Despite much research on the function of the insular cortex, few studies have investigated functional subdivisions of the insula in humans. The present study used resting-state functional connectivity magnetic resonance imaging (MRI) to parcellate the human insular lobe based on clustering of functional connectivity patterns. Connectivity maps were computed for each voxel in the insula based on resting-state functional MRI (fMRI) data and segregated using cluster analysis. We identified 3 insular subregions with distinct patterns of connectivity: a posterior region, functionally connected with primary and secondary somatomotor cortices; a dorsal anterior to middle region, connected with dorsal anterior cingulate cortex, along with other regions of a previously described control network; and a ventral anterior region, primarily connected with pregenual anterior cingulate cortex. Applying these regions to a separate task data set, we found that dorsal and ventral anterior insula responded selectively to disgusting images, while posterior insula did not. These results demonstrate that clustering of connectivity patterns can be used to subdivide cerebral cortex into anatomically and functionally meaningful subregions; the insular regions identified here should be useful in future investigations on the function of the insula.

Neuroimaging studies have identified a common network of brain regions involving the prefrontal and parietal cortices across a variety of working memory (WM) tasks. However, previous studies have also reported category-specific dissociations of activation within this network. In this study, we investigated the development of category-specific activation in a WM task with digits, letters, and faces. Eight-year-old children and adults performed a 2-back WM task while their brain activity was measured using functional magnetic resonance imaging (fMRI). Overall, children were significantly slower and less accurate than adults on all three WM conditions (digits, letters, and faces); however, within each age group, behavioral performance across the three conditions was very similar. FMRI results revealed category-specific activation in adults but not children in the intraparietal sulcus for the digit condition. Likewise, during the letter condition, category-specific activation was observed in adults but not children in the left occipital-temporal cortex. In contrast, children and adults showed highly similar brain-activity patterns in the lateral fusiform gyri when solving the 2-back WM task with face stimuli. Our results suggest that 8-year-old children do not yet engage the typical brain regions that have been associated with abstract or semantic processing of numerical symbols and letters when these processes are task-irrelevant and the primary task is demanding. Nevertheless, brain activity in letter-responsive areas predicted children's spelling performance underscoring the relationship between abstract processing of letters and linguistic abilities. Lastly, behavioral performance on the WM task was predictive of math and language abilities highlighting the connection between WM and other cognitive abilities in development.

Disruptive behavior in autism spectrum disorder (ASD) is an important clinical problem, but its neural basis remains poorly understood. The current research aims to better understand the neural underpinnings of disruptive behavior in ASD, while addressing whether the neural basis is shared with or separable from that of core ASD symptoms.

Sex differences in brain structure in children with disruptive behavior disorders (DBD) remain poorly understood. This study examined sex differences in gray matter volume in children with DBD in a priori regions-of-interest implicated in the pathophysiology of disruptive behavior. We then conducted a whole-brain analysis of cortical thickness to examine sex differences in regions not included in our hypothesis. Exploratory analyses investigated unique associations between structure, and dimensional measures of severity of disruptive behavior and callous-unemotional traits. This cross-sectional study included 88 children with DBD (30 females) aged 8-16 years and 50 healthy controls (20 females). Structural MRI data were analyzed using surface-based morphometry to test for interactions between sex and group. Multiple-regression analyses tested for sex-specific associations between structure, callous-unemotional traits, and disruptive behavior severity. Boys with DBD showed reduced gray matter volume in the left ventromedial prefrontal cortex (vmPFC) and reduced cortical thickness in the supramarginal gyrus, but not girls compared to respective controls. Dimensional analyses revealed associations between sex, callous-unemotional traits, and disruptive behavior for amygdala and vmPFC volume, and ventrolateral prefrontal cortex cortical thickness. Sex-specific differences in prefrontal structures involved in emotion regulation may support identification of neural biomarkers of disruptive behavior to inform target-based treatments.

Resting-state functional magnetic resonance imaging (rsfMRI) studies reveal a complex pattern of hyper- and hypo-connectivity in children with autism spectrum disorder (ASD). Whereas rsfMRI findings tend to implicate the default mode network and subcortical areas in ASD, task fMRI and behavioral experiments point to social dysfunction as a unifying impairment of the disorder. Here, we leverage a novel Bayesian framework for whole-brain functional connectomics that aggregates population differences in connectivity to localize a subset of foci that are most affected by ASD. Our approach is entirely data-driven and does not impose spatial constraints on the region foci or dictate the trajectory of altered functional pathways. We apply our method to data from the openly shared Autism Brain Imaging Data Exchange (ABIDE) and pinpoint two intrinsic functional networks that distinguish ASD patients from typically developing controls. One network involves foci in the right temporal pole, left posterior cingulate cortex, left supramarginal gyrus, and left middle temporal gyrus. Automated decoding of this network by the Neurosynth meta-analytic database suggests high-level concepts of "language" and "comprehension" as the likely functional correlates. The second network consists of the left banks of the superior temporal sulcus, right posterior superior temporal sulcus extending into temporo-parietal junction, and right middle temporal gyrus. Associated functionality of these regions includes "social" and "person". The abnormal pathways emanating from the above foci indicate that ASD patients simultaneously exhibit reduced long-range or inter-hemispheric connectivity and increased short-range or intra-hemispheric connectivity. Our findings reveal new insights into ASD and highlight possible neural mechanisms of the disorder.

Adult humans, infants, pre-school children, and non-human animals appear to share a system of approximate numerical processing for non-symbolic stimuli such as arrays of dots or sequences of tones. Behavioral studies of adult humans implicate a link between these non-symbolic numerical abilities and symbolic numerical processing (e.g., similar distance effects in accuracy and reaction-time for arrays of dots and Arabic numerals). However, neuroimaging studies have remained inconclusive on the neural basis of this link. The intraparietal sulcus (IPS) is known to respond selectively to symbolic numerical stimuli such as Arabic numerals. Recent studies, however, have arrived at conflicting conclusions regarding the role of the IPS in processing non-symbolic, numerosity arrays in adulthood, and very little is known about the brain basis of numerical processing early in development. Addressing the question of whether there is an early-developing neural basis for abstract numerical processing is essential for understanding the cognitive origins of our uniquely human capacity for math and science. Using functional magnetic resonance imaging (fMRI) at 4-Tesla and an event-related fMRI adaptation paradigm, we found that adults showed a greater IPS response to visual arrays that deviated from standard stimuli in their number of elements, than to stimuli that deviated in local element shape. These results support previous claims that there is a neurophysiological link between non-symbolic and symbolic numerical processing in adulthood. In parallel, we tested 4-y-old children with the same fMRI adaptation paradigm as adults to determine whether the neural locus of non-symbolic numerical activity in adults shows continuity in function over development. We found that the IPS responded to numerical deviants similarly in 4-y-old children and adults. To our knowledge, this is the first evidence that the neural locus of adult numerical cognition takes form early in development, prior to sophisticated symbolic numerical experience. More broadly, this is also, to our knowledge, the first cognitive fMRI study to test healthy children as young as 4 y, providing new insights into the neurophysiology of human cognitive development.

Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain's reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation-one that could, in future, be harnessed to augment behavioral treatments for ASD.

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP - induced osteoblast differentiation (p<10-20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences.

Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.

Individuals with autism spectrum disorder (ASD) have been characterized by altered cerebral cortical structures; however, the field has yet to identify consistent markers and prior studies have included mostly adolescents and adults. While there are multiple cortical morphological measures, including cortical thickness, surface area, cortical volume, and cortical gyrification, few single studies have examined all these measures. The current study analyzed all of the four measures and focused on pre-adolescent children with ASD.

Measuring treatment efficacy in individuals with Autism Spectrum Disorder (ASD) relies primarily on behaviors, with limited evidence as to the neural mechanisms underlying these behavioral gains. This pilot study addresses this void by investigating neural and behavioral changes in a Phase I trial in young adults with high-functioning ASD who received an evidence-based behavioral intervention, Virtual Reality-Social Cognition Training over 5 weeks for a total of 10 hr. The participants were tested pre- and post-training with a validated biological/social versus scrambled/nonsocial motion neuroimaging task, previously shown to activate regions within the social brain networks. Three significant brain-behavior changes were identified. First, the right posterior superior temporal sulcus, a hub for socio-cognitive processing, showed increased brain activation to social versus nonsocial stimuli in individuals with greater gains on a theory-of-mind measure. Second, the left inferior frontal gyrus, a region for socio-emotional processing, tracked individual gains in emotion recognition with decreased activation to social versus nonsocial stimuli. Finally, the left superior parietal lobule, a region for visual attention, showed significantly decreased activation to nonsocial versus social stimuli across all participants, where heightened attention to nonsocial contingencies has been considered a disabling aspect of ASD. This study provides, albeit preliminary, some of the first evidence of the harnessable neuroplasticity in adults with ASD through an age-appropriate intervention in brain regions tightly linked to social abilities. This pilot trial motivates future efforts to develop and test social interventions to improve behaviors and supporting brain networks in adults with ASD. Autism Res 2018, 11: 713-725. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc.

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.

Infants are responsive to and show a preference for human vocalizations from very early in development. While previous studies have provided a strong foundation of understanding regarding areas of the infant brain that respond preferentially to social vs. non-social sounds, how the infant brain responds to sounds of varying social significance over time, and how this relates to behavior, is less well understood. The current study uniquely examined longitudinal brain responses to social sounds of differing social-communicative value in infants at 3 and 6 months of age using functional near-infrared spectroscopy (fNIRS). At 3 months, infants showed similar patterns of widespread activation in bilateral temporal cortices to communicative and non-communicative human non-speech vocalizations, while by 6 months infants showed more similar, and focal, responses to social sounds that carried increased social value (infant-directed speech and human non-speech communicative sounds). In addition, we found that brain activity at 3 months of age related to later brain activity and receptive language abilities as measured at 6 months. These findings suggest areas of consistency and change in auditory social perception between 3 and 6 months of age.

Mentalizing, in particular the successful attribution of complex mental states to others, is crucial for navigating social interactions. This ability is highly influenced by external factors within one's daily life, such as stress. We investigated the impact of stress on the brain basis of mentalization in adults. Using a novel modification of the Reading the Mind in the Eyes Test (RMET-R) we compared the differential effects of two personalized stress induction procedures: a general stress induction (GSI) and an attachment-related stress induction (ASI). Participants performed the RMET-R at baseline and after each of the two inductions. Baseline results replicated and extended previous findings regarding the neural correlates of the RMET-R. Additionally, we identified brain regions associated with making complex age judgments from the same stimuli. Results after stress exposure showed that the ASI condition resulted in reduced mentalization-related activation in the left posterior superior temporal sulcus (STS), left inferior frontal gyrus and left temporoparietal junction (TPJ). Moreover, the left middle frontal gyrus and left anterior insula showed greater functional connectivity to the left posterior STS after the ASI. Our findings indicate that attachment-related stress has a unique effect on the neural correlates of mentalization.

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.

Interpersonal neural synchrony (INS) occurs when neural electrical activity temporally aligns between individuals during social interactions. It has been used as a metric for interpersonal closeness, often during naturalistic child-parent interactions. This study evaluated whether other biological correlates of social processing predicted the prevalence of INS during child-parent interactions, and whether their observed cooperativity modulated this association. Child-parent dyads (n = 27) performed a visuospatial tower-building task in cooperative and competitive conditions. Neural activity was recorded using mobile electroencephalogram (EEG) headsets, and experimenters coded video-recordings post-hoc for behavioral attunement. DNA methylation of the oxytocin receptor gene (OXTRm) was measured, an epigenetic modification associated with reduced oxytocin activity and socioemotional functioning. Greater INS during competition was associated with lower child OXTRm, while greater behavioral attunement during competition and cooperation was associated with higher parent OXTRm. These differential relationships suggest that interpersonal dynamics as measured by INS may be similarly reflected by other biological markers of social functioning, irrespective of observed behavior. Children's self-perceived communication skill also showed opposite associations with parent and child OXTRm, suggesting complex relationships between children's and their parents' social functioning. Our findings have implications for ongoing developmental research, supporting the utility of biological metrics in characterizing interpersonal relationships.