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Investigating the role of puberty on executive function (EF) development is important for understanding how maturation and its related changes can impact neural systems underlying EF in autistic (AT) adolescents. Studies document chronological age-related differences in EF among AT youth, but the impact of puberty is understudied. We examined the role of cross-sectional pubertal status (Pubertal Development Scale adrenal and gonadal indices), autism status, and assigned sex at birth on parent-reported EF (Behavior Rating Inventory of Executive Function: inhibition, shift, working memory) in AT and non-autistic (NA) youth. We hypothesized AT youth, particularly females, would show more EF problems in late puberty relative to NA youth. AT males and females and NA females in late puberty had fewer shift problems relative to pre-pubertal youth, whereas NA males in late puberty had more shift problems relative to pre-pubertal NA males. There were no significant assigned sex or puberty differences in working memory for adrenal development and in any EF domain for gonadal development. Findings suggest adrenal puberty contributes to flexibility and may promote certain EF domains in AT youth. Longitudinal research using diverse measures of puberty and EF is needed to clarify findings.

The common intersection of autism and transgender identities has been described in clinical and community contexts. This study investigates autism-related neurophenotypes among transgender youth. Forty-five transgender youth, evenly balanced across non-autistic, slightly subclinically autistic, and full-criteria autistic subgroupings, completed resting-state functional magnetic resonance imaging to examine functional connectivity. Results confirmed hypothesized default mode network (DMN) hub hyperconnectivity with visual and motor networks in autism, partially replicating previous studies comparing cisgender autistic and non-autistic adolescents. The slightly subclinically autistic group differed from both non-autistic and full-criteria autistic groups in DMN hub connectivity to ventral attention and sensorimotor networks, falling between non-autistic and full-criteria autistic groups. Autism traits showed a similar pattern to autism-related group analytics, and also related to hyperconnectivity between DMN hub and dorsal attention network. Internalizing, gender dysphoria, and gender minority-related stigma did not show connectivity differences. Connectivity differences within DMN followed previously reported patterns by designated sex at birth (i.e. female birth designation showing greater within-DMN connectivity). Overall, findings suggest behavioral diagnostics and autism traits in transgender youth correspond to observable differences in DMN hub connectivity. Further, this study reveals novel neurophenotypic characteristics associated with slightly subthreshold autism, highlighting the importance of research attention to this group.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by social and communication differences. Recent research suggests ASD affects 1-in-44 children in the United States. ASD is diagnosed more commonly in males, though it is unclear whether this diagnostic disparity is a result of a biological predisposition or limitations in diagnostic tools, or both. One hypothesis centers on the ‘female protective effect,’ which is the theory that females are biologically more resistant to the autism phenotype than males. In this examination, phenotypic data were acquired and combined from four leading research institutions and subjected to multivariate linear discriminant analysis. A linear discriminant model was trained on the training set and then deployed on the test set to predict group membership. Multivariate analyses of variance were performed to confirm the significance of the overall analysis, and individual analyses of variance were performed to confirm the significance of each of the resulting linear discriminant axes. Two discriminant dimensions were identified between the groups: a dimension separating groups by the diagnosis of ASD (LD1: 87% of variance explained); and a dimension reflective of a diagnosis-by-sex interaction (LD2: 11% of variance explained). The strongest discriminant coefficients for the first discriminant axis divided the sample in domains with known differences between ASD and comparison groups, such as social difficulties and restricted repetitive behavior. The discriminant coefficients for the second discriminant axis reveal a more nuanced disparity between boys with ASD and girls with ASD, including executive functioning and high-order behavioral domains as the dominant discriminators. These results indicate that phenotypic differences between males and females with and without ASD are identifiable using parent report measures, which could be utilized to provide additional specificity to the diagnosis of ASD in female patients, potentially leading to more targeted clinical strategies and therapeutic interventions. The study helps to isolate a phenotypic basis for future empirical work on the female protective effect using neuroimaging, EEG, and genomic methodologies.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8–17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts., Females are less frequently diagnosed with autism than males. Using functional brain imaging and genetic analyses, Jack et al. show that differences in the striatum, a part of the brain involved in attaching motivational value to stimuli in the environment, may contribute to autism risk in girls.

Adaptive functioning, or the suite of skills essential for real-world, day-to-day functioning, includes daily living, communication, and socialization abilities. Even in the absence of co-occurring intellectual disability (IQ 70) ASD (females = 75, males = 102), and 178 typically developing (TD) (females = 87, males = 91) youth, aged 8–17 years. We examined whether each group evidenced a gap between full-scale IQ and adaptive skills and its associations with age. ASD youth evinced significantly lower adaptive skills and a significantly greater IQ-adaptive functioning gap than their same-sex TD peers. In this cross-sectional sample, the increase in the IQ-adaptive functioning gap with age was of similar magnitude for ASD males and females, but only reached statistical significance in males. We discuss unique implications the profound IQ-socialization skills gap in particular may have for ASD females. Lay abstract Adaptive functioning refers to skills that are vital to success in day-to-day life, including daily living (e.g. grocery shopping, food preparation, transportation use), communication (e.g. verbal expression of needs), and socialization skills (e.g. interpersonal skills, including expressing and recognizing emotions, and understanding turn-taking in conversation). Among autistic individuals without intellectual disability, adaptive functioning is not commensurate with intellectual ability (IQ), and instead a gap exists between these individuals’ intellectual ability and their adaptive skills. Further, these autistic individuals show a widening of this gap with increasing age. Existing studies of the gap between IQ and adaptive functioning have studied predominantly male samples. Thus, we do not know if the gap also exists in autistic females. We therefore looked at adaptive functioning and the gap between IQ and adaptive functioning in a large sample of autistic girls and boys without intellectual disability. To disentangle effects of group (autistic vs typically developing) from effects of sex (girls vs boys), we compared autistic girls and boys to one another as well as to their same-sex typically developing peers. Analyses took into consideration differences in IQ between autistic and typically developing youth. We found autistic girls, like autistic boys, show lower adaptive functioning than their same-sex typically developing peers. Results underscore the need to evaluate adaptive functioning in autistic individuals without intellectual disability and to provide necessary supports. The large gap between intellectual ability and socialization skills, in particular, may be of critical importance in improving our understanding of outcomes and mental health difficulties among autistic females.

Our aim was to use theta coherence as a quantitative trait to investigate the relation of the polymorphisms in NKCC1 (rs3087889) and KCC2 (rs9074) channel protein genes to autistic traits (AQ) in neurotypicals. Coherence values for candidate connection regions were calculated from eyes-closed resting EEGs in two independent groups. Hypersynchrony within the right anterior region was related to AQ in both groups (p

Despite advances in early detection, the average age of autism spectrum disorder (ASD) diagnosis exceeds 4 years and is often later in females. In typical development, biological sex predicts inter-individual variation across multiple developmental milestones, with females often exhibiting earlier progression. The goal of this study was to examine sex differences in caregiver-reported developmental milestones (first word, phrase, walking) and their contribution to timing of initial concerns expressed by caregivers and eventual age of diagnosis. 195 (105 males) children and adolescents aged 8 to 17 years with a clinical diagnosis of ASD were recruited to the study (mean IQ = 99.76). While developmental milestones did not predict timing of diagnosis or age parents first expressed concerns, females had earlier first words and phrases than males. There was a marginal difference in the age of diagnosis, with females receiving their diagnosis 1 year later than males. Despite sex differences in developmental milestones and diagnostic variables, IQ was the most significant predictor in the timing of initial concerns and eventual diagnosis, suggesting children with lower IQ, regardless of sex, are identified and diagnosed earlier. Overall, biological sex and developmental milestones did not account for a large proportion of variance for the eventual age of ASD diagnosis, suggesting other factors (such as IQ and the timing of initial concerns) are potentially more influential. LAY SUMMARY: In this study, a later age of diagnosis in females having ASD was confirmed; however, biological sex was not the stronger predictor of age of diagnosis. Parents reported that females learned language more quickly than males, and parents noted their first concerns when females were older than males. In this sample, the strongest predictor of age of diagnosis was the age of first concerns.

Background Childhood aggression has been linked to white matter abnormalities, but research has been inconsistent with regard to both regions of alterations and directionality of the associations. We examined white matter microstructure correlates of aggression using a novel diffusion imaging analysis technique, fixel-based analysis, which leverages connectivity and crossing-fiber information to assess fiber bundle density. Methods The sample included 70 children with aggressive behavior and 25 healthy control children without aggressive behavior. Aggression was measured by the parent-rated Aggressive Behavior scale of the Child Behavior Checklist. Fixel-based analysis was conducted at the whole-brain and region-of-interest levels, including the uncinate fasciculus, inferior longitudinal fasciculus, fornix, cingulum bundle, and genu, body, isthmus, and splenium of the corpus callosum. Results Whole-brain analysis of covariance revealed that children with aggressive behavior, relative to control children, had lower fiber density in a cluster of limbic and cortical pathways, including the inferior fronto-occipital fasciculus, fornix, middle cerebellar peduncle, and superior thalamic radiations (familywise error–corrected p Conclusions Diminished white matter density in pathways connecting limbic and cortical regions is associated with childhood aggression. Abnormal interhemispheric connectivity via corpus callosum may also reflect a potential neural mechanism involved in aggression.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8–17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Few studies have examined self-reported perceived stress in autistic adults. Existing studies have included relatively small, predominantly male samples and have not included older autistic adults. Using a large autistic sample (N = 713), enriched for individuals designated female at birth (59.3%), and spanning younger, middle, and older adulthood, we examined perceived stress and its associations with independence in activities of daily living and subjective quality of life (QoL). Perceived stress for autistic adults designated male or female at birth was compared to their same birth-sex counterparts in a general population sample. In addition, within the autistic sample, effects of sex designated at birth, age, and their interaction were examined. Regression modeling examined associations between perceived stress and independence in activities of daily living and domains of subjective QoL in autistic adults, after controlling for age, sex designated at birth, and household income. Autistic adults reported significantly greater perceived stress than a general population comparison sample. Relative to autistic adults designated male at birth, those designated female at birth demonstrated significantly elevated perceived stress. Perceived stress contributed significantly to all regression models, with greater perceived stress associated with less independence in activities of daily living, and poorer subjective QoL across all domains-Physical, Psychological, Social, Environment, and Autism-related QoL. Findings are contextualized within the literature documenting that autistic individuals experience elevated underemployment and unemployment, heightened rates of adverse life events, and increased exposure to minority stress. LAY SUMMARY: This study looked at self-reported perceived stress in a large sample of autistic adults. Autistic adults reported more perceived stress than non-autistic adults. Autistic individuals designated female at birth reported higher stress than autistic individuals designated male at birth. In autistic adults, greater perceived stress is related to less independence in activities of daily living and poorer subjective quality of life.

Aggressive behavior is common across childhood-onset psychiatric disorders and is associated with impairments in social cognition and communication. The present study examined whether amygdala connectivity and reactivity during face emotion processing in children with maladaptive aggression are moderated by social impairment. This cross-sectional study included a well-characterized transdiagnostic sample of 101 children of age 8–16 years old with clinically significant levels of aggressive behavior and 32 typically developing children without aggressive behavior. Children completed a face emotion perception task of fearful and calm faces during functional magnetic resonance imaging. Aggressive behavior and social functioning were measured by standardized parent ratings. Relative to controls, children with aggressive behavior showed reduced connectivity between the amygdala and the dorsolateral prefrontal cortex (PFC) during implicit emotion processing. In children with aggressive behavior, the association between reduced amygdala–ventrolateral PFC connectivity and greater severity of aggression was moderated by greater social impairment. Amygdala reactivity to fearful faces was also associated with severity of aggressive behavior for children without social deficits but not for children with social deficits. Social impairments entail difficulties in interpreting social cues and enacting socially appropriate responses to frustration or provocation, which increase the propensity for an aggressive response via diminished connectivity between the amygdala and the ventral PFC.

INTRODUCTION The purpose of this study is to understand the neurological differences between patients born with combined sagittal and metopic craniosynostosis (SMc) and isolated sagittal craniosynostosis (ISc) by studying aberrations in functional brain connectivity and white matter microstructure, before surgery, utilizing functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). METHODS The authors collected DTI and resting-state (ie, no sedation and asleep) functional connectivity MRI data in 10 infant patients preoperatively: 5 in the SMc group (4.3 ± 1 months) and 5 in the ISc group (4.8 ± 1.1 months). Resting state fMRI imaging and DTI data were acquired using a 3-T Siemens Trio MRI system (Erlangen, Germany) while the infant patients slept. fMRI data were corrected for movement using SPM, underwent cerebrospinal fluid and white matter signal regression and further analyzed with BioImageSuite. For the DTI data, 3 diffusion runs were averaged, processed utilizing FMRIB Software Library, and analyzed statistically using BioImageSuite. RESULTS Comparing the SMc versus ISc groups, SMc demonstrated that there was increased connectivity, statistically significant differences, in neural networks between children with sagittal synostosis alone versus those with sagittal with metopic synostosis, in the right BA 31 and BA 23 (corresponding to the posterior cingulate cortex (PCC) (P

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by primary difficulties in social function. Individuals with ASD display slowed neural processing of faces, as indexed by the latency of the N170, a face-sensitive event-related potential. Currently, there are no objective biomarkers of ASD useful in clinical care or research. Efficacy of behavioral treatment is currently evaluated through subjective clinical impressions. To explore whether the N170 might have utility as an objective index of treatment response, we examined N170 before and after receipt of an empirically validated behavioral treatment in children with ASD.Method: Electroencephalography (EEG) data were obtained on a preliminary cohort of preschool-aged children with ASD before and after a 16-week course of PRT and in a subset of participants in waitlist control (16-weeks before the start of PRT) and follow-up (16-weeks after the end of PRT). EEG was recorded while participants viewed computer-generated faces with neutral and fearful affect.Results: Significant reductions in N170 latency to faces were observed following 16 weeks of PRT intervention. Change in N170 latency was not observed in the waitlist-control condition.Conclusions: This exploratory study offers suggestive evidence that N170 latency may index response to behavioral treatment. Future, more rigorous, studies in larger samples are indicated to evaluate whether the N170 may be useful as a biomarker of treatment response.

INTRODUCTION In this study, the authors seek to clarify the neurological changes before and after whole vault cranioplasty (WVC) in patients born with sagittal craniosynostosis. METHODS A case control study design was performed that included thirty functional MRI scans, from 25 individual patients. Functional MRI and diffusion tension imaging data were analyzed with BioImageSuite (Yale University, USA). 9 functional brain networks were analyzed, with appropriate correlated functional regions of the brain and utilized for analysis. RESULTS Comparing functional MRI the infants after WVC versus infants before WVC group, the after WVC group demonstrated an increased connectivity in the left frontoparietal, secondary (V2), and third (V3) visual networks (P