Journal of Neurodevelopmental Disorders最新文献

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 One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine.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).

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.

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.

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.

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.