J Neurodev Disord [JOURNAL]
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200 papers
Validation of the Food Safe Zone questionnaire for families of individuals with Prader-Willi syndrome.
Dykens EM, Roof E, Hunt-Hawkins H … +1 more , Strong TV
J Neurodev Disord · 2025 Feb · PMID 39923017 · Full text
BACKGROUND: Prader-Willi syndrome (PWS), a genetic neurodevelopmental disorder, is characterized by hyperphagia and significant behavioral problems. Hyperphagic individuals with PWS are chronically hungry yet rarely feel...
BACKGROUND: Prader-Willi syndrome (PWS), a genetic neurodevelopmental disorder, is characterized by hyperphagia and significant behavioral problems. Hyperphagic individuals with PWS are chronically hungry yet rarely feel sated, and often engage in food-seeking behaviors. To avoid life-threatening obesity in their children, families implement food security strategies (e.g., locking food sources, constant supervision around food, alerting others). Although widely used, these strategies have yet to be systematically examined. We thus developed and analyzed the psychometric properties of a new measure of these diverse strategies, the Food Safe Zone, and evaluated them in relation to hyperphagic symptoms and demographic variables. In doing so, we also shine a light on the extraordinary efforts of families in managing their children's hyperphagia. METHODS: Our team developed 20 FSZ items that were revised for clarity and completeness in an iterative feedback process with stakeholders, including parents, PWS specialists, and individuals with PWS. The FSZ was pilot tested, descriptive findings were reviewed by additional stakeholders, and then administered to 624 parents in a large-scale study. Based on an open-ended question, "Is there anything else you do to ensure food safety?" two additional items were added and evaluated in a follow-up study. RESULTS: Principal component analyses revealed that 21 FSZ items loaded onto 5 factors that were readily interpretable, accounting for 67% of test variance: Alerting Others and Food Supervision in the Community; Locking or Restricting Food Sources; Checking for Food; At Home Supervision and Meals; and Avoiding Food Settings. Internal consistency and test-rest reliability were robust. Convergent validity analyses revealed that parents implemented FSZ strategies in response to the severity of their child's hyperphagia, and not their child's age, gender or PWS genetic subtype. CONCLUSIONS: The psychometrically sound FSZ holds promise for future research, especially on the effects of food safety tactics on family members. In future clinical trials, the FSZ could also be used to help parents think critically about their food safety tactics in relation to their child's hyperphagia, or as an exploratory endpoint; if hyperphagia is lessened, so too may food safety tactics, thereby enhancing familial quality of life.
Regional hippocampal thinning and gyrification abnormalities and associated cognition in children with prenatal alcohol exposure.
Gimbel BA, Wozniak JR, Mueller BA … +6 more , Tuominen KA, Ernst AM, Anthony ME, de Water E, CIFASD, Roediger DJ
J Neurodev Disord · 2025 Feb · PMID 39910445 · Full text
BACKGROUND: Prenatal alcohol exposure (PAE) impacts hippocampal structure and function, contributing to deficits in memory and decision-making in affected individuals. Here, we evaluate hippocampal anomalies in children...
BACKGROUND: Prenatal alcohol exposure (PAE) impacts hippocampal structure and function, contributing to deficits in memory and decision-making in affected individuals. Here, we evaluate hippocampal anomalies in children with PAE and an unexposed comparison group using advanced MRI methods that characterize hippocampal curvature and thickness. METHODS: Participants, ages 8 to 16 years, included children with PAE (n = 48) and an unexposed comparison group (n = 46) who underwent a dysmorphology exam, neuropsychological assessment, and an MRI scan. Height, weight, head circumference, and dysmorphic facial features were evaluated. Of those with PAE, 4.2% had fetal alcohol syndrome (FAS), 22.9% had partial FAS, and 72.9% had alcohol-related neurodevelopmental disorder. Neuropsychological testing included measures of intelligence and memory functioning. T1-weighted anatomical data were processed with the Hippunfold pipeline, which "unfolds" the complex hippocampal structure onto a template surface and provides measures of thickness and gyrification/curvature at each vertex. Permutation Analysis of Linear Models (PALM) was used to test for group differences (PAE vs. comparison) in hippocampal thickness and gyrification at each vertex and also to assess correlations with cognitive functioning. RESULTS: There were significant regional differences in thickness and gyrification across bilateral hippocampi, with the PAE group showing substantially thinner tissue and less curvature than the comparison group, especially in CA1 and subiculum regions. For those with PAE, thinner subicular tissue (bilateral) was associated with lower IQ. Also in the PAE group, lower episodic memory performance was associated with thinness in the right hippocampus, especially in the subiculum region. There were no significant regional hippocampal patterns that were associated with cognitive functioning for individuals in the unexposed comparison group. CONCLUSIONS: We used a novel MRI method to evaluate hippocampal structure in children with PAE and an unexposed comparison group. The data suggest that PAE disrupts hippocampal development, impacting both the early-stage folding of the structure and its ultimate thickness. The data also demonstrate that these developmental anomalies have functional consequences in terms of core memory functions as well as global intellectual functioning in children with PAE.
Reduced white matter integrity and disrupted brain network in children with type 2 and 3 spinal muscular atrophy.
Nie H, Lan S, Wang H … +9 more , Xiang P, Yan M, Fan Y, Shen W, Li Y, Tang W, Yang Z, Liang Y, Chen Y
J Neurodev Disord · 2025 Jan · PMID 39856544 · Full text
BACKGROUND: Spinal muscular atrophy (SMA) is caused by reduced expression of survival motor neuron (SMN) protein. Previous studies indicated SMA causes not only lower motor neuron degeneration but also extensive brain in...
BACKGROUND: Spinal muscular atrophy (SMA) is caused by reduced expression of survival motor neuron (SMN) protein. Previous studies indicated SMA causes not only lower motor neuron degeneration but also extensive brain involvement. This study aimed to investigate the changes of brain white matter and structural network using diffusion tensor imaging (DTI) in children with type 2 and 3 SMA. METHODS: Forty-two type 2 and 3 pediatric SMA patients and 42 age- and gender-matched healthy controls (HC) were prospectively enrolled in this study. The tract-based spatial statistics (TBSS) was used to assess white matter integrity and the structural network properties were calculated based on DTI white matter fiber tracking and the graph theory approach. A partial correlation was performed to explore the relationship between white matter parameters and clinical characteristics. RESULTS: In total, 42 patients (mean age, 10.86 ± 4.07 years; 23 men) were included. TBSS analysis revealed widespread white matter changes in SMA patients. The SMA patients showed changes in multiple small-world and network efficiency parameters. Compared to the HC group, SMA showed increased characteristic path length (L), normalized clustering coefficient (γ), small-world characteristic (σ), and decreased global efficiency (E) (all p < 0.05). In the node properties, right supramarginal gyrus, right orbital part of superior frontal gyrus, right supplementary motor area, and left median cingulate and paracingulate gyri changed in SMA patients. A decreased axial diffusivity (AD) value was associated with lower Hammersmith Functional Motor Scale-Expanded scores (r = 0.45, p = 0.02), which means that the symptoms of SMA patients are more severe. CONCLUSIONS: This study found white matter and DTI-based brain network abnormalities in SMA patients, suggesting SMN protein deficiency may affect white matter development.
A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome.
Campbell K, Neul JL, Lieberman DN … +9 more , Berry-Kravis E, Benke TA, Fu C, Percy A, Suter B, Morris D, Carpenter RL, Marsh ED, von Hehn J
J Neurodev Disord · 2025 Jan · PMID 39856538 · Full text
BACKGROUND: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies ha...
BACKGROUND: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy. DESIGN: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy. METHODS: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity. RESULTS: Twenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019-11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine. CONCLUSIONS: Short-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT. TRIAL REGISTRATION: Registered at clinicaltrials.gov NCT03633058.
Resting state EEG in young children with Tuberous Sclerosis Complex: associations with medications and seizures.
Clements CC, Engelstad AM, Wilkinson CL … +6 more , Hyde C, Hartney M, Simmons A, Tager-Flusberg H, Jeste S, Nelson CA
J Neurodev Disord · 2025 Jan · PMID 39827117 · Full text
BACKGROUND: Tuberous Sclerosis Complex (TSC) is a rare genetic condition caused by mutation to TSC1 or TSC2 genes, with a population prevalence of 1/7000 births. TSC manifests behaviorally with features of autism, epilep...
BACKGROUND: Tuberous Sclerosis Complex (TSC) is a rare genetic condition caused by mutation to TSC1 or TSC2 genes, with a population prevalence of 1/7000 births. TSC manifests behaviorally with features of autism, epilepsy, and intellectual disability. Resting state electroencephalography (EEG) offers a window into neural oscillatory activity and may serve as an intermediate biomarker between gene expression and behavioral manifestations. Such a biomarker could be useful in clinical trials as an endpoint or predictor of treatment response. However, seizures and antiepileptic medications also affect resting neural oscillatory activity and could undermine the utility of resting state EEG features as biomarkers in neurodevelopmental disorders such as TSC. METHODS: This paper compares resting state EEG features in a cross-sectional cohort of young children with TSC (n = 49, ages 12-37 months) to 49 age- and sex-matched typically developing controls. Within children with TSC, associations were examined between resting state EEG features, seizure severity composite score, and use of GABA agonists. RESULTS: Compared to matched typically developing children, children with TSC showed significantly greater beta power in permutation cluster analyses. Children with TSC also showed significantly greater aperiodic offset (reflecting nonoscillatory neuronal firing) after power spectra were parameterized using SpecParam into aperiodic and periodic components. Within children with TSC, both greater seizure severity and use of GABAergic antiepileptic medication were significantly and independently associated with increased periodic peak beta power. CONCLUSIONS: The elevated peak beta power observed in children with TSC compared to matched typically developing controls may be driven by both seizures and GABA agonist use. It is recommended to collect seizure and medication data alongside EEG data for clinical trials. These results highlight the challenge of using resting state EEG features as biomarkers in trials with neurodevelopmental disabilities when epilepsy and anti-epileptic medication are common.
Acute administration of NLX-101, a Serotonin 1A receptor agonist, improves auditory temporal processing during development in a mouse model of Fragile X Syndrome.
Tao X, Croom K, Newman-Tancredi A … +2 more , Varney M, Razak KA
J Neurodev Disord · 2025 Jan · PMID 39754065 · Full text
BACKGROUND: Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent and debilitating phenotype of FXS is auditory hypers...
BACKGROUND: Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent and debilitating phenotype of FXS is auditory hypersensitivity that may lead to delayed language and high anxiety. Consistent with findings in FXS human studies, the mouse model of FXS, the Fmr1 knock out (KO) mouse, shows auditory hypersensitivity and temporal processing deficits. In electroencephalograph (EEG) recordings from humans and mice, these deficits manifest as increased N1 amplitudes in event-related potentials (ERP), increased gamma band single trial power (STP) and reduced phase locking to rapid temporal modulations of sound. In our previous study, we found that administration of the selective serotonin-1 A (5-HT)receptor biased agonist, NLX-101, protected Fmr1 KO mice from auditory hypersensitivity-associated seizures. Here we tested the hypothesis that NLX-101 will normalize EEG phenotypes in developing Fmr1 KO mice. METHODS: To test this hypothesis, we examined the effect of NLX-101 on EEG phenotypes in male and female wildtype (WT) and Fmr1 KO mice. Using epidural electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at two ages, postnatal (P) 21 and 30 days, from both auditory and frontal cortices of awake, freely moving mice, following NLX-101 (at 1.8 mg/kg i.p.) or saline administration. RESULTS: Saline-injected Fmr1 KO mice showed increased N1 amplitudes, increased STP and reduced phase locking to auditory gap-in-noise stimuli versus wild-type mice, reproducing previously published EEG phenotypes. An acute injection of NLX-101 did not alter ERP amplitudes at either P21 or P30, but significantly reduces STP at P30. Inter-trial phase clustering was significantly increased in both age groups with NLX-101, indicating improved temporal processing. The differential effects of serotonin modulation on ERP, background power and temporal processing suggest different developmental mechanisms leading to these phenotypes. CONCLUSIONS: These results suggest that NLX-101 could constitute a promising treatment option for targeting post-synaptic 5-HT receptors to improve auditory temporal processing, which in turn may improve speech and language function in FXS.
Objective approach to diagnosing attention deficit hyperactivity disorder by using pixel subtraction and machine learning classification of outpatient consultation videos.
Chiu YH, Lee YH, Wang SY … +4 more , Ouyang CS, Wu RC, Yang RC, Lin LC
J Neurodev Disord · 2024 Dec · PMID 39716052 · Full text
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder, affecting between 5% and 7% of school-age children. ADHD is typically characterized by persistent patterns of...
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder, affecting between 5% and 7% of school-age children. ADHD is typically characterized by persistent patterns of inattention or hyperactivity-impulsivity, and it is diagnosed on the basis of the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, through subjective observations and information provided by parents and teachers. Diagnosing ADHD in children is challenging, despite several assessment tools, such as the Swanson, Nolan, and Pelham questionnaire, being widely available. Such scales provide only a subjective understanding of the disorder. In this study, we employed video pixel subtraction and machine learning classification to objectively categorize 85 participants (43 with a diagnosis of ADHD and 42 without) into an ADHD group or a non-ADHD group by quantifying their movements. METHODS: We employed pixel subtraction movement quantization by analyzing movement features in videos of patients in outpatient consultation rooms. Pixel subtraction is a technique in which the number of pixels in one frame is subtracted from that in another frame to detect changes between the two frames. A difference between the pixel values indicates the presence of movement. In the current study, the patients' subtracted image sequences were characterized using three movement feature values: mean, variance, and Shannon entropy value. A classification analysis based on six machine learning models was performed to compare the performance indices and the discriminatory power of various features. RESULTS: The results revealed that compared with the non-ADHD group, the ADHD group had significantly larger values for all movement features. Notably, the Shannon entropy values were 2.38 ± 0.59 and 1.0 ± 0.38 in the ADHD and non-ADHD groups, respectively (P < 0.0001). The Random Forest machine learning classification model achieved the most favorable results, with an accuracy of 90.24%, sensitivity of 88.85%, specificity of 91.75%, and area under the curve of 93.87%. CONCLUSION: Our pixel subtraction and machine learning classification approach is an objective and practical method that can aid to clinical decisions regarding ADHD diagnosis.
Brain volumes, cognitive, and adaptive skills in school-age children with Down syndrome.
Grzadzinski R, Mata K, Bhatt AS … +21 more , Jatkar A, Garic D, Shen MD, Girault JB, St John T, Pandey J, Zwaigenbaum L, Estes A, Shen AM, Dager S, Schultz R, Botteron K, Marrus N, Styner M, Evans A, Kim SH, McKinstry R, Gerig G, Piven J, Hazlett H, IBIS Network
J Neurodev Disord · 2024 Dec · PMID 39701965 · Full text
BACKGROUND: Down syndrome (DS) is the most common congenital neurodevelopmental disorder, present in about 1 in every 700 live births. Despite its prevalence, literature exploring the neurobiology underlying DS and how t...
BACKGROUND: Down syndrome (DS) is the most common congenital neurodevelopmental disorder, present in about 1 in every 700 live births. Despite its prevalence, literature exploring the neurobiology underlying DS and how this neurobiology is related to behavior is limited. This study fills this gap by examining cortical volumes and behavioral correlates in school-age children with DS. METHODS: School-age children (mean = 9.7 years ± 1.1) underwent comprehensive assessments, including cognitive and adaptive assessments, as well as an MRI scan without the use of sedation. Children with DS (n = 35) were compared to available samples of typically developing (TD; n = 80) and ASD children (n = 29). ANOVAs were conducted to compare groups on cognitive and adaptive assessments. ANCOVAs (covarying for age, sex, and total cerebral volume; TCV) compared cortical brain volumes between groups. Correlations between behavioral metrics and cortical and cerebellar volumes (separately for gray (GM) and white matter (WM)) were conducted separately by group. RESULTS: As expected, children with DS had significantly lower cognitive skills compared to ASD and TD children. Daily Living adaptive skills were comparable between ASD children and children with DS, and both groups scored lower than TD children. Children with DS exhibited a smaller TCV compared to ASD and TD children. Additionally, when controlling for TCV, age, and sex, children with DS had significantly smaller total GM and tissue volumes. Cerebellum volumes were significantly correlated with Daily Living adaptive behaviors in the DS group only. CONCLUSIONS: Despite children with DS exhibiting lower cognitive skills and smaller brain volume overall than children with ASD, their deficits in Socialization and Daily Living adaptive skills are comparable. Differences in lobar volumes (e.g., Right Frontal GM/WM, Left Frontal WM, and Left and Right Temporal WM) were observed above and beyond overall differences in total volume. The correlation between cerebellum volumes and Daily Living adaptive behaviors in the DS group provides a novel area to explore in future research.
Effects of elastic therapeutic taping on reducing drooling in children with neurological disorders: a systematic review of randomized controlled trials.
Lam KTT, Hung ATW, Lau K … +1 more , Lee EKP
J Neurodev Disord · 2024 Dec · PMID 39701960 · Full text
BACKGROUND & AIMS: Effective treatment for anterior drooling in children with neurological disorders can lead to improved social interactions, reduced physical complications such as perioral infections, and enhanced qual...
BACKGROUND & AIMS: Effective treatment for anterior drooling in children with neurological disorders can lead to improved social interactions, reduced physical complications such as perioral infections, and enhanced quality of life for both patients and their parents. Elastic therapeutic taping (ETT) has emerged a novel intervention for drooling, but its evidence was limited. This study systematically reviewed the effectiveness of ETT on reducing anterior drooling in children with neurological disorders. METHODS: Multiple electronic databases, such as Ovid MEDLINE, Embase, and Cochrane Library were searched from inception till 30th October 2024. Randomized controlled trials (RCTs) were included if they: (a) used ETT as a treatment for drooling or swallowing difficulties; (b) included participants aged < 18 years old; (c) included participants with anterior drooling and neurological disorders; (d) compared effects of ETT alone or combined with other treatments (e.g. oral motor therapy (OMT)) with no taping, sham taping or other treatments, and (e) published in English. The Cochrane Risk-of-Bias tool was used to assess risk of bias for the included studies. RESULTS: Seven parallel-arm RCTs, which were conducted in South/southwest Asia, Africa, South America and Middle East, were included. In total, 220 children aged 1 to 11 were included, of which 97 received solely ETT in 4 studies, while 24 received ETT plus OMT in 2 studies. ETT combined with OMT was more effective in reducing drooling in the included 2 RCTs, though the results of ETT alone were inconsistent, likely due to heterogeneity observed in control conditions, application methods, and outcome measures. No side effects were reported in all studies. CONCLUSIONS: This review suggests that ETT combined with OMT is effective in reducing drooling in children with neurological disorders, with no evidence of side effects. TRIAL REGISTRATION: (PROSPERO no.: CRD42023488664).
Specialization of the brain for language in children with Fragile X Syndrome: a functional Near Infrared Spectroscopy study.
Smith E, Dominick KC, Schmitt LM … +2 more , Pedapati EV, Erickson CA
J Neurodev Disord · 2024 Dec · PMID 39701935 · Full text
Specialization of the brain for language is early emerging and essential for language learning in young children. Fragile X Syndrome (FXS) is a neurogenetic disorder marked by high rates of delays in both expressive and...
Specialization of the brain for language is early emerging and essential for language learning in young children. Fragile X Syndrome (FXS) is a neurogenetic disorder marked by high rates of delays in both expressive and receptive language, but neural activation patterns during speech and language processing are unknown. We report results of a functional Near Infrared Spectroscopy (fNIRS) study of responses to speech and nonspeech sounds in the auditory cortex in a sample of 2- to 10-year-old children with FXS and typically developing controls (FXS n = 23, TDC n = 15, mean age = 6.44 and 7.07 years, respectively). Specifically, we measured changes in oxygenated and deoxygenated hemoglobin in the auditory cortex during blocks of speech and nonspeech matched noise in children with FXS and sex-and-age-matched controls. Similar to controls, children with FXS showed hemodynamic change consistent with neural activation of the primary auditory regions for speech as well as leftward lateralization for speech sound processing, strength of which was associated with higher verbal abilities in FXS. However, while controls showed neural differentiation of speech and nonspeech in the left auditory cortex, children with FXS did not demonstrate differentiation of the two conditions in this study. In addition, the children with FXS showed a greater neural activation to the nonspeech condition overall. Overall, these results suggest that basic patterns of neural activation for speech are present in FXS in childhood, but neural response to nonspeech sounds may differ in FXS when compared to controls.
Attenuated processing of vowels in the left temporal cortex predicts speech-in-noise perception deficit in children with autism.
Fadeev KA, Romero Reyes IV, Goiaeva DE … +8 more , Obukhova TS, Ovsiannikova TM, Prokofyev AO, Rytikova AM, Novikov AY, Kozunov VV, Stroganova TA, Orekhova EV
J Neurodev Disord · 2024 Dec · PMID 39643915 · Full text
BACKGROUND: Difficulties with speech-in-noise perception in autism spectrum disorders (ASD) may be associated with impaired analysis of speech sounds, such as vowels, which represent the fundamental phoneme constituents...
BACKGROUND: Difficulties with speech-in-noise perception in autism spectrum disorders (ASD) may be associated with impaired analysis of speech sounds, such as vowels, which represent the fundamental phoneme constituents of human speech. Vowels elicit early (< 100 ms) sustained processing negativity (SPN) in the auditory cortex that reflects the detection of an acoustic pattern based on the presence of formant structure and/or periodic envelope information (f0) and its transformation into an auditory "object". METHODS: We used magnetoencephalography (MEG) and individual brain models to investigate whether SPN is altered in children with ASD and whether this deficit is associated with impairment in their ability to perceive speech in the background of noise. MEG was recorded while boys with ASD and typically developing boys passively listened to sounds that differed in the presence/absence of f0 periodicity and formant structure. Word-in-noise perception was assessed in the separate psychoacoustic experiment using stationary and amplitude modulated noise with varying signal-to-noise ratio. RESULTS: SPN was present in both groups with similarly early onset. In children with ASD, SPN associated with processing formant structure was reduced predominantly in the cortical areas lateral to and medial to the primary auditory cortex, starting at ~ 150-200 ms after the stimulus onset. In the left hemisphere, this deficit correlated with impaired ability of children with ASD to recognize words in amplitude-modulated noise, but not in stationary noise. CONCLUSIONS: These results suggest that perceptual grouping of vowel formants into phonemes is impaired in children with ASD and that, in the left hemisphere, this deficit contributes to their difficulties with speech perception in fluctuating background noise.
Cortical Vision Impairment (CVI)-informed assessment and treatment of challenging behavior in a child with SCN2A-related disorder.
Thomas BR, Ludwig NN, Pelletier D … +4 more , Bauer M, Hommer R, Smith-Hicks C, O'Connor JT
J Neurodev Disord · 2024 Nov · PMID 39609790 · Full text
This report presents results of parent-implemented behavioral treatments for a child with cortical visual impairment (CVI), intellectual disability (ID), epilepsy, and autism spectrum disorder (ASD) associated with a pat...
This report presents results of parent-implemented behavioral treatments for a child with cortical visual impairment (CVI), intellectual disability (ID), epilepsy, and autism spectrum disorder (ASD) associated with a pathogenic variant in the SCN2A gene (i.e., SCN2A-Related Disorder). Treatment evaluations were informed by combined results of functional behavior assessment (FBA) and functional vision assessment (FVA) which yielded CVI-related accommodations. The treatment of escape-maintained challenging behavior involved the evaluation of behavioral prompting strategies in accordance with CVI-related accommodations, extinction (EXT), and differential reinforcement modifications. The treatment for behavior problems maintained by access to food (tangible-edible) included functional communication training (FCT), EXT, and schedule thinning with schedule-correlated visual signals. Overall, integrating child-specific CVI-related accommodations was essential for developing effective behavioral interventions for this child. FVAs are accessible and practical for uptake by behavior analysts in vision-informed assessment and treatment of challenging behavior.
Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.
Mottolese N, Loi M, Trazzi S … +6 more , Tassinari M, Uguagliati B, Candini G, Iqbal K, Medici G, Ciani E
J Neurodev Disord · 2024 Nov · PMID 39592934 · Full text
BACKGROUND: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absenc...
BACKGROUND: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer's disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD. METHODS: We used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects. RESULTS: We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit. CONCLUSIONS: At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.
Investigating social orienting in children with Phelan-McDermid syndrome and 'idiopathic' autism.
San José Cáceres A, Wilkinson E, Cooke J … +11 more , Baskett V, Blackmore C, Crawley DV, Durkin A, Halpern D, Núñez M, Siper P, Murphy DG, Foss-Feig J, Kolevzon A, Loth E
J Neurodev Disord · 2024 Nov · PMID 39563223 · Full text
BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic syndrome characterized by developmental delay/intellectual disability, absent or delayed speech, physical dysmorphic features and high rates of autistic featur...
BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic syndrome characterized by developmental delay/intellectual disability, absent or delayed speech, physical dysmorphic features and high rates of autistic features. However, it is currently unknown whether people with PMS have similar neurocognitive atypicalities to those previously identified in idiopathic autism. Disruption in social orienting has previously been suggested as an early hallmark feature of idiopathic autism that impacts social learning and social interaction. METHODS: This study used a semi-naturalistic task to explore orienting to social versus non-social stimuli and its relation to clinical features in individuals diagnosed with PMS, autism, and neurotypical children recruited in the United States and the United Kingdom. RESULTS: At the group level, autistic and neurotypical children responded on average more often to social than non-social stimuli, while children with PMS responded similarly to both stimulus types. Both clinical groups responded significantly less often to social stimuli than neurotypical children. In addition, we found considerable variability in orienting responses within each group that were of clinical relevance. In the autism group, non-social orienting was associated with mental age, while in the PMS group social and non-social orienting were related to strength of autistic features. CONCLUSIONS: These findings do not support specific social motivation difficulties in either clinical group. Instead, they highlight the importance of exploring individual differences in orienting responses in Phelan-McDermid Syndrome in relation to autistic features. TRIAL REGISTRATION: NA.
Predicting neurodevelopmental disorders using machine learning models and electronic health records - status of the field.
Rajagopalan SS, Tammimies K
J Neurodev Disord · 2024 Nov · PMID 39548397 · Full text
Machine learning (ML) is increasingly used to identify patterns that could predict neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). One key...
Machine learning (ML) is increasingly used to identify patterns that could predict neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). One key source of multilevel data for ML prediction models includes population-based registers and electronic health records. These can contain rich information on individual and familial medical histories and socio-demographics. This review summarizes studies published between 2010-2022 that used ML algorithms to develop predictive models for NDDs using population-based registers and electronic health records. A literature search identified 1191 articles, of which 32 were retained. Of these, 47% developed ASD prediction models and 25% ADHD models. Classical ML methods were used in 82% of studies and in particular tree-based prediction models performed well. The sensitivity of the models was lower than 75% for most studies, while the area under the curve (AUC) was greater than 75%. The most important predictors were patient and familial medical history and sociodemographic factors. Using private in-house datasets makes comparing and validating model generalizability across studies difficult. The ML model development and reporting guidelines were adopted only in a few recently reported studies. More work is needed to harness the power of data for detecting NDDs early.
The utility of wearable electroencephalography combined with behavioral measures to establish a practical multi-domain model for facilitating the diagnosis of young children with attention-deficit/hyperactivity disorder.
Chen IC, Chang CL, Chang MH … +1 more , Ko LW
J Neurodev Disord · 2024 Nov · PMID 39528958 · Full text
BACKGROUND: A multi-method, multi-informant approach is crucial for evaluating attention-deficit/hyperactivity disorders (ADHD) in preschool children due to the diagnostic complexities and challenges at this developmenta...
BACKGROUND: A multi-method, multi-informant approach is crucial for evaluating attention-deficit/hyperactivity disorders (ADHD) in preschool children due to the diagnostic complexities and challenges at this developmental stage. However, most artificial intelligence (AI) studies on the automated detection of ADHD have relied on using a single datatype. This study aims to develop a reliable multimodal AI-detection system to facilitate the diagnosis of ADHD in young children. METHODS: 78 young children were recruited, including 43 diagnosed with ADHD (mean age: 68.07 ± 6.19 months) and 35 with typical development (mean age: 67.40 ± 5.44 months). Machine learning and deep learning methods were adopted to develop three individual predictive models using electroencephalography (EEG) data recorded with a wearable wireless device, scores from the computerized attention assessment via Conners' Kiddie Continuous Performance Test Second Edition (K-CPT-2), and ratings from ADHD-related symptom scales. Finally, these models were combined to form a single ensemble model. RESULTS: The ensemble model achieved an accuracy of 0.974. While individual modality provided the optimal classification with an accuracy rate of 0.909, 0.922, and 0.950 using the ADHD-related symptom rating scale, the K-CPT-2 score, and the EEG measure, respectively. Moreover, the findings suggest that teacher ratings, K-CPT-2 reaction time, and occipital high-frequency EEG band power values are significant features in identifying young children with ADHD. CONCLUSIONS: This study addresses three common issues in ADHD-related AI research: the utility of wearable technologies, integrating databases from diverse ADHD diagnostic instruments, and appropriately interpreting the models. This established multimodal system is potentially reliable and practical for distinguishing ADHD from TD, thus further facilitating the clinical diagnosis of ADHD in preschool young children.
Early onset and increasing disparities in neurodevelopmental delays from birth to age 6 in children from low socioeconomic backgrounds.
Han TH, Chae KY, Han B … +4 more , Kim JH, Ha EK, Rhie S, Han MY
J Neurodev Disord · 2024 Nov · PMID 39501156 · Full text
OBJECTIVE: To analyze the complex relationship between socioeconomic status (SES) and neurodevelopmental achievements by investigating the temporal dynamics of these associations from birth to age 6. METHODS: This retros...
OBJECTIVE: To analyze the complex relationship between socioeconomic status (SES) and neurodevelopmental achievements by investigating the temporal dynamics of these associations from birth to age 6. METHODS: This retrospective cohort study was conducted over 6 years using population-based data from the National Health Insurance Service and integrated data from the National Health Screening Program for Infants and Children. Participants were children born between 2009 and 2011 in Korea without neurodevelopmental delays with potential developmental implications. We analyzed results from the Korean Developmental Screening Test, administered at age 6, which covered overall assessment and six domains of gross and fine motor function, cognition, language, sociality, and self-care. The secondary outcome was to determine when neurodevelopmental outcomes began after birth and how these differences changed over time. RESULTS: Of 276,167 individuals (49.2% males), 66,325, 138,980, and 60,862 had low, intermediate, and high SES, respectively. Neurodevelopmental delays observed across all developmental domains were more prevalent in the low-SES group than in the high-SES group. Disparities in neurodevelopment according to these statuses were apparent as early as age 2 and tended to increase over time (interaction, P < 0.001). The cognition and language domains exhibited the most substantial disparities between SES levels. These disparities persisted in subgroup analyses of sex, birthweight, head circumference, birth data, and breastfeeding variables. CONCLUSIONS: Low SES was significantly associated with an increased risk of adverse neurodevelopmental outcomes in preschool children, particularly those affecting cognitive and language domains. These differences manifested in early childhood and widened over time.
The effect of anxiety and autism symptom severity on restricted and repetitive behaviors over time in children with fragile X syndrome.
Moskowitz LJ, Will EA, Black CJ … +1 more , Roberts JE
J Neurodev Disord · 2024 Nov · PMID 39501150 · Full text
BACKGROUND: Restricted and repetitive behaviors (RRBs) are highly prevalent and reduce function in individuals with fragile X syndrome (FXS). As transdiagnostic features of intellectual disability, elevated rates of RRBs...
BACKGROUND: Restricted and repetitive behaviors (RRBs) are highly prevalent and reduce function in individuals with fragile X syndrome (FXS). As transdiagnostic features of intellectual disability, elevated rates of RRBs in FXS could represent various underlying known co-occurring conditions in FXS such as anxiety or autism spectrum disorder (ASD), yet this distinction has not been investigated. Further, delineating whether RRBs are more indicative of anxiety or ASD in FXS may clarify phenotypic profiles within FXS and improve differential assessment. METHODS: We longitudinally examined the potentially independent or multiplicative effect of ASD and anxiety symptom severity on RRBs in 60 children with FXS. Anxiety was measured using the Child Behavior Checklist (CBCL), ASD severity was measured using the Childhood Autism Rating Scale (CARS), and RRBs were measured using the Repetitive Behavior Scale - Revised (RBS-R). We estimated a series of moderated regression models with anxiety and ASD symptoms at the initial assessment (Time 1) as predictors of RRBs at the outcome assessment two years later (Time 2), along with an anxiety-by-ASD interaction term to determine the potential multiplicative effect of these co-occurring conditions on RRBs. RESULTS: Results identified a significant interaction between ASD and anxiety symptom severity at the initial assessment that predicted elevated sensory-motor RRBs two years later. Increased sensory-motor RRBs were predicted by elevated ASD symptoms only when anxiety symptom severity was low. Likewise, increased sensory-motor RRBs were predicted by elevated anxiety symptoms only when ASD symptom severity was low. Interestingly, this relationship was isolated to Sensory-Motor RRBs, with evidence that it could also apply to total RRBs. CONCLUSIONS: Findings suggest that ASD and anxiety exert independent and differential effects on Sensory-Motor RRBs when at high severity levels and a multiplicative effect when at moderate levels, which has important implications for early and targeted interventions.
Associations between genotype, phenotype and behaviours measured by the Rett syndrome behaviour questionnaire in Rett syndrome.
Downs J, Wong K, Leonard H
J Neurodev Disord · 2024 Oct · PMID 39455915 · Full text
INTRODUCTION: Rett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour...
INTRODUCTION: Rett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to describe the behavioural and emotional features of RTT. Little is known how RSBQ scores are associated with genetic and clinical characteristics in RTT. This study investigated relationships between genotype, age, walking, hand function, sleep, and RSBQ total and subscale scores in RTT. METHODS: This is a cross-sectional analysis of data collected in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database. Parent caregivers completed the RSBQ and Sleep Disturbance Scale for Children [subscales for disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence (DOES)], and provided information on age, variant type, functional abilities (mobility, hand function), seizure frequency and gastrointestinal problems. Associations between the RSBQ scores and the independent variables were modelled using linear regression. RESULTS: Data were available for 365 individuals with RTT [median (range) age 17.8 (2.9-51.9) years, 2 males]. Compared to adults, 2- to 12-year-old children had higher mean Total, Night-time Behaviour and Fear/Anxiety scores. Compared to individuals with a C-terminal deletion, individuals with the p.Arg255* variant had higher mean Total and Night-time Behaviours scores, whereas the p.Arg294* variant had higher mean Mood scores. Individuals with intermediate mobility and hand function abilities had a higher mean Total score. Total RSBQ and subscale scores were similar across categories for seizures, constipation, and reflux, but were higher with abnormal DIMS and abnormal DOES scores. CONCLUSION: Except for associations with sleep, the RSBQ measures the behavioural phenotype rather than clinical severity in RTT, as traditionally conceptualised in terms of functional abilities and comorbidities. When designing clinical trials, the RSBQ needs to be complemented by other outcome measures to assess specific core functions and associated comorbidities in RTT.
Changes in the prevalence of intellectual disability among 10-year-old children in Sweden during 2011 through 2021: a total population study.
Morinaga M, Ahlqvist VH, Lundberg M … +3 more , Hollander AC, Rai D, Magnusson C
J Neurodev Disord · 2024 Oct · PMID 39443872 · Full text
BACKGROUND: Recent studies have suggested an increasing prevalence of intellectual disability diagnoses in some countries. Our aim was to describe the trend in the prevalence of intellectual disability diagnoses in Swede...
BACKGROUND: Recent studies have suggested an increasing prevalence of intellectual disability diagnoses in some countries. Our aim was to describe the trend in the prevalence of intellectual disability diagnoses in Sweden and explore whether associated sociodemographic and perinatal factors can explain changes in the prevalence. METHODS: We used a register-based nationwide cohort of residents in Sweden born between 2001 and 2011. We calculated the prevalence of intellectual disability diagnoses by age 10 for each birth cohort and the prevalence ratios in relation to the baseline year 2011, overall and by severity of intellectual disability, and comorbidity of autism and attention-deficit/hyperactivity disorder. The prevalence ratios were stratified and adjusted for associated sociodemographic and perinatal factors. RESULTS: Among 1,096,800 individuals, 8,577 were diagnosed with intellectual disability by age 10. Among these, 3,949 (46%) and 2,768 (32%) were also diagnosed with autism and attention-deficit/hyperactivity disorder, respectively, and 4% were diagnosed with profound, 8% severe, 20% moderate, 52% mild, and 16% other/unspecific intellectual disability. The recorded age-10 prevalence of intellectual disability diagnoses increased from 0.64% (95% confidence interval 0.59-0.69%) in 2011 to 1.00% (0.94-1.06%) in 2021, corresponding to an annual prevalence ratio of 1.04 (1.04-1.05). The increase was, however, restricted to mild, moderate, and other/unspecific intellectual disability diagnoses, while the trends for profound and severe intellectual disability diagnoses were stable. The increasing trend was perhaps less pronounced among females and children with diagnosed attention-deficit/hyperactivity disorder, but independent of the co-occurrence of autism. The prevalence ratios did not change with stratification or adjustment for other associated demographic and perinatal factors. CONCLUSION: The recorded prevalence of diagnosed mild and moderate intellectual disability among 10-year-olds in Sweden has increased over the recent decade. This increase could not be explained by changes in associated sociodemographic or perinatal factors, including birth weight, gestational age, and parental age, migration status, and education at the child's birth. The increase instead may be due to changes in diagnostic practices in Sweden over time.
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