Background Sensory processing dysfunction (SPD) is linked to altered white matter (WM) microstructure in school-age children. Sensory over-responsivity (SOR), a form of SPD, affects at least 2.5% of all children and has substantial deleterious impact on learning and mental health. However, SOR has not been well studied using microstructural imaging such as diffusion MRI (dMRI). Since SOR involves hypersensitivity to external stimuli, we test the hypothesis that children with SOR require compensatory neuroplasticity in the form of superior WM microstructural integrity to protect against internalizing behavior, leaving those with impaired WM microstructure vulnerable to somatization and depression. Methods Children ages 8–12 years old with neurodevelopmental concerns were assessed for SOR using a comprehensive structured clinical evaluation, the Sensory Processing 3 Dimensions Assessment, and underwent 3 Tesla MRI with multishell multiband dMRI. Tract-based spatial statistics was used to measure diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics from global WM and nineteen selected WM tracts. Correlations of DTI and NODDI measures with measures of somatization and emotional disturbance from the Behavioral Assessment System for Children, 3rd edition (BASC-3), were computed in the SOR group and in matched children with neurodevelopmental concerns but not SOR. Results Global WM fractional anisotropy (FA) is negatively correlated with somatization and with emotional disturbance in the SOR group but not the non-SOR group. Also observed in children with SOR are positive correlations of radial diffusivity (RD) and free water fraction (FISO) with somatization and, in most cases, emotional disturbance. These effects are significant in boys with SOR, whereas the study is underpowered for girls. The most affected white matter are medial lemniscus and internal capsule sensory tracts, although effects of SOR are observed in many cerebral, cerebellar, and brainstem tracts. Conclusion White matter microstructure is related to affective behavior in children with SOR.

Children with autism and other neurodevelopmental concerns (NDC) frequently exhibit an array of sensory processing dysfunction phenotypes, posing a significant challenge their adaptive development. Additionally, these children often encounter difficulties with self-regulation, including emotion dysregulation, anxiety, and symptoms associated with attention and hyperactivity. However, further research is required to comprehend how patterns of sensory processing differences across neurodevelopmental conditions may contribute to regulatory control problems. Adopting a transdiagnostic perspective within the Research Domain Criteria (RDoC) framework, this study examined the relationship between clusters of sensory processing phenotypes and differential patterns of self-regulation behaviors. We recruited a sample of 117 participants (8-12 years) with a diverse range of neurodevelopmental concerns including autism, ADHD, anxiety, and sensory processing differences. This study aimed to (1) establish the prevalence of self-regulation problems in a community-recruited cohort of children with diverse NDCs; (2) construct data-driven sensory processing latent subtypes; (3) investigate group differences in emotion dysregulation, anxiety, and ADHD symptoms. Results showed that 39% of NDC children met clinically concerning thresholds for emotion dysregulation, 19% for anxiety, and 62% for ADHD. Second, latent profile analysis identified five sensory processing subtypes categorized by modality: Typical Processing, Intermediate/Mixed, Sensory Over-Responsive, Sensory Seeking, and Sensory Under-Responsive. Notably, the Sensory Over-Responsive group exhibited distinctively elevated anxiety scores, while the Sensory Seeking and Sensory Under-Responsive groups showed heightened ADHD scores. Intriguingly, the Sensory Over-Responsive, Sensory Under-Responsive, and Sensory Seeking subgroups all demonstrated elevated emotion dysregulation scores, suggesting a potential shared mechanism of emotion dysregulation that might elucidate the connection between sensory processing differences and increased anxiety and ADHD behaviors in children with autism and other NDCs.

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains without disease trait associations. Using exome sequencing and family-based rare variant analysis, we identified 20 individuals with de novo , ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative HPO analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from a patient with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.(Gly411Glu) and p.(Arg761Gln), altered DHX9 ATPase activity. The severe NDD-associated variant p.(Arg141Gln) did not impact DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9 -/-mice exhibit hypoactivity in novel environments, tremor, and sensorineural hearing loss. Taken together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

Children with autism and other neurodevelopmental concerns (NDC) present an array of sensory processing patterns and frequently encounter challenges with self-regulation, including emotion dysregulation, anxiety, and ADHD symptoms. Adopting a transdiagnostic perspective within the Research Domain Criteria (RDoC) framework, this study examined the relationship between clusters of sensory processing phenotypes and differential patterns of self-regulation behaviors. In a sample of 117 participants (8–12 years), this study aimed to: 1) establish the prevalence of self-regulation problems in a community-recruited cohort of children with diverse NDCs; 2) construct data-driven sensory processing latent subtypes; 3) investigate group differences in emotion dysregulation, anxiety, and ADHD symptoms. Results indicated that 40, 20, and 62% of NDC children met clinically concerning thresholds for emotion dysregulation, anxiety, and ADHD, respectively. Second, latent profile analysis identified five sensory processing subtypes categorized by modality: Typical Processing, Intermediate/Mixed, Sensory Seeking (SS), Sensory Under-responsive (SUR), and Sensory Over-Responsive (SOR). Notably, the SOR group exhibited distinctively elevated anxiety scores, while the SS and SUR groups showed heightened ADHD scores. Intriguingly, the SOR, SUR, SS, and Intermediate/Mixed subgroups all demonstrated elevated emotion dysregulation scores, suggesting a potential shared mechanism of emotion dysregulation that might elucidate the connection between sensory processing differences and increased anxiety and ADHD behaviors in children with autism and other NDCs.

Sensory Over-Responsivity (SOR) is an increasingly recognized challenge among children with neurodevelopmental concerns (NDC). To investigate, we characterized the incidence of auditory and tactile over-responsivity (AOR, TOR) among 82 children with NDC. We found that 70% of caregivers reported concern for their child’s sensory reactions. Direct assessment further revealed that 54% of the NDC population expressed AOR, TOR, or both – which persisted regardless of autism spectrum disorder (ASD) diagnosis. These findings support the high prevalence of SOR as well as its lack of specificity to ASD. Additionally, AOR is revealed to be over twice as prevalent as TOR. These conclusions present several avenues for further exploration, including deeper analysis of the neural mechanisms and genetic contributors to sensory processing challenges.