Journal of Neurodevelopmental Disorders最新文献

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.

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_Cohen = 0.81), and between the 22qDS and control cohorts (D_Cohen = 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.

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.

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.

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.

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_p), normalized clustering coefficient (γ), small-world characteristic (σ), and decreased global efficiency (E_glob) (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.

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.

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_1A)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_1A receptors to improve auditory temporal processing, which in turn may improve speech and language function in FXS.

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.

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).