1. Bellinger DC. Lithium in Drinking Water-A Novel Environmental Risk Factor for Autism Spectrum Disorder?. JAMA Pediatr;2023 (Apr 3)

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2. Bishop SL, Lord C. Commentary: Best practices and processes for assessment of autism spectrum disorder – the intended role of standardized diagnostic instruments. J Child Psychol Psychiatry;2023 (Apr 2)

Development of standardized diagnostic instruments has facilitated the systematic characterization of individuals with autism spectrum disorders (ASD) in clinical and research settings. However, overemphasis on scores from specific instruments has significantly detracted from the original purpose of these tools. Rather than provide a definitive « answer, » or even a confirmation of diagnosis, standardized diagnostic instruments were designed to aid clinicians in the process of gathering information about social communication, play, and repetitive and sensory behaviors relevant to diagnosis and treatment planning. Importantly, many autism diagnostic instruments are not validated for certain patient populations, including those with severe vision, hearing, motor, and/or cognitive impairments, and they cannot be administered via a translator. In addition, certain circumstances, such as the need to wear personal protective equipment (PPE), or behavioral factors (e.g., selective mutism) may interfere with standardized administration or scoring procedures, rendering scores invalid. Thus, understanding the uses and limitations of specific tools within specific clinical or research populations, as well as similarities or differences between these populations and the instrument validation samples, is paramount. Accordingly, payers and other systems must not mandate the use of specific tools in cases when their use would be inappropriate. To ensure equitable access to appropriate assessment and treatment services, it is imperative that diagnosticians be trained in best practice methods for the assessment of autism, including if, how, and when to appropriately employ standardized diagnostic instruments.

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3. Grönniger B, Fritschka E, Fahrig I, Danzer A, Sadowski G. Water Sorption in Rubbery and Glassy Polymers, Nifedipine, and Their ASDs. Mol Pharm;2023 (Apr 3);20(4):2194-2206.

Polymers like poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) are commonly used as a matrix for amorphous solid dispersions (ASDs) to enhance the bioavailability of the active pharmaceutical ingredients (APIs). The stability of ASDs is strongly influenced by the water sorption in the ASD from the surrounding air. In this work, the water sorption in the neat polymers PVPVA and HPMCAS, in the neat API nifedipine (NIF), and in their ASDs of different drug loads was measured above and below the glass-transition temperature. The equilibrium water sorption was predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) combined with the Non-Equilibrium Thermodynamics of Glassy Polymers (NET-GP).The water-sorption kinetics were modeled using the Maxwell-Stefan approach whereas the thermodynamic driving force was calculated using PC-SAFT and NET-GP. The water diffusion coefficients in the polymers, NIF, or ASDs were determined using the Free-Volume Theory. Using the water-sorption kinetics of the pure polymers and of NIF, the water-sorption kinetics of the ASDs were successfully predicted, thus providing the water diffusion coefficients in the ASD as a function of relative humidity and of the water concentration in polymers or ASDs.

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4. James S, Hallur S, Anbar J, Matthews N, Pierce K, Smith CJ. Consistency between parent report and direct assessment of development in toddlers with autism spectrum disorder and other delays: Does sex assigned at birth matter?. Autism Res;2023 (Apr 3)

The current study examined differences between parent report and diagnostician direct assessment of receptive language, expressive language, and fine motor abilities in toddlers with autism spectrum disorder (ASD) and other delays. Additionally, this study examined whether parent-diagnostician consistency varied by child diagnosis and sex assigned at birth (SAB). Initial mixed analysis of variances (ANOVAs) were conducted using data from a sample of 646 toddlers to examine whether parent-diagnostician consistency differed by child diagnosis. Matched samples (using child age, SAB, and nonverbal IQ) were then created within each diagnostic group and mixed ANOVAs were conducted to examine if consistency was similar in matched diagnostic subsamples and whether it differed by SAB. Findings from the full sample mostly replicated previous research that has documented consistency between parent report and direct observation regardless of child diagnosis. However, when examined in matched diagnostic subgroups, more nuanced patterns were observed. Parent report of receptive language was lower in ASD and ASD features subgroups and parent report of fine motor skills was lower than direct observation in the ASD, ASD features, and developmental delay groups. When examining the moderating effect of SAB, only expressive language was impacted for children in the ASD group. Results indicate the importance of considering child demographic characteristics and that child SAB may impact parent report and/or diagnostician perception of expressive language.

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5. Li R, Lightbody AA, Lee CH, Bartholomay KL, Marzelli MJ, Reiss AL. Association of Intrinsic Functional Brain Network and Longitudinal Development of Cognitive-Behavioral Symptoms in Young Girls with Fragile X Syndrome. Biol Psychiatry;2023 (Mar 31)

BACKGROUND: Fragile X syndrome (FXS) is an X chromosome-linked, genetic disorder characterized by increased risk for behavioral, social, and neurocognitive deficits. Due to a more severe phenotype relative to females, research has focused largely on identifying neural abnormalities in all-male or mixed-sex participants with FXS. Therefore, very little is known about the neural alterations that contribute to cognitive-behavioral symptoms in females with FXS. This cross-sectional study aimed to elucidate the large-scale resting-state brain networks associated with the multi-domain cognitive-behavioral phenotype in girls with FXS. METHODS: We recruited 38 girls with full mutation FXS (11.58 ± 3.15 years) and 32 girls without FXS (11.66 ± 2.27 years). Both groups were matched on age, verbal IQ, and multi-domain cognitive-behavioral symptoms. Resting-state functional magnetic resonance imaging data were collected. RESULTS: Compared to the control group, girls with FXS showed significantly greater resting-state functional connectivity of the default mode network (DMN), lower nodal strength at the right middle temporal gyrus, stronger nodal strength at the left caudate, and higher global efficiency of DMN. These aberrant brain network characteristics map directly onto the cognitive-behavioral symptoms commonly observed in girls with FXS. An exploratory analysis suggested that brain network patterns at a prior time point (Time 1) were predictive of the longitudinal development of participants’ multi-domain cognitive-behavioral symptoms. CONCLUSIONS: These findings represent the first examination of large-scale brain network alterations in a large sample of girls with FXS, expanding our knowledge of potential neural mechanisms underlying the development of cognitive-behavioral symptoms in girls with FXS.

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6. Liew Z, Meng Q, Yan Q, Schullehner J, Hansen B, Kristiansen SM, Voutchkova DD, Olsen J, Ersbøll AK, Ketzel M, Raaschou-Nielsen O, Ritz BR. Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark. JAMA Pediatr;2023 (Apr 3)

IMPORTANCE: Lithium is a naturally occurring and trace element that has mood-stabilizing effects. Maternal therapeutic use of lithium has been associated with adverse birth outcomes. In animal models, lithium modulates Wnt/β-catenin signaling that is important for neurodevelopment. It is unknown whether exposure to lithium in drinking water affects brain health in early life. OBJECTIVE: To evaluate whether autism spectrum disorder (ASD) in offspring is associated with maternal exposure to lithium in drinking water during pregnancy. DESIGN, SETTING AND PARTICIPANTS: This nationwide population-based case-control study in Denmark identified 8842 children diagnosed with ASD born from 2000 through 2013 and 43 864 control participants matched by birth year and sex from the Danish Medical Birth Registry. These data were analyzed from March 2021 through November 2022. EXPOSURES: Geocoded maternal residential addresses during pregnancy were linked to lithium level (range, 0.6 to 30.7 μg/L) in drinking water estimated using kriging interpolation based on 151 waterworks measurements of lithium across all regions in Denmark. MAIN OUTCOMES AND MEASURES: ASD diagnoses were ascertained using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes recorded in the Danish Psychiatric Central Register. The study team estimated odds ratios (ORs) and 95% CIs for ASD according to estimated geocoded maternal exposure to natural source of lithium in drinking water as a continuous (per IQR) or a categorical (quartile) variable, adjusting for sociodemographic factors and ambient air pollutants levels. The study team also conducted stratified analyses by birth years, child’s sex, and urbanicity. RESULTS: A total of 8842 participants with ASD (male, 7009 [79.3%]) and 43 864 control participants (male, 34 749 [79.2%]) were studied. Every IQR increase in estimated geocoded maternal exposure to natural source of lithium in drinking water was associated with higher odds for ASD in offspring (OR, 1.23; 95% CI, 1.17-1.29). Elevated odds among offspring for ASD were estimated starting from the second quartile (7.36 to 12.67 μg/L) of estimated maternal exposure to drinking water with lithium and the OR for the highest quartile (more than 16.78 μg/L) compared with the reference group (less than 7.39 μg/L) was 1.46 (95% CI, 1.35-1.59). The associations were unchanged when adjusting for air pollution exposures and no differences were apparent in stratified analyses. CONCLUSIONS AND RELEVANCE: Estimated maternal prenatal exposure to lithium from naturally occurring drinking water sources in Denmark was associated with an increased ASD risk in the offspring. This study suggests that naturally occurring lithium in drinking water may be a novel environmental risk factor for ASD development that requires further scrutiny.

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7. Maffei MF, Chenausky KV, Gill SV, Tager-Flusberg H, Green JR. Oromotor skills in autism spectrum disorder: A scoping review. Autism Res;2023 (Apr 3)

Oromotor functioning plays a foundational role in spoken communication and feeding, two areas of significant difficulty for many autistic individuals. However, despite years of research and established differences in gross and fine motor skills in this population, there is currently no clear consensus regarding the presence or nature of oral motor control deficits in autistic individuals. In this scoping review, we summarize research published between 1994 and 2022 to answer the following research questions: (1) What methods have been used to investigate oromotor functioning in autistic individuals? (2) Which oromotor behaviors have been investigated in this population? and (3) What conclusions can be drawn regarding oromotor skills in this population? Seven online databases were searched resulting in 107 studies meeting our inclusion criteria. Included studies varied widely in sample characteristics, behaviors analyzed, and research methodology. The large majority (81%) of included studies report a significant oromotor abnormality related to speech production, nonspeech oromotor skills, or feeding within a sample of autistic individuals based on age norms or in comparison to a control group. We examine these findings to identify trends, address methodological aspects hindering cross-study synthesis and generalization, and provide suggestions for future research.

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8. McCanlies EC, Gu JK, Kashon M, Yucesoy B, Ma CC, Sanderson WT, Kim K, Ludeña-Rodriguez YJ, Hertz-Picciotto I. Parental occupational exposure to solvents and autism spectrum disorder: An exploratory look at gene-environment interactions. Environ Res;2023 (Mar 31):115769.

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9. McDonnell CG, Andrzejewski T, Gomez Batista S, DeLucia EA, Fok M, Stanton K. Demographic Factors Relate to Autism Diagnostic Certainty: Implications for Enhancing Equitable Diagnosis Among Youth. J Clin Child Adolesc Psychol;2023 (Apr 3):1-11.

OBJECTIVE: Autism diagnosis is fraught with inequities, including misdiagnosis and delayed identification that disproportionately affect minoritized youth. Aspects of clinician decision-making, particularly diagnostic certainty, may contribute to these inequities. Little is known about how closely clinician certainty corresponds with autistic traits, nor whether certainty relates to socio-demographic factors. METHOD: Autistic youth from the Simons Simplex Collection (N = 2,853) completed assessments after which clinicians rated how certain they were that the child met autism diagnostic criteria. Core clinical factors included clinician-observed (Autism Diagnostic Observation Schedule; ADOS) and parent-reported autistic traits (Social Communication Questionnaire), and an overall IQ score. RESULTS: Clinician certainty was moderately positively associated with parent-reported and observed autistic traits and was just as strongly negatively associated with IQ. Socio-demographic factors significantly associated with certainty, even accounting for clinical measures. Lower income and older child age related to less certainty. In contrast, clinicians rated higher certainty for youth identified as Hispanic, Black or African American, or Asian. Race and income also moderated the concordance between certainty with clinical factors. The agreement between higher ADOS scores and higher certainty was significantly weaker for lower-income families. The association between lower IQ and higher certainty was non-significant for Asian youth. CONCLUSIONS: Diagnostic certainty ratings do not necessarily correspond closely with the level of autistic traits, and clinician perception of autism diagnosis may be related to demographic factors. Caution is needed when relying on clinician certainty to inform diagnosis. Future research on diagnostic practices is urgently needed among diverse and minoritized communities.

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10. O’Brien EM, Stricker PA, Harris KA, Liu H, Griffis H, Muhly WT. Perioperative Management and Outcomes in Patients With Autism Spectrum Disorder: A Retrospective Cohort Study. Anesth Analg;2023 (Apr 3)

BACKGROUND: Autism spectrum disorder (ASD) is a neurocognitive disorder characterized by impairments in communication and socialization. There are little data comparing the differences in perioperative outcomes in children with and without ASD. We hypothesized that children with ASD would have higher postoperative pain scores than those without ASD. METHODS: Pediatric patients undergoing ambulatory tonsillectomy/adenoidectomy, ophthalmological surgery, general surgery, and urologic procedures between 2016 and 2021 were included in this retrospective cohort study. ASD patients, defined by International Classification of Diseases-9/10 codes, were compared to controls utilizing inverse probability of treatment weighting based on surgical category/duration, age, sex, race and ethnicity, anesthetizing location, American Society of Anesthesiology physical status, intraoperative opioid dose, and intraoperative dexmedetomidine dose. The primary outcome was the maximum postanesthesia care unit (PACU) pain score, and secondary outcomes included premedication administration, behavior at induction, PACU opioid administration, postoperative vomiting, emergence delirium, and PACU length of stay. RESULTS: Three hundred thirty-five children with ASD and 11,551 non-ASD controls were included. Maximum PACU pain scores in the ASD group were not significantly higher than controls (median, 5; interquartile range [IQR], 0-8; ASD versus median, 5; IQR, 0-8 controls; median difference [95% confidence interval {CI}] of 0 [-1.1 to 1.1]; P = .66). There was no significant difference in the use of premedication (96% ASD versus 95% controls; odds ratio [OR], 1.5; [95% CI, 0.9-2.7]; P = .12), but the ASD cohort had significantly higher odds of receiving an intranasal premedication (4.2% ASD versus 1.2% controls; OR, 3.5 [95% CI, 1.8-6.8]; P < .001) and received ketamine significantly more frequently (0.3% ASD versus <0.1% controls; P < .001). Children with ASD were more likely to have parental (4.9% ASD versus 1.0% controls; OR, 5 [95% CI, 2.1-12]; P < .001) and child life specialist (1.3% ASD versus 0.1% controls; OR, 9.9 [95% CI, 2.3-43]; P < .001) presence at induction, but were more likely to have a difficult induction (11% ASD versus 3.4% controls; OR, 3.42 [95% CI, 1.7-6.7]; P < .001). There were no significant differences in postoperative opioid administration, emergence delirium, vomiting, or PACU length of stay between cohorts. CONCLUSIONS: We found no difference in maximum PACU pain scores in children with ASD compared to a similarly weighted cohort without ASD. Children with ASD had higher odds of a difficult induction despite similar rates of premedication administration, and significantly higher parental and child life specialist presence at induction. These findings highlight the need for future research to develop evidence-based interventions to optimize the perioperative care of this population.

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11. Perini S, Filosi M, Domenici E. Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs. Transl Psychiatry;2023 (Apr 3);13(1):109.

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues.

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12. Pettersson E, Christensen BM, Berglund IG, Huus K. Healthcare professionals’ experiences of situations during a procedure with a child with autism spectrum disorder in the high-technology environment. Child Care Health Dev;2023 (Apr 3)

BACKGROUND: High technological environments can be challenging for children with autism spectrum disorders (ASD), because they can be sensitive to new environments, new faces and changes in daily routines. Those children are frequent visitors in those settings, and due to their heightened healthcare needs and their comorbidities, it could constitute a challenge for healthcare professionals to encounter those children. Exploring the healthcare professionals’ experiences can contribute to facilitate the procedure for a child with ASD. METHOD: A qualitative descriptive retrospective design with a critical incident technique has been used to capture the situations. Twenty healthcare professionals were interviewed about situations affecting the procedure in the high-technology environments, defined as anaesthesia and radiology departments. RESULT: The findings revealed both favourable situations and unfavourable situations affecting the procedure in the high-technology environment. The situations described by the healthcare professionals often involved their interactions with the child and the parents. The interactions were influenced by the parents’ attitudes to the procedure and also the healthcare professionals and the parents’ different expectations on the procedure. Other experiences described by the healthcare professionals were the unpredictability in different situations. Those situations were related to the child’s unpredictable behaviour in those environments and also to the unpredictable effect of premedication provided to the child. Moreover, the result revealed the organizational prerequisites for facilitating a procedure, such as not feeling any time pressure when leading a child through a procedure. CONCLUSIONS: Interactions between healthcare professionals, children with ASD and parents in the high-technology environment are complex. Unpredictability characterizes situations when leading a child with ASD through a procedure. This place demands on the healthcare professional, the environment and the organization.

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13. Pham AV, Charles LC. Racial Disparities in Autism Diagnosis, Assessment, and Intervention among Minoritized Youth: Sociocultural Issues, Factors, and Context. Curr Psychiatry Rep;2023 (Apr 1)

PURPOSE OF REVIEW: Despite the increasing prevalence of autism spectrum disorder (ASD) among youth, disparities exist when it comes to access to diagnostic assessment and intervention of ASD in clinical and school settings. A review of the literature on sociocultural issues that contribute to these disparities would allow psychiatrists, clinicians, and researchers to better understand these challenges and aid in the development of culturally responsive approaches to support racially, ethnically, and linguistically diverse families of youth with ASD. RECENT FINDINGS: Disparities in ASD services are primarily due to system-level factors, including access to information or healthcare, stigma, and discrimination. Similarly, interactional factors, such as language/communication barriers, a lack of trust in professionals, and limited training in cultural responsiveness, can hinder support for diverse families of youth with ASD. This review focuses on several areas: (1) structural inequities that contribute to disparities in ASD services, (2) sociocultural issues in assessment and diagnosis, (3) sociocultural issues in interventions and service use, and (4) neurodiversity. This review underscores the importance of including diverse samples in ASD research to improve understanding of the strengths, challenges, perspectives, and preferences of underrepresented and underserved families of youth with ASD. These efforts can lead to culturally responsive service delivery.

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14. Prince N, Chu SH, Chen Y, Mendez KM, Hanson E, Green-Snyder L, Brooks E, Korrick S, Lasky-Su JA, Kelly RS. Phenotypically driven subgroups of ASD display distinct metabolomic profiles. Brain Behav Immun;2023 (Mar 31);111:21-29.

Autism Spectrum Disorder (ASD) is a heterogeneous condition that includes a broad range of characteristics and associated comorbidities; however, the biology underlying the variability in phenotypes is not well understood. As ASD impacts approximately 1 in 100 children globally, there is an urgent need to better understand the biological mechanisms that contribute to features of ASD. In this study, we leveraged rich phenotypic and diagnostic information related to ASD in 2001 individuals aged 4 to 17 years from the Simons Simplex Collection to derive phenotypically driven subgroups and investigate their respective metabolomes. We performed hierarchical clustering on 40 phenotypes spanning four ASD clinical domains, resulting in three subgroups with distinct phenotype patterns. Using global plasma metabolomic profiling generated by ultrahigh-performance liquid chromatography mass spectrometry, we characterized the metabolome of individuals in each subgroup to interrogate underlying biology related to the subgroups. Subgroup 1 included children with the least maladaptive behavioral traits (N = 862); global decreases in lipid metabolites and concomitant increases in amino acid and nucleotide pathways were observed for children in this subgroup. Subgroup 2 included children with the highest degree of challenges across all phenotype domains (N = 631), and their metabolome profiles demonstrated aberrant metabolism of membrane lipids and increases in lipid oxidation products. Subgroup 3 included children with maladaptive behaviors and co-occurring conditions that showed the highest IQ scores (N = 508); these individuals had increases in sphingolipid metabolites and fatty acid byproducts. Overall, these findings indicated distinct metabolic patterns within ASD subgroups, which may reflect the biological mechanisms giving rise to specific patterns of ASD characteristics. Our results may have important clinical applications relevant to personalized medicine approaches towards managing ASD symptoms.

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15. Rattaz C, Loubersac J, Michelon C, Picot MC, Baghdadli A. Changes in mothers’ and fathers’ stress level, mental health and coping strategies during the 3 years following ASD diagnosis. Res Dev Disabil;2023 (Mar 31);137:104497.

BACKGROUND: ASD in a child affects parental mental health, with elevated levels of stress, anxiety and depression reported in parents. METHOD: In this study, we examined mothers’ and fathers’ stress, anxiety and depression, as well as their coping strategies in a sample of 103 children and adolescents enrolled in the ELENA cohort study in France at diagnosis and three years after diagnosis. RESULTS: Results showed that mothers had higher levels of stress and anxiety / depression than fathers and used more social support coping strategies at diagnosis, which might be explained by increased levels of parental involvement. Mothers’ stress level significantly decreased during the three years following ASD diagnosis but no such decrease was observed in fathers’ stress level. A significant decrease in anxiety and depression was observed for both parents, suggesting that parental distress is particularly elevated during the critical diagnosis period. Results finally yielded a significant decrease in emotion-focused coping strategy in mothers over the three-year period, an ineffective strategy that takes places at the time of diagnosis but then decreases during the period following ASD diagnosis, in relation to the acceptance process. CONCLUSIONS: Implications in terms of addressing the unmet mental health needs of parents and their coping strategies are discussed.

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16. Wagner L, Banchik M, Okada NJ, McDonald N, Jeste SS, Bookheimer SY, Green SA, Dapretto M. Associations between thalamocortical functional connectivity and sensory over-responsivity in infants at high likelihood for ASD. Cereb Cortex;2023 (Mar 31)

Despite growing evidence implicating thalamic functional connectivity atypicalities in autism spectrum disorder (ASD), it remains unclear how such alterations emerge early in human development. Because the thalamus plays a critical role in sensory processing and neocortical organization early in life, its connectivity with other cortical regions could be key for studying the early onset of core ASD symptoms. Here, we investigated emerging thalamocortical functional connectivity in infants at high (HL) and typical (TL) familial likelihood for ASD in early and late infancy. We report significant thalamo-limbic hyperconnectivity in 1.5-month-old HL infants, and thalamo-cortical hypoconnectivity in prefrontal and motor regions in 9-month-old HL infants. Importantly, early sensory over-responsivity (SOR) symptoms in HL infants predicted a direct trade-off in thalamic connectivity whereby stronger thalamic connectivity with primary sensory regions and basal ganglia was inversely related to connectivity with higher order cortices. This trade-off suggests that ASD may be characterized by early differences in thalamic gating. The patterns reported here could directly underlie atypical sensory processing and attention to social vs. nonsocial stimuli observed in ASD. These findings lend support to a theoretical framework of ASD whereby early disruptions in sensorimotor processing and attentional biases early in life may cascade into core ASD symptomatology.

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