationship between linguistic and autobiographical memory skills. METHODS: Fifteen adolescents and young adults with 22q11DS were compared with 15 age- and sex-matched controls. Narrative ability was assessed with a storytelling task and included microstructural, macrostructural, and pragmatic linguistic measures. Episodic autobiographical memory was assessed using a paradigm involving recall of past personal memories and future thinking conditions. RESULTS: Adolescents and young adults with 22q11DS still struggled with high-level language skills such as storytelling tasks, and all linguistic levels were impaired, i.e., the microstructural, macrostructural, and pragmatic components of narrative. Second, 22q11DS carriers showed poor episodic autobiographical recall of their personal memories and reduced access to sensory details (visual, auditory…) compared to controls. Their poor autobiographical episodic memory skills were independent of language impairment, and there were no effects of age or intellectual level on their autobiographical (past) memories recollection. On the other hand, age and verbal intellectual functioning significantly contributed to their ability to produce episodic narratives in the future thinking condition, suggesting that the future thinking task relies on more complex and intricate factors than pure episodic memory ability. CONCLUSIONS: Verbal narrative impairments did not account for poor recall of personal memories, suggesting dysfunctional episodic memory networks between hippocampi and posterior cortical areas in 22q11DS, where neuroanatomical and neurofunctional alterations have indeed been reported.
Modifying quantitative sensory testing to investigate tactile sensory function and behavioral reactivity in children with intellectual and developmental disabilities: establishing feasibility and testing sex, autism, and self-injury effects.
Gunderson J, Worthley E, Byiers B … +6 more , Merbler A, Huebner A, Hofschulte D, Lee J, Riodique C, Symons F
J Neurodev Disord · 2025 Mar · PMID 40148783 · Full text
BACKGROUND: Sensory reactivity differences are common across neurodevelopmental disorders (NDDs), however very few studies specifically examine tactile or pain responses in children with NNDs, especially those with commu...
BACKGROUND: Sensory reactivity differences are common across neurodevelopmental disorders (NDDs), however very few studies specifically examine tactile or pain responses in children with NNDs, especially those with communication challenges. The current study aimed to (a) replicate the feasibility of a modified quantitative sensory test (mQST) with a sample of children with NDDs, (b) assess validity evidence based on behavioral reactivity during mQST application and the corresponding behavioral measurement coding system, and (c) explore group differences in behavioral reactivity to mQST stimuli by demographic (sex), clinical (autism status), and behavioral pathology (self-injury) variables. METHODS: The mQST protocol was implemented and blindly coded across 47 participants aged 2-12 years (M age = 6.7 years, SD = 2.6; 70% male) with NDDs. Feasibility was measured by completion of the mQST protocol and interobserver agreement. Validity was assessed using paired t-tests investigating differences between behavioral reactivity to active stimuli compared to a sham trial. Boxplots were used to visually explore differences in group characteristics (sex, autism status, and self-injurious behavior), with two-sample t-tests used to further characterize differences in SIB group characteristics in behavioral reactivity to mQST stimuli. RESULTS: The mQST provided codable data across 91% of stimuli applications with high IOA (84.7% [76.7-95%]). Behavioral reactivity was significantly higher for active vs. sham stimuli. Children reported to engage in self-injurious behavior showed significantly more reactivity to the second half of the repeated von Frey stimulus application compared to children without caregiver-reported self-injurious behavior (M = 6.14, SD = 3.44), t (40)= -2.247, p =.04). CONCLUSION: The mQST is a feasible approach to investigate tactile reactivity in children with NDDs and complex communication needs. The mQST may be useful in understanding sensory variables in relation to developmental and behavioral outcomes such as self-injurious behavior.
Pubertal developmental, body mass index, and cardiovascular autonomic function in children and adolescents with and without autism spectrum disorder: a four-time point accelerated longitudinal study.
Muscatello RA, Cola M, Vandekar S … +1 more , Corbett BA
J Neurodev Disord · 2025 Mar · PMID 40108514 · Full text
BACKGROUND: The Autonomic Nervous System (ANS) regulates 'automatic' functions such as heart rate, and alterations may have significant impacts on health outcomes. Cardiovascular measures of autonomic function such as he...
BACKGROUND: The Autonomic Nervous System (ANS) regulates 'automatic' functions such as heart rate, and alterations may have significant impacts on health outcomes. Cardiovascular measures of autonomic function such as heart rate variability are of interest as biological markers in autism spectrum disorder (ASD). The interplay between the ANS and physical health establishes a need to examine cardiovascular autonomic functioning in youth with and without ASD over development. The current study aimed to identify change in autonomic function and balance across the parasympathetic and sympathetic branches over time as a function of diagnosis, age, pubertal development, and physical health status. METHODS: The study included 244 ASD (N = 140) or neurotypical (NT) (N = 104) youth, ages 10 to 13 years at enrollment and followed over four years. Resting state autonomic functioning was measured using respiratory sinus arrhythmia (RSA; parasympathetic) and pre-ejection period (PEP; sympathetic). Autonomic balance and regulation were also examined as outcomes. Linear mixed models tested between- and within-group differences in the primary autonomic outcomes as well as the influence of pubertal development, body weight, and medication use. RESULTS: Baseline models showed diagnostic differences, with lower parasympathetic regulation, in youth with ASD, but no differences were observed for the other three outcomes. Adding body mass index (BMI) percentile and medication use removed the statistically significant diagnostic effect, while both variables were significantly related to lower RSA and overall autonomic regulation. Parasympathetic function (RSA) was stable over age and pubertal stage, while a notable decrease in sympathetic control (increased PEP) was found for age and pubertal stage. BMI percentile at enrollment significantly predicted autonomic function, while change in BMI over time did not. CONCLUSIONS: Minimal research to date has explored physical health (e.g., BMI) and autonomic outcomes in ASD. The current study observed few group differences yet demonstrates important effects of physical health on ANS function in both ASD and neurotypical youth. Findings further emphasize a need to focus on individual traits such as BMI and medication use to elucidate the extent to which autonomic differences are related to health status, irrespective of diagnostic category, across the lifespan.
Integrating parent report, observed behavior, and physiological measures to identify biomarkers of sensory over-responsivity in autism.
Chaturvedi A, Ramappa S, Anderson A … +4 more , Banchik M, Shah U, Craske M, Green S
J Neurodev Disord · 2025 Mar · PMID 40097941 · Full text
BACKGROUND: Sensory over-responsivity (SOR) is a heightened reaction to environmental stimuli commonly seen in autism spectrum disorder (ASD) which impacts daily functioning. Parent-reported and observed behavioral asses...
BACKGROUND: Sensory over-responsivity (SOR) is a heightened reaction to environmental stimuli commonly seen in autism spectrum disorder (ASD) which impacts daily functioning. Parent-reported and observed behavioral assessments are used to study SOR, but show limited associations with each other, possibly because they measure different aspects of SOR or because children inhibit their responses during standardized assessments. Physiological measures provide an objective measure of sensory reactivity, and atypical heart rate (HR) responses to aversive stimuli have been shown to be related to SOR in ASD youth. This study aimed to compare how reported and observed measures of SOR predict HR and to examine if the level of reported behavioral inhibition in ASD youth affects how observed SOR behaviors correlate with physiological reactivity. METHODS: Participants were 54 typically developing (TD) and 83 ASD youth, ages 8-17, who completed a standardized behavioral assessment of SOR while electrocardiogram recordings were collected. Participants' parents also reported on their child's SOR symptoms and behavioral inhibition. RESULTS: ASD youth showed lower inter-beat-intervals (IBI; higher HR) across all auditory and tactile stimuli. For ASD youth, parent-reported SOR interacted with observed SOR to predict HR changes across the stimulation periods, indicating that ASD participants whose parents reported they had high SOR in their daily life, and showed high observed SOR in the lab assessment, exhibited reduced HR deceleration (orienting) after the onset of the stimulus and subsequent increased HR acceleration. Finally, we found that ASD participants who had lower parent-reported behavioral inhibition had a stronger correlation between observed SOR behavior and atypical HR responses. CONCLUSIONS: Results support prior findings that increased HR responses to aversive stimuli is related to both ASD and SOR. Furthermore, observed and parent-reported SOR interacted to predict HR, suggesting that a multi-method approach may best capture the extent of SOR for an individual. However, observed SOR measures may be most accurate for ASD youth who are less likely to inhibit their behavioral responses. This study illustrates the importance of integrating multiple measures of sensory reactivity to identify SOR. HR measures of sensory reactivity have the potential to serve as a biomarker of SOR across a diverse range of individuals.
Disrupted visual attention relates to cognitive development in infants with Neurofibromatosis Type 1.
Begum-Ali J, Mason L, Charman T … +5 more , Johnson MH, Green J, Garg S, Jones EJH, and the STAARS and EDEN Teams
J Neurodev Disord · 2025 Mar · PMID 40087579 · Full text
BACKGROUND: Neurofibromatosis Type 1 is a genetic condition diagnosed in infancy that substantially increases the likelihood of a child experiencing cognitive and developmental difficulties, including Autism Spectrum Dis...
BACKGROUND: Neurofibromatosis Type 1 is a genetic condition diagnosed in infancy that substantially increases the likelihood of a child experiencing cognitive and developmental difficulties, including Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). Children with NF1 show clear differences in attention, but whether these differences emerge in early development and how they relate to broader difficulties with cognitive and learning skills is unclear. To address this question requires longitudinal prospective studies from infancy, where the relation between domains of visual attention (including exogenous and endogenous shifting) and cognitive development can be mapped over time. METHODS: We report data from 28 infants with NF1 tested longitudinally at 5, 10 and 14 months compared to cohorts of 29 typical likelihood infants (with no history of NF1 or ASD and/or ADHD), and 123 infants with a family history of ASD and/or ADHD. We used an eyetracking battery to measure both exogenous and endogenous control of visual attention. RESULTS: Infants with NF1 demonstrated intact social orienting, but slower development of endogenous visual foraging. This slower development presented as prolonged engagement with a salient stimulus in a static display relative to typically developing infants. In terms of exogenous attention shifting, NF1 infants showed faster saccadic reaction times than typical likelihood infants. However, the NF1 group demonstrated a slower developmental improvement from 5 to 14 months of age. Individual differences in foraging and saccade times were concurrently related to visual reception abilities within the full infant cohort (NF1, typical likelihood and those with a family history of ASD/ADHD). CONCLUSIONS: Our results provide preliminary evidence that alterations in saccadic reaction time and visual foraging may contribute to learning difficulties in infants with NF1.
Differences in sleep EEG coherence and spindle metrics in toddlers with and without receptive/expressive language delay: a prospective observational study.
Hong X, Farmer C, Kozhemiako N … +5 more , Holmes GL, Thompson L, Manwaring S, Thurm A, Buckley A
J Neurodev Disord · 2025 Feb · PMID 39987026 · Full text
BACKGROUND: Changes in brain connectivity during development are thought to reflect organizational and maturational processes that correspond to skill acquisition in domains like motor, language, and cognition. This theo...
BACKGROUND: Changes in brain connectivity during development are thought to reflect organizational and maturational processes that correspond to skill acquisition in domains like motor, language, and cognition. This theory is supported by findings in typically developing children as well as observations of abnormal connectivity among children with neurodevelopmental differences. However, few coherence studies have capitalized on the potential of sleep electroencephalogram (EEG) to examine the developing brain, especially among very young children for whom formal neurodevelopmental diagnosis is not yet possible. Sleep microarchitecture in young children may offer key insights into neurophysiological abnormalities associated with neurodevelopmental trajectories and potentially aid in early detection and intervention. In this study, we explored sleep EEG coherence and sleep spindles in typically developing toddlers and toddlers at increased risk of later neurodevelopmental diagnoses. METHODS: We investigated EEG coherence and sleep spindles in 16 toddlers with receptive and expressive language delay (LangD) and 39 typically developing (TD) toddlers. Participants were aged 12-22 months at baseline, and 34 (LangD, n=11; TD, n=23) participants were evaluated again at 36 months of age. RESULTS: Average EEG coherence was stronger in the LangD group than the TD group, with differences most prominent during slow-wave sleep. Some age-related increases in coherence were observed, but these did not differ between groups. Sleep spindle density, duration, and frequency changed between baseline and follow-up for both groups, with the LangD group demonstrating a smaller magnitude of change than the TD group. The direction of change was frequency band-dependent for both groups. CONCLUSIONS: These findings indicate that atypical sleep EEG connectivity and sleep spindle development can be detected in toddlers at risk of later neurodevelopmental diagnoses. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT01339767 ; Registration date: 4/20/2011.
DNA methylation biomarkers of intellectual/developmental disability across the lifespan.
LaSalle JM
J Neurodev Disord · 2025 Feb · PMID 39972408 · Full text
Epigenetic mechanisms, including DNA methylation, act at the interface of genes and environment by allowing a static genome to respond and adapt to a dynamic environment during the lifespan of an individual. Genome-wide...
Epigenetic mechanisms, including DNA methylation, act at the interface of genes and environment by allowing a static genome to respond and adapt to a dynamic environment during the lifespan of an individual. Genome-wide DNA methylation analyses on a wide range of human biospecimens are beginning to identify epigenetic biomarkers that can predict risk of intellectual/developmental disabilities (IDD). DNA methylation-based epigenetic signatures are becoming clinically useful in categorizing benign from pathogenic genetic variants following exome sequencing. While DNA methylation marks differ by tissue source, recent studies have shown that accessible perinatal tissues, such as placenta, cord blood, newborn blood spots, and cell free DNA may serve as accessible surrogate tissues for testing epigenetic biomarkers relevant to understanding genetic, environmental, and gene by environment interactions on the developing brain. These DNA methylation signatures may also provide important information about the biological pathways that become dysregulated prior to disease progression that could be used to develop early pharmacological interventions. Future applications could involve preventative screenings using DNA methylation biomarkers during pregnancy or the newborn period for IDDs and other neurodevelopmental disorders. DNA methylation biomarkers in adolescence and adulthood are also likely to be clinically useful for tracking biological aging or co-occurring health conditions that develop across the lifespan. In conclusion, DNA methylation biomarkers are expected to become more common in clinical diagnoses of IDD, to improve understanding of complex IDD etiologies, to improve endpoints for clinical trials, and to monitor potential health concerns for individuals with IDD as they age.
Atypical audio-visual neural synchrony and speech processing in early autism.
Wang X, Bouton S, Kojovic N … +2 more , Giraud AL, Schaer M
J Neurodev Disord · 2025 Feb · PMID 39966708 · Full text
BACKGROUND: Children with Autism Spectrum disorder (ASD) often exhibit communication difficulties that may stem from basic auditory temporal integration impairment but also be aggravated by an audio-visual integration de...
BACKGROUND: Children with Autism Spectrum disorder (ASD) often exhibit communication difficulties that may stem from basic auditory temporal integration impairment but also be aggravated by an audio-visual integration deficit, resulting in a lack of interest in face-to-face communication. This study addresses whether speech processing anomalies in young autistic children (mean age 3.09-year-old) are associated with alterations of audio-visual temporal integration. METHODS: We used high-density electroencephalography (HD-EEG) and eye tracking to record brain activity and gaze patterns in 31 children with ASD (6 females) and 33 typically developing (TD) children (11 females), while they watched cartoon videos. Neural responses to temporal audio-visual stimuli were analyzed using Temporal Response Functions model and phase analyses for audiovisual temporal coordination. RESULTS: The reconstructability of speech signals from auditory responses was reduced in children with ASD compared to TD, but despite more restricted gaze patterns in ASD it was similar for visual responses in both groups. Speech reception was most strongly affected when visual speech information was also present, an interference that was not seen in TD children. These differences were associated with a broader phase angle distribution (exceeding pi/2) in the EEG theta range in children with ASD, signaling reduced reliability of audio-visual temporal alignment. CONCLUSION: These findings show that speech processing anomalies in ASD do not stand alone and that they are associated already at a very early development stage with audio-visual imbalance with poor auditory response encoding and disrupted audio-visual temporal coordination.
The striatal matrix compartment is expanded in autism spectrum disorder.
Waugh JL, Hassan AOA, Funk AT … +1 more , Maldjian JA
J Neurodev Disord · 2025 Feb · PMID 39955485 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is the second-most common neurodevelopmental disorder in childhood. This complex developmental disorder manifests with restricted interests, repetitive behaviors, and difficulti...
BACKGROUND: Autism spectrum disorder (ASD) is the second-most common neurodevelopmental disorder in childhood. This complex developmental disorder manifests with restricted interests, repetitive behaviors, and difficulties in communication and social awareness. The inherited and acquired causes of ASD impact many and diverse brain regions, challenging efforts to identify a shared neuroanatomical substrate for this range of symptoms. The striatum and its connections are among the most implicated sites of abnormal structure and/or function in ASD. Striatal projection neurons develop in segregated tissue compartments, the matrix and striosome, that are histochemically, pharmacologically, and functionally distinct. Immunohistochemical assessment of ASD and animal models of autism described abnormal matrix:striosome volume ratios, with an possible shift from striosome to matrix volume. Shifting the matrix:striosome ratio could result from expansion in matrix, reduction in striosome, spatial redistribution of the compartments, or a combination of these changes. Each type of ratio-shifting abnormality may predispose to ASD but yield different combinations of ASD features. METHODS: We developed a cohort of 426 children and adults (213 matched ASD-control pairs) and performed connectivity-based parcellation (diffusion tractography) of the striatum. This identified voxels with matrix-like and striosome-like patterns of structural connectivity. RESULTS: Matrix-like volume was increased in ASD, with no evident change in the volume or organization of the striosome-like compartment. The inter-compartment volume difference (matrix minus striosome) within each individual was 31% larger in ASD. Matrix-like volume was increased in both caudate and putamen, and in somatotopic zones throughout the rostral-caudal extent of the striatum. Subjects with moderate elevations in ADOS (Autism Diagnostic Observation Schedule) scores had increased matrix-like volume, but those with highly elevated ADOS scores had 3.7-fold larger increases in matrix-like volume. CONCLUSIONS: Matrix and striosome are embedded in distinct structural and functional networks, suggesting that compartment-selective injury or maldevelopment may mediate specific and distinct clinical features. Previously, assessing the striatal compartments in humans required post mortem tissue. Striatal parcellation provides a means to assess neuropsychiatric diseases for compartment-specific abnormalities. While this ASD cohort had increased matrix-like volume, other mechanisms that shift the matrix:striosome ratio may also increase the chance of developing the diverse social, sensory, and motor phenotypes of ASD.
An exploratory fetal MRI study examining the impact of 22q11.2 microdeletion syndrome on early brain growth.
Cromb D, Finck T, Bonthrone AF … +8 more , Uus A, Van Poppel M, Steinweg J, Lloyd DF, Pushparajah K, Razavi R, Counsell SJ, Rutherford M
J Neurodev Disord · 2025 Feb · PMID 39939911 · Full text
BACKGROUND: Improved long-term outcomes, related to advances in surgical and clinical care of infants with congenital heart disease (CHD), has shifted focus onto the accompanying and later-onset cognitive and neuropsychi...
BACKGROUND: Improved long-term outcomes, related to advances in surgical and clinical care of infants with congenital heart disease (CHD), has shifted focus onto the accompanying and later-onset cognitive and neuropsychiatric disorders in those who also have 22q11.2 deletion syndrome (22qDS). 22qDS is itself associated with neurodevelopmental impairments and altered brain growth. However, when brain growth in 22qDS first deviates from normal is unknown, and whether impaired brain development is primarily genetics-driven or a secondary consequence of the underlying CHD remains incompletely understood. METHODS: In this small, exploratory study, we use fetal MRI to assess volumetric brain development in 22qDS by comparing fetal brain morphometry to a set of gestation and sex-matched healthy controls, and a cohort of gestation and sex-matched fetuses with the same CHD diagnoses but without 22q11.2 deletion. Structural T2-weighted fetal brain images were acquired using a 1.5T MRI scanner. MR scanner and sequence parameters were identical in all cohorts. Motion-corrected images underwent segmentation using an automated pipeline developed for fetal brain MRI. Total brain tissue volumes, volumes for four different tissue regions (cortical grey matter, white matter, deep grey matter and cerebellum), cerebrospinal fluid and total intracranial volumes were calculated. RESULTS: Antenatal imaging was acquired between 29 and 35 weeks gestation. Thirty-three fetuses were included (7 22qDS; 14 isolated CHD; 12 healthy control). White matter volumes were significantly reduced in fetuses with 22qDS compared to control fetuses (p = 0.028), but not to those with CHD without 22q11.2 deletion (p = 0.09). Large effect-sizes were seen between the 22qDS and isolated CHD cohorts (D = 0.81), and between the 22qDS and control cohorts (D = 1.2) for white matter volumes. No significant differences were seen in volumes of other brain regions between groups. CONCLUSIONS: This exploratory study expands our existing knowledge on neurodevelopmental impairments in 22qDS to the fetal period by highlighting reduced white matter volumes compared to gestation and sex-matched control fetuses during this time-period. Our findings suggest that impaired white matter growth in fetuses with both 22qDS and CHD may not be fully explained by any underlying CHD.
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