Sensory over-responsivity and atypical neural responses to socially relevant stimuli in autism.

Although aversive responses to sensory stimuli are common in autism spectrum disorder (ASD), it remains unknown whether the social relevance of aversive sensory inputs affects their processing. We used functional magnetic resonance imaging (fMRI) to investigate neural responses to mildly aversive nonsocial and social sensory stimuli as well as how sensory over-responsivity (SOR) severity relates to these responses. Participants included 21 ASD and 25 typically-developing (TD) youth, aged 8.6-18.0 years. Results showed that TD youth exhibited significant neural discrimination of socially relevant versus irrelevant aversive sensory stimuli, particularly in the amygdala and orbitofrontal cortex (OFC), regions that are crucial for sensory and social processing. In contrast, ASD youth showed reduced neural discrimination of social versus nonsocial stimuli in the amygdala and OFC, as well as overall greater neural responses to nonsocial compared with social stimuli. Moreover, higher SOR in ASD was associated with heightened responses in sensory-motor regions to socially-relevant stimuli. These findings further our understanding of the relationship between sensory and social processing in ASD, suggesting limited attention to the social relevance compared with aversiveness level of sensory input in ASD versus TD youth, particularly in ASD youth with higher SOR.

Substance use patterns in 9-10 year olds: Baseline findings from the adolescent brain cognitive development (ABCD) study.

BACKGROUND: The Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12. METHODS: This study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort's early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD). PRIMARY RESULTS: At baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine, <0.1 % used any other drug of abuse). Analyses revealed that total caffeine use and early alcohol sipping were associated with demographic variables (p's<.05), externalizing symptoms (caffeine p = 0002; sipping p = .0003), and parental history of AUD (sipping p = .03). CONCLUSIONS: ABCD Study participants aged 9-10 years old reported caffeine use and alcohol sipping experimentation, but very rare other SU. Variables linked with early childhood alcohol sipping and caffeine use should be examined as contributing factors in future longitudinal analyses examining escalating trajectories of SU in the ABCD Study cohort.

Sex Differences in Internalizing Symptoms and Amygdala Functional Connectivity in Neurotypical Youth.

Amygdala resting-state functional connectivity (rsFC) is altered in adolescents with internalizing disorders, though the relationship between rsFC and subclinical symptomatology in neurotypical youth remains unclear. Here we examined whether amygdala rsFC varied across a continuum of internalizing symptoms in 110 typically-developing (TD) youths 8 to 17 years old using functional magnetic resonance imaging (fMRI). We assessed overall internalizing symptoms, as well as anxious-depressed, withdrawn-depressed, and somatic complaints. Given known sex differences in the prevalence of internalizing disorders, we compared connectivity between males and females. As compared to males, females with greater internalizing, anxious-depressed, and somatic symptoms displayed greater connectivity with the cingulate gyrus, insula, and somatosensory cortices. In contrast, males with greater anxious-depressed symptoms demonstrated weaker connectivity with the subcallosal prefrontal cortex. Sex differences in rsFC in relation to symptom severity were evident for the whole amygdala and for two of its subnuclei (centromedial and superficial amygdala). Overall, results suggest that, for females, higher internalizing symptoms are associated with greater rsFC between the amygdala and regions implicated in emotional and somatosensory processing, salience detection, and action selection. Future longitudinal investigations are needed to determine whether this hyperconnectivity may confer resilience to, or pose risk for, the development of internalizing disorders.

Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism.

Several common alleles in the oxytocin receptor gene (OXTR) are associated with altered brain function in reward circuitry in neurotypical adults and may increase risk for autism spectrum disorders (ASD). Yet, it is currently unknown how variation in the OXTR relates to brain functioning in individuals with ASD, and, critically, whether neural endophenotypes vary as a function of aggregate genetic risk. Here, for we believe the first time, we use a multi-locus approach to examine how genetic variation across several OXTR single-nucleotide polymorphisms (SNPs) affect functional connectivity of the brain's reward network. Using data from 41 children with ASD and 41 neurotypical children, we examined functional connectivity of the nucleus accumbens (NAcc) - a hub of the reward network - focusing on how connectivity varies with OXTR risk-allele dosage. Youth with ASD showed reduced NAcc connectivity with other areas in the reward circuit as a function of increased OXTR risk-allele dosage, as well as a positive association between risk-allele dosage and symptom severity, whereas neurotypical youth showed increased NAcc connectivity with frontal brain regions involved in mentalizing. In addition, we found that increased NAcc-frontal cortex connectivity in typically developing youth was related to better scores on a standardized measure of social functioning. Our results indicate that cumulative genetic variation on the OXTR impacts reward system connectivity in both youth with ASD and neurotypical controls. By showing differential genetic effects on neuroendophenotypes, these pathways elucidate mechanisms of vulnerability versus resilience in carriers of disease-associated risk alleles.

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

Altered functional and structural brain network organization in autism.

Structural and functional underconnectivity have been reported for multiple brain regions, functional systems, and white matter tracts in individuals with autism spectrum disorders (ASD). Although recent developments in complex network analysis have established that the brain is a modular network exhibiting small-world properties, network level organization has not been carefully examined in ASD. Here we used resting-state functional MRI (n = 42 ASD, n = 37 typically developing; TD) to show that children and adolescents with ASD display reduced short and long-range connectivity within functional systems (i.e., reduced functional integration) and stronger connectivity between functional systems (i.e., reduced functional segregation), particularly in default and higher-order visual regions. Using graph theoretical methods, we show that pairwise group differences in functional connectivity are reflected in network level reductions in modularity and clustering (local efficiency), but shorter characteristic path lengths (higher global efficiency). Structural networks, generated from diffusion tensor MRI derived fiber tracts (n = 51 ASD, n = 43 TD), displayed lower levels of white matter integrity yet higher numbers of fibers. TD and ASD individuals exhibited similar levels of correlation between raw measures of structural and functional connectivity (n = 35 ASD, n = 35 TD). However, a principal component analysis combining structural and functional network properties revealed that the balance of local and global efficiency between structural and functional networks was reduced in ASD, positively correlated with age, and inversely correlated with ASD symptom severity. Overall, our findings suggest that modeling the brain as a complex network will be highly informative in unraveling the biological basis of ASD and other neuropsychiatric disorders.

Semantic Processing and Thought Disorder in Childhood-Onset Schizophrenia: Insights from fMRI.

Impairments in language processing and thought disorder are core symptoms of schizophrenia. Here we used fMRI to investigate functional abnormalities in the neural networks subserving sentence-level language processing in childhood-onset schizophrenia (COS). Fourteen children with COS (mean age: 13.34; IQ: 95) and 14 healthy controls (HC; mean age: 12.37; IQ: 104) underwent fMRI while performing a semantic judgment task previously shown to differentially engage semantic and syntactic processes. We report four main results. First, different patterns of functional specialization for semantic and syntactic processing were observed within each group, despite similar level of task performance. Second, after regressing out IQ, significant between-group differences were observed in the neural correlates of semantic and, to a lesser extent, syntactic processing, with HC children showing overall greater activity than COS children. Third, while these group differences were not related to effects of medications, a significant negative correlation was observed in the COS group between neuroleptic dosage and activity in the left inferior frontal gyrus for the semantic condition. Finally, COS children's level of thought disorder was significantly correlated with task-related activity in language-relevant networks. Taken together, these findings suggest that children with COS exhibit aberrant patterns of neural activity during semantic, and to a lesser extent syntactic, processing and that these functional abnormalities in language-relevant networks are significantly related to severity of thought disorder.

Making sense during conversation: an fMRI study.

Although language is thought of as a left hemisphere function, there is increasing evidence that the right hemisphere contributes to language processing by identifying the theme of spoken and written language. Using fMRI, we examined the role played by the right and left hemispheres in making sense of a conversation. When this process involves implicit appraisal of changes in the conversation's topic, the neural network has a right hemisphere bias and includes Broca's and Wernicke's areas, their right hemisphere homologues, right dorsolateral prefrontal cortex, and the cerebellum. When making sense of conversation involves appraisal of the conversation's reasoning, however, the network includes Broca's and Wernicke's areas. Thus, right and left hemisphere systems contribute uniquely to the linguistic skills involved in making sense of a conversation.

Language switching and language representation in Spanish-English bilinguals: an fMRI study.

The current experiment was designed to investigate the nature of cognitive control in within- and between-language switching in bilingual participants. To examine the neural substrate of language switching we used functional magnetic resonance imaging (fMRI) as subjects named pictures in one language only or switched between languages. Participants were also asked to name (only in English) a separate set of pictures as either the actions or the objects depicted or to switch between these two types of responses on each subsequent picture. Picture naming compared to rest revealed activation in the dorsolateral prefrontal cortex, which extended down into Broca's area in the left hemisphere. There were no differences in the activation pattern for each language. English and Spanish both activated overlapping areas of the brain. Similarly, there was no difference in activation for naming actions or objects in English. However, there was increased intensity of activation in the dorsolateral prefrontal cortex for switching between languages relative to no-switching, an effect which was not observed for naming of actions or objects in English. We suggest that the dorsolateral prefrontal cortex serves to attenuate interference that results from having to actively enhance and suppress two languages in alternation. These results are consistent with the view that switching between languages involves increased general executive processing. Finally, our results are consistent with the view that different languages are represented in overlapping areas of the brain in early bilinguals.

The development of word retrieval abilities in the second year and its relation to early vocabulary growth.

The present research investigated the development of word retrieval abilities late in the second year when most children display a marked increase in word production. When asked what was hidden in a given box, children with still quite limited productive vocabularies were reliably less likely to produce the labels of the hidden objects than were children with larger productive vocabularies even though (1) all children could name those objects and (2) all children did well when asked to find those same hidden objects. Additionally, the provision of pictorial cues facilitated word retrieval, especially in the early stage of lexical development. Naming errors during a naturalistic book-reading session peaked in children whose productive vocabularies had recently begun to expand, further suggesting that word retrieval processes undergo significant changes at this time.

Functional MRI in children with epilepsy.

Advances in brain mapping with functional magnetic resonance imaging (fMRI) have opened an important window into understanding how language is organized in the developing brain. Children with epilepsy, particularly those anticipating surgical intervention, may benefit from preoperative language localization with fMRI, thus minimizing the risk of incurring new deficits. Clinical applications of fMRI, however, await more information on how different linguistic skills are represented in the developing brain and how epileptic lesions impact on this organization at different stages of cognitive development. This article presents some of the current methods for brain mapping in children as well as early results using fMRI for language mapping in pediatric epilepsy.

Form and content: dissociating syntax and semantics in sentence comprehension.

The distinction between syntax (sentence form) and semantics (sentence meaning) is fundamental to our thinking about language. Whether and where this distinction is represented at the neural level is still a matter of considerable debate. In the present fMRI study, we examined the neural correlates of syntactic and semantic functions using an innovative activation paradigm specifically designed to unequivocally disentangle syntactic from lexicosemantic aspects of sentence processing. Our findings strongly indicate that a part of Broca's area (BA 44, pars opercularis) is critically implicated in processing syntactic information, whereas the lower portion of the left inferior frontal gyrus (BA 47, pars orbitalis) is selectively involved in processing the semantic aspects of a sentence.

Creation and use of a Talairach-compatible atlas for accurate, automated, nonlinear intersubject registration, and analysis of functional imaging data.

Spatial normalization in functional imaging can encompass various processes, including nonlinear warping to correct for intersubject differences, linear transformations to correct for identifiable head movements, and data detrending to remove residual motion correlated artifacts. We describe the use of AIR to create a custom, site-specific, normal averaged brain atlas that can be used to map T2 weighted echo-planar images and coplanar functional images directly into a Talairach-compatible space. We also discuss extraction of characteristic descriptors from sets of linear transformation matrices describing head movements in a functional imaging series. Scores for these descriptors, derived using principal components analysis with singular value decomposition, can be treated as confounds associated with each individual image in the series and systematically removed prior to voxel-by-voxel statistical analysis.