1. Ban R, Kopajtich R, Lv J, Stenton SL, Shimura M, Wang Z, Yuan Y, Wang J, Han X, Liu Z, Shi Q, Pu C, Prokisch H, Fang F, Elstner M. The phenotypic spectrum of COX20-associated mitochondrial disorder. Brain : a journal of neurology. 2022; 145(12): e125-e7.

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2. Bhat A. Multidimensional motor performance in children with autism mostly remains stable with age and predicts social communication delay, language delay, functional delay, and repetitive behavior severity after accounting for intellectual disability or cognitive delay: A SPARK dataset analysis. Autism research : official journal of the International Society for Autism Research. 2022.

When motor difficulties continue into adolescence/adulthood, they could negatively impact an individual with autism spectrum disorder (ASD)’s daily living skills, physical fitness, as well as physical and mental health/well-being. Few studies have examined motor difficulties in children with ASD as a function of sex or age; however, greater cognitive challenges are associated with worse general motor performance. Based on the Developmental Coordination Disorder-Questionnaire (DCD-Q) data from the SPARK study sample, 87%-88% children with ASD were at-risk for a general motor impairment that persisted until 15 years and was related to their core and co-occurring difficulties. Bhat et al. confirmed motor difficulties in children with ASD on multiple motor dimensions that predicted core and co-occurring conditions after accounting for age and sex. However, presence of intellectual disability (ID) or cognitive delay was not controlled in the previous analysis. Additionally, the effects of age, sex, and cognitive ability on multidimensional motor difficulties of the SPARK sample have not been discussed before. Therefore, this analysis examines the effects of age, sex, and cognitive ability (presence of ID or level of cognitive delay) on the motor performance of children from the SPARK sample using the DCD-Q. Except fine motor skills, multiple motor domains did not change with age in children with ASD. Females without ID improved their fine motor scores with age, and performed better compared to males without ID. Children with ASD and ID had greater motor difficulties across multiple motor domains than those without ID. Even after controlling for age, sex, and presence of ID/cognitive delay; motor performance was predictive of social communication skills, repetitive behavior severity, as well as language and functional delays. Gross motor skills contributed more than fine motor and general motor competence skills in predicting social communication delay. However, fine motor and general motor competence skills contributed more than gross motor skills in predicting repetitive behavior severity and language delay. Both, fine and gross motor skills predicted functional delay. In light of consistent findings on motor difficulties in children with ASD, adding motor issues as a specifier within the ASD definition could provide a clear clinical route for movement clinicians to address motor difficulties of individuals with ASD.

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3. Chen YL, Ho HY. Comprehensive Comparisons of Family Health Between Families With One Immigrant Parent and Native Families in Taiwan: Nationwide Population-Based Cohort Study. JMIR public health and surveillance. 2022; 8(12): e33624.

BACKGROUND: Mothers and children in families with one immigrant parent have been reported to be healthier than those in native families; however, the health of the fathers in these families has rarely been discussed in literature. OBJECTIVE: We aimed to comprehensively compare the health of all the family members between families with one immigrant parent (native fathers, immigrant mothers, and their children) and native families (native fathers, native mothers, and their children). METHODS: We conducted a cohort study by using the Taiwan Maternal and Child Health Database to recruit live-born children and their parents from 2004 to 2016. Overall, we identified 90,670 fathers, 91,270 mothers, and 132,457 children in families with one immigrant parent and 1,666,775 fathers, 1,734,104 mothers, and 2,637,191 children in native families and followed up with them from 2004 to 2017. The outcomes comprised common physical and mental disorders, catastrophic illnesses, mortality, and child adversities and accidents. The covariates comprised the child’s year of birth, parental age, low-income status, and physical or mental disorder status. Logistic regression was performed to compare the risks of the outcomes between families with one immigrant parent and native families. RESULTS: The parents in families with one immigrant parent were more likely to be of low-income status and were older than the parents in native families. After adjusting for the covariates, fathers in families with one immigrant parent were found to have higher risks of physical and mental disorders, catastrophic illness, and mortality than fathers in native families. Conversely, mothers in families with one immigrant parent had lower risks of physical and mental disorders, catastrophic illness, and mortality than mothers in native families. Finally, the children in families with one immigrant parent generally had better physical and mental health but higher risks for leukemia, liver diseases, autism spectrum disorder, and road traffic accidents than children in native families. CONCLUSIONS: The health status of the members of families with one immigrant parent was nonhomogeneous, and the poorer general health of fathers in such families suggests health inequalities in families with one immigrant parent.

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4. Como DH, Floríndez-Cox LI, Stein Duker LI, Cermak SA. Oral Health Barriers for African American Caregivers of Autistic Children. International journal of environmental research and public health. 2022; 19(24).

The most persistent oral health disparities in the United States impact children from racial and ethnic minoritized groups and children diagnosed as autistic. This paper aims to describe barriers to oral care as depicted by Black/African American (B/AA) parents of autistic children to further explore how and why oral health disparities persist in this population. A purposeful sample of eleven caregivers of autistic children, ages 4 to 14 years, who identified as B/AA were interviewed twice for approximately 60-90 min each. Thematic analysis utilizing a narrative approach was employed. Three themes emerged from the data concerning the barriers that affect oral health experiences: (a) difficulty in maintaining good oral health practices, (b) challenges with access to care and resources, and (c) poor patient-provider relationships. Due to the limited research that examines the intersection of autism, B/AA culture, and oral health practices, this study provides a rich picture of the barriers families face when obtaining oral care. Many families raised issues that other parents of autistic children also identified. B/AA caregivers have demonstrated that despite their own negative dental experiences, they understand the value of good oral care practices and are willing to pursue oral care for their children.

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5. Li F, Ke H, Wang S, Mao W, Fu C, Chen X, Fu Q, Qin X, Huang Y, Li B, Li S, Xing J, Wang M, Deng W. Leaky Gut Plays a Critical Role in the Pathophysiology of Autism in Mice by Activating the Lipopolysaccharide-Mediated Toll-Like Receptor 4-Myeloid Differentiation Factor 88-Nuclear Factor Kappa B Signaling Pathway. Neuroscience bulletin. 2022.

Increased intestinal barrier permeability, leaky gut, has been reported in patients with autism. However, its contribution to the development of autism has not been determined. We selected dextran sulfate sodium (DSS) to disrupt and metformin to repair the intestinal barrier in BTBR T(+)tf/J autistic mice to test this hypothesis. DSS treatment resulted in a decreased affinity for social proximity; however, autistic behaviors in mice were improved after the administration of metformin. We found an increased affinity for social proximity/social memory and decreased repetitive and anxiety-related behaviors. The concentration of lipopolysaccharides in blood decreased after the administration of metformin. The expression levels of the key molecules in the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-nuclear factor kappa B (NF-κB) pathway and their downstream inflammatory cytokines in the cerebral cortex were both repressed. Thus, « leaky gut » could be a trigger for the development of autism via activation of the lipopolysaccharide-mediated TLR4-MyD88-NF-κB pathway.

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6. Li YJ, Li CY, Li CY, Hu DX, Xv ZB, Zhang SH, Li Q, Zhang P, Tian B, Lan XL, Chen XQ. KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice. Molecular neurobiology. 2022.

Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental disorders characterized by impaired social interaction skills. Whole exome sequencing has identified loss-of-function mutations in lysine methyltransferase 2E (KMT2E, also named MLL5) in ASD patients and it is listed as an ASD high-risk gene in humans. However, experimental evidence of KMT2E in association with ASD-like manifestations or neuronal function is still missing. Relying on KMT2E(+/-) mice, through animal behavior analyses, positron emission tomography (PET) imaging, and neuronal morphological analyses, we explored the role of KMT2E haploinsufficiency in ASD-like symptoms. Behavioral results revealed that KMT2E haploinsufficiency was sufficient to produce social deficit, accompanied by anxiety in mice. Whole-brain (18)F-FDG-PET analysis identified that relative amygdala glycometabolism was selectively decreased in KMT2E(+/-) mice compared to wild-type mice. The numbers and soma sizes of amygdala neurons in KMT2E(+/-) mice were prominently increased. Additionally, KMT2E mRNA levels in human amygdala were significantly decreased after birth during brain development. Our findings support a causative role of KMT2E in ASD development and suggest that amygdala neuronal development abnormality is likely a major underlying mechanism.

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7. Long F, Zheng J, Zhou J, Hu P, Xiong B. Knockout of tanc2 causes autism-like behavior and sleep disturbance in zebrafish. Autism research : official journal of the International Society for Autism Research. 2022.

Tanc2 is a large multi-domain postsynaptic scaffold protein mainly expressed in the brain. In humans, tanc2 mutations have been associated with autism spectrum disorder (ASD) and other related neurodevelopmental disorders. However, the role of tanc2 in neurodevelopment and in controlling behaviors are not fully understood. Here, we generated and characterized a tanc2 knockout allele in zebrafish. Loss of tanc2 increases the larval brain size and body length by promoting proliferation and inhibiting apoptosis. We observed that the glutamatergic neuron population is significantly increased in tanc2 mutants while the GABAergic and the glycinergic neurons are not affected, suggesting that an excitatory/inhibitory (E/I) imbalance. Indeed, the tanc2 knockout larvae exhibited increase sleep. In adult zebrafish, the mutants display anxiolytic-behavior, reduced aggression, and impaired social preference. The alterations in these behaviors are phenotypically similar to the ASD patients carrying tanc2 mutations. Therefore, the tanc2 knockout allele could serve as a valuable model to further study the role of tanc2 in the nervous system.

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8. Luo T, Chen SS, Ruan Y, Chen HY, Chen YM, Li YM, Zhou W. Downregulation of DDIT4 ameliorates abnormal behaviors in autism by inhibiting ferroptosis via the PI3K/Akt pathway. Biochemical and biophysical research communications. 2022; 641: 168-76.

Autism spectrum disorder (ASD) is a complex disease with unclear etiology. Studies have shown that ferroptosis is also related to ASD progression, but the specific mechanism is still unclear. Valproic acid (VPA) induced neuronal ferroptosis in vitro. Mechanistic studies showed that both VPA and ferroptosis inducers promoted the expression of DDIT4 in neurons, thereby inhibiting the activation of the PI3K/Akt pathway. DDIT4 increased the accumulation of ROS, MDA and Fe(2+), inhibited neuronal viability and downregulated GPX4 expression by inactivating the PI3K/Akt pathway. Ferroptosis inhibitors reversed the anti-survival effect of DDIT4, indicating that DDIT4 enhances ferroptosis through the PI3K/Akt pathway, thereby inhibiting neuronal viability. Further in vivo experiments found that autistic mice had high levels of ROS, MDA and Fe(2+), increased DDIT4 expression, and downregulated expression levels of GPX4, p-PI3K and p-Akt; after downregulation of DDIT4 expression, the accumulation of ROS, MDA and Fe(2+) was significantly reduced, while the expression levels of GPX4, p-PI3K and p-Akt were upregulated, indicating that DDIT4 knockdown reduces ferroptosis in autistic mice. In addition, DDIT4 downregulation, PI3K/Akt pathway activation, and ferroptosis inhibitors all improved social behavior deficits, repetitive stereotyped and compulsive behaviors, anxiety and exploratory behaviors in autistic mice, but PI3K/Akt pathway inhibitors significantly blocked the rescue of abnormal behaviors by DDIT4 downregulation in autistic mice. Therefore, downregulation of DDIT4 expression ameliorates abnormal behaviors in autism by inhibiting ferroptosis via the PI3K/Akt pathway, indicating that DDIT4, the PI3K/Akt pathway and ferroptosis have key roles in autism.

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9. Mikami M, Hirota T, Adachi M, Takahashi M, Nishimura T, Saito M, Nakamura K, Yamada J. Trajectories of emotional and behavioral problems in school-age children with coordination difficulties and their relationships to ASD/ADHD traits. Research in developmental disabilities. 2022; 133: 104394.

BACKGROUND: Although research has demonstrated associations between motor coordination difficulties and psychological problems in school-age children, including emotional and behavioral problems, longitudinal changes in these problems in children with motor coordination difficulties are not fully understood. AIMS: The current study aimed to identify patterns in the trajectory of emotional and behavioral problems in school-age children with motor coordination difficulties, and to elucidate the effect of co-existing neurodevelopmental traits on the occurrence and course of these problems. METHODS AND PROCEDURES: Using the Developmental Coordination Disorder Questionnaire, 773 children were defined as cases with motor coordination difficulties and followed for 4 years, from 6 to 10 years of age. Emotional and behavioral problems were assessed using the Strengths and Difficulties Questionnaire completed by children’s parents or guardians. OUTCOMES AND RESULTS: We identified four trajectory patterns of emotional and behavioral problems. Children with higher autism spectrum disorder and attention deficit hyperactivity disorder traits were more likely to be assigned to poor prognostic trajectory patterns. CONCLUSIONS AND IMPLICATIONS: Our findings emphasize the importance of assessing emotional and behavioral problems and co-existing neurodevelopmental traits in children with motor coordination difficulties in early elementary school.

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10. Milne N, Longeri L, Patel A, Pool J, Olson K, Basson A, Gross AR. Spinal manipulation and mobilisation in the treatment of infants, children, and adolescents: a systematic scoping review. BMC pediatrics. 2022; 22(1): 721.

PURPOSE: To i) identify and map the available evidence regarding effectiveness and harms of spinal manipulation and mobilisation for infants, children and adolescents with a broad range of conditions; ii) identify and synthesise policies, regulations, position statements and practice guidelines informing their clinical use. DESIGN: Systematic scoping review, utilising four electronic databases (PubMed, Embase, CINHAL and Cochrane) and grey literature from root to 4(th) February 2021. PARTICIPANTS: Infants, children and adolescents (birth to < 18 years) with any childhood disorder/condition. INTERVENTION: Spinal manipulation and mobilisation OUTCOME MEASURES: Outcomes relating to common childhood conditions were explored. METHOD: Two reviewers (A.P., L.L.) independently screened and selected studies, extracted key findings and assessed methodological quality of included papers using Joanna Briggs Institute Checklist for Systematic Reviews and Research Synthesis, Joanna Briggs Institute Critical Appraisal Checklist for Text and Opinion Papers, Mixed Methods Appraisal Tool and International Centre for Allied Health Evidence Guideline Quality Checklist. A descriptive synthesis of reported findings was undertaken using a levels of evidence approach. RESULTS: Eighty-seven articles were included. Methodological quality of articles varied. Spinal manipulation and mobilisation are being utilised clinically by a variety of health professionals to manage paediatric populations with adolescent idiopathic scoliosis (AIS), asthma, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), back/neck pain, breastfeeding difficulties, cerebral palsy (CP), dysfunctional voiding, excessive crying, headaches, infantile colic, kinetic imbalances due to suboccipital strain (KISS), nocturnal enuresis, otitis media, torticollis and plagiocephaly. The descriptive synthesis revealed: no evidence to explicitly support the effectiveness of spinal manipulation or mobilisation for any condition in paediatric populations. Mild transient symptoms were commonly described in randomised controlled trials and on occasion, moderate-to-severe adverse events were reported in systematic reviews of randomised controlled trials and other lower quality studies. There was strong to very strong evidence for 'no significant effect' of spinal manipulation for managing asthma (pulmonary function), headache and nocturnal enuresis, and inconclusive or insufficient evidence for all other conditions explored. There is insufficient evidence to draw conclusions regarding spinal mobilisation to treat paediatric populations with any condition. CONCLUSION: Whilst some individual high-quality studies demonstrate positive results for some conditions, our descriptive synthesis of the collective findings does not provide support for spinal manipulation or mobilisation in paediatric populations for any condition. Increased reporting of adverse events is required to determine true risks. Randomised controlled trials examining effectiveness of spinal manipulation and mobilisation in paediatric populations are warranted.

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11. Regev O, Hadar A, Meiri G, Flusser H, Michaelovski A, Dinstein I, Hershkovitz R, Menashe I. Association between ultrasonography foetal anomalies and autism spectrum disorder. Brain : a journal of neurology. 2022; 145(12): 4519-30.

Multiple pieces of evidence support the prenatal predisposition of autism spectrum disorder (ASD). Nevertheless, robust data about abnormalities in foetuses later developing into children diagnosed with ASD are lacking. Prenatal ultrasound is an excellent tool to study abnormal foetal development as it is frequently used to monitor foetal growth and identify foetal anomalies throughout pregnancy. We conducted a retrospective case-sibling-control study of children diagnosed with ASD (cases); their own typically developing, closest-in-age siblings (TDS); and typically developing children from the general population (TDP), matched by year of birth, sex and ethnicity to investigate the association between ultrasonography foetal anomalies and ASD. The case group was drawn from all children diagnosed with ASD enrolled at the National Autism Research Center of Israel. Foetal ultrasound data from the foetal anatomy survey were obtained from prenatal ultrasound clinics of Clalit Health Services in southern Israel. The study comprised 659 children: 229 ASD, 201 TDS and 229 TDP. Ultrasonography foetal anomalies were found in 29.3% of ASD cases versus only 15.9% and 9.6% in the TDS and TDP groups [adjusted odds ratio (aOR) = 2.23, 95% confidence interval (CI) = 1.32-3.78, and aOR = 3.50, 95%CI = 2.07-5.91, respectively]. Multiple co-occurring ultrasonography foetal anomalies were significantly more prevalent among ASD cases. Ultrasonography foetal anomalies in the urinary system, heart, and head and brain were the most significantly associated with ASD diagnosis (aORUrinary = 2.08, 95%CI = 0.96-4.50 and aORUrinary = 2.90, 95%CI = 1.41-5.95; aORHeart = 3.72, 95%CI = 1.50-9.24 and aORHeart = 8.67, 95%CI = 2.62-28.63; and aORHead&Brain = 1.96, 95%CI = 0.72-5.30 and aORHead&Brain = 4.67, 95%CI = 1.34-16.24; versus TDS and TDP, respectively). ASD females had significantly more ultrasonography foetal anomalies than ASD males (43.1% versus 25.3%, P = 0.013) and a higher prevalence of multiple co-occurring ultrasonography foetal anomalies (15.7% versus 4.5%, P = 0.011). No sex differences were seen among TDS and TDP controls. ASD foetuses were characterized by a narrower head and a relatively wider ocular-distance versus TDP foetuses (ORBPD = 0.81, 95%CI = 0.70-0.94, and aOROcular distance = 1.29, 95%CI = 1.06-1.57). Ultrasonography foetal anomalies were associated with more severe ASD symptoms. Our findings shed important light on the multiorgan foetal anomalies associated with ASD.

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12. Rogers MA, Elison JT, Blain SD, DeYoung CG. A cybernetic theory of autism: Autism as a consequence of low trait Plasticity. Journal of personality. 2022.

According to Cybernetic Big Five Theory (CB5T), personality traits reflect variation in the parameters of evolved cybernetic mechanisms, and extreme manifestations of these traits correspond to a risk for psychopathology because they threaten the organism’s ability to pursue its goals effectively. Our theory of autism as a consequence of low Plasticity extends CB5T to provide a cybernetic account of the origin of autistic traits. The theory argues that, because all psychological competencies are initially developed through exploration, typical development requires sensitivity to the incentive reward value of the unknown (i.e., the unpredicted). According to CB5T, motivation to explore the unknown is the core function underlying the metatrait Plasticity, the shared variance of Extraversion and Openness/Intellect. This theory makes predictions regarding the downstream developmental consequences of early low Plasticity, and each prediction maps well onto autistic symptomatology. This approach may help to explain the heterogeneity of autism, as there are many ways that rigidity can reinforce itself to create a developmental trap influencing the development of competencies. We end by presenting preliminary meta-analytic and new data showing a strong negative relation between Plasticity and autistic symptomatology.

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13. Scher MS. A Bio-Social Model during the First 1000 Days Optimizes Healthcare for Children with Developmental Disabilities. Biomedicines. 2022; 10(12).

Most children with developmental disabilities (DD) live in resource-limited countries (LMIC) or high-income country medical deserts (HICMD). A social contract between healthcare providers and families advocates for accurate diagnoses and effective interventions to treat diseases and toxic stressors. This bio-social model emphasizes reproductive health of women with trimester-specific maternal and pediatric healthcare interactions. Lifelong neuronal connectivity is more likely established across 80% of brain circuitries during the first 1000 days. Maladaptive gene-environment (G x E) interactions begin before conception later presenting as maternal-placental-fetal (MPF) triad, neonatal, or childhood neurologic disorders. Synergy between obstetrical and pediatric healthcare providers can reduce neurologic morbidities. Partnerships between healthcare providers and families should begin during the first 1000 days to address diseases more effectively to moderate maternal and childhood adverse effects. This bio-social model lowers the incidence and lessens the severity of sequalae such as DD. Access to genetic-metabolomic, neurophysiologic and neuroimaging evaluations enhances clinical decision-making for more effective interventions before full expression of neurologic dysfunction. Diagnostic accuracy facilitates developmental interventions for effective preschool planning. A description of a mother-child pair in a HIC emphasizes the time-sensitive importance for early interventions that influenced brain health throughout childhood. Partnership by her parents with healthcare providers and educators provided effective healthcare and lessened adverse effects. Effective educational interventions were later offered through her high school graduation. Healthcare disparities in LMIC and HICMD require that this bio-social model of care begin before the first 1000 days to effectively treat the most vulnerable women and children. Prioritizing family planning followed by prenatal, neonatal and child healthcare improves wellness and brain health. Familiarity with educational neuroscience for teachers applies neurologic diagnoses for effective individual educational plans. Integrating diversity and inclusion into medical and educational services cross socioeconomic, ethnic, racial, and cultural barriers with life-course benefits. Families require knowledge to recognize risks for their children and motivation to sustain relationships with providers and educators for optimal outcomes. The WHO sustainable development goals promote brain health before conception through the first 1000 days. Improved education, employment, and social engagement for all persons will have intergenerational and transgenerational benefits for communities and nations.

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14. Surgent O, Riaz A, Ausderau KK, Adluru N, Kirk GR, Guerrero-Gonzalez J, Skaletski EC, Kecskemeti SR, Dean Iii DC, Weismer SE, Alexander AL, Travers BG. Brainstem white matter microstructure is associated with hyporesponsiveness and overall sensory features in autistic children. Molecular autism. 2022; 13(1): 48.

BACKGROUND: Elevated or reduced responses to sensory stimuli, known as sensory features, are common in autistic individuals and often impact quality of life. Little is known about the neurobiological basis of sensory features in autistic children. However, the brainstem may offer critical insights as it has been associated with both basic sensory processing and core features of autism. METHODS: Diffusion-weighted imaging (DWI) and parent-report of sensory features were acquired from 133 children (61 autistic children with and 72 non-autistic children, 6-11 years-old). Leveraging novel DWI processing techniques, we investigated the relationship between sensory features and white matter microstructure properties (free-water-elimination-corrected fractional anisotropy [FA] and mean diffusivity [MD]) in precisely delineated brainstem white matter tracts. Follow-up analyses assessed relationships between microstructure and sensory response patterns/modalities and analyzed whole brain white matter using voxel-based analysis. RESULTS: Results revealed distinct relationships between brainstem microstructure and sensory features in autistic children compared to non-autistic children. In autistic children, more prominent sensory features were generally associated with lower MD. Further, in autistic children, sensory hyporesponsiveness and tactile responsivity were strongly associated with white matter microstructure in nearly all brainstem tracts. Follow-up voxel-based analyses confirmed that these relationships were more prominent in the brainstem/cerebellum, with additional sensory-brain findings in the autistic group in the white matter of the primary motor and somatosensory cortices, the occipital lobe, the inferior parietal lobe, and the thalamic projections. LIMITATIONS: All participants communicated via spoken language and acclimated to the sensory environment of an MRI session, which should be considered when assessing the generalizability of this work to the whole of the autism spectrum. CONCLUSIONS: These findings suggest unique brainstem white matter contributions to sensory features in autistic children compared to non-autistic children. The brainstem correlates of sensory features underscore the potential reflex-like nature of behavioral responses to sensory stimuli in autism and have implications for how we conceptualize and address sensory features in autistic populations.

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