When the Brain Cares: Personal interests amplify engagement of language, self-reference, and reward regions in the brains of children with and without autism.

Human language is shaped by individual experiences and interests. However, to study language in the brain, researchers use generic stimuli, avoiding the variable personal interests that typically animate language. Thus, it is unknown how personal interests affect language function in the brain. We conducted personalized functional magnetic resonance imaging (fMRI) in 20 typically-developing children as they listened to personalized narratives about their specific interest and non-personalized, generic narratives. Personally-interesting narratives amplified engagement of language regions, producing more consistent activation patterns across individuals - even though each narrative was unique - than the generic narratives. The personalized narratives also engaged self-reference and reward areas of the brain associated with motivation. Amplification of brain responses to personally-interesting narratives was also observed in 15 autistic children, a condition characterized by both intense specific interests and difficulties with communication. Here we show that personal interests significantly affect language processing in the human brain.

Diminished Repetition Suppression Reveals Selective and Systems-Level Face Processing Differences in ASD.

Repeated exposure to a stimulus results in reduced neural response, or repetition suppression, in brain regions responsible for processing that stimulus. This rapid accommodation to repetition is thought to underlie learning, stimulus selectivity, and strengthening of perceptual expectations. Importantly, reduced sensitivity to repetition has been identified in several neurodevelopmental, learning, and psychiatric disorders, including autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by challenges in social communication and repetitive behaviors and restricted interests. Reduced ability to exploit or learn from repetition in ASD is hypothesized to contribute to sensory hypersensitivities, and parallels several theoretical frameworks claiming that ASD individuals show difficulty using regularities in the environment to facilitate behavior. Using fMRI in autistic and neurotypical human adults (females and males), we assessed the status of repetition suppression across two modalities (vision, audition) and with four stimulus categories (faces, objects, printed words, and spoken words). ASD individuals showed domain-specific reductions in repetition suppression for face stimuli only, but not for objects, printed words, or spoken words. Reduced repetition suppression for faces was associated with greater challenges in social communication in ASD. We also found altered functional connectivity between atypically adapting cortical regions and higher-order face recognition regions, and microstructural differences in related white matter tracts in ASD. These results suggest that fundamental neural mechanisms and system-wide circuits are selectively altered for face processing in ASD and enhance our understanding of how disruptions in the formation of stable face representations may relate to higher-order social communication processes.SIGNIFICANCE STATEMENT A common finding in neuroscience is that repetition results in plasticity in stimulus-specific processing regions, reflecting selectivity and adaptation (repetition suppression [RS]). RS is reduced in several neurodevelopmental and psychiatric conditions including autism spectrum disorder (ASD). Theoretical frameworks of ASD posit that reduced adaptation may contribute to associated challenges in social communication and sensory processing. However, the scope of RS differences in ASD is unknown. We examined RS for multiple categories across visual and auditory domains (faces, objects, printed words, spoken words) in autistic and neurotypical individuals. We found reduced RS in ASD for face stimuli only and altered functional connectivity and white matter microstructure between cortical face-recognition areas. RS magnitude correlated with social communication challenges among autistic individuals.

Cerebellar correlates of social dysfunction among individuals at clinical high risk for psychosis.

Introduction: Social deficits are a significant feature among both individuals with psychosis and those at clinical high-risk (CHR) for developing psychosis. Critically, the psychosis risk syndrome emerges in adolescence and young adulthood, when social skill development is being fine-tuned. Yet, the underlying pathophysiology of social deficits in individuals at CHR for psychosis remains unclear. Literature suggests the cerebellum plays a critical role in social functioning. Cerebellar dysfunction in psychosis and CHR individuals is well-established, yet limited research has examined links between the cerebellum and social functioning deficits in this critical population. Method: In the current study, 68 individuals at CHR for developing psychosis and 66 healthy controls (HCs) completed social processing measures (examining social interaction, social cognition, and global social functioning) and resting-state MRI scans. Seed-to-voxel resting-state connectivity analyses were employed to examine the relationship between social deficits and lobular cerebellar network connectivity. Results: Analyses indicated that within the CHR group, each social domain variable was linked to reduced connectivity between social cerebellar subregions (e.g., Crus II, lobules VIIIa and VIIIb) and cortical regions (e.g., frontal pole and frontal gyrus), but a control cerebellar subregion (e.g., lobule X) and was unrelated to these social variables. Discussion: These results indicate an association between several cerebellar lobules and specific deficits in social processing. The cerebellum, therefore, may be particularly salient to the social domain and future research is need to examine the role of the cerebellum in psychosis.

Exclusion of females in autism research: Empirical evidence for a "leaky" recruitment-to-research pipeline.

Autism spectrum disorder (ASD) is characterized by challenges in social communication and the presence of repetitive behaviors or restricted interests. Notably, males are four times as likely as females to be diagnosed with autism. Despite efforts to increase representation and characterization of autistic females, research studies consistently enroll small samples of females, or exclude females altogether. Importantly, researchers often rely on standardized measures to confirm diagnosis prior to enrollment in research studies. We retrospectively analyzed the effects of one such measure (Autism Diagnostic Observation Schedule, ADOS) on research inclusion/exclusion rates by sex in autistic adults, all of whom had a preexisting community diagnosis of autism (n = 145, 95 male, 50 female). Using the ADOS as a confirmatory diagnostic measure resulted in the exclusion of autistic females at a rate over 2.5 times higher than that of autistic males. We compared sex ratios in our sample to those in other large, publically available datasets that rely either on community diagnosis (6 datasets, total n = 42,209) or standardized assessments (2 datasets, total n = 214) to determine eligibility of participants for research. Reliance on community diagnosis rather than confirmatory diagnostic assessments resulted in significantly more equal sex ratios. These results provide evidence for a "leaky" recruitment-to-research pipeline for females in autism research. LAY SUMMARY: Despite efforts to increase the representation of autistic females in research, studies consistently enroll small samples of females or exclude females altogether. We find that despite making up almost 50% of the initially recruited sample based upon self-report of community diagnosis, autistic females are disproportonately excluded from research participation as a result of commonly used autism diagnostic measures. In our sample, and several other publically available datasets, reliance on community diagnosis resulted in significantly more equal sex ratios.

Cerebellar Contributions to Social Cognition in ASD: A Predictive Processing Framework.

Functional, structural, and cytoarchitectural differences in the cerebellum are consistently reported in Autism Spectrum Disorders (ASD). Despite this, the mechanisms governing cerebellar contributions to ASD, particularly within the sociocognitive domain, are not well understood. Recently, it has been suggested that several core features of ASD may be associated with challenges creating and using prior expectations or predictions to rapidly adapt to changing stimuli or situations, also known as adaptive prediction. Importantly, neuroimaging, clinical, and animal work find that the cerebellum supports adaptive prediction in both motor and non-motor domains. Perturbations to the cerebellum via injury or neuromodulation have been associated with impairments in predictive skills. Here, we review evidence for a cerebellar role in social cognition and adaptive prediction across individuals with and without ASD.

Reward-Related Neural Circuitry in Depressed and Anxious Adolescents: A Human Connectome Project.

OBJECTIVE: Although depression and anxiety often have distinct etiologies, they frequently co-occur in adolescence. Recent initiatives have underscored the importance of developing new ways of classifying mental illness based on underlying neural dimensions that cut across traditional diagnostic boundaries. Accordingly, the aim of the study was to clarify reward-related neural circuitry that may characterize depressed-anxious youth. METHOD: The Boston Adolescent Neuroimaging of Depression and Anxiety Human Connectome Project tested group differences regarding subcortical volume and nucleus accumbens activation during an incentive processing task among 14- to 17-year-old adolescents presenting with a primary depressive and/or anxiety disorder (n = 129) or no lifetime history of mental disorders (n = 64). In addition, multimodal modeling examined predictors of depression and anxiety symptom change over a 6-month follow-up period. RESULTS: Our findings highlighted considerable convergence. Relative to healthy youth, depressed-anxious adolescents exhibited reduced nucleus accumbens volume and activation following reward receipt. These findings remained when removing all medicated participants (∼59% of depressed-anxious youth). Subgroup analyses comparing anxious-only, depressed-anxious, and healthy youth also were largely consistent. Multimodal modeling showed that only structural alterations predicted depressive symptoms over time. CONCLUSION: Multimodal findings highlight alterations within nucleus accumbens structure and function that characterize depressed-anxious adolescents. In the current hypothesis-driven analyses, however, only reduced nucleus accumbens volume predicted depressive symptoms over time. An important next step will be to clarify why structural alterations have an impact on reward-related processes and associated symptoms.

Anxiety, Motivation, and Competence in Mathematics and Reading for Children With and Without Learning Difficulties.

Knowledge of the relations among learners' socio-emotional characteristics and competencies as they engage in mathematics and reading is limited, especially for children with academic difficulties. This study examined the relations between anxiety, motivation, and competence in mathematics and reading, within and across domains, in an academically-diverse set of 8-13-year-old learners (n = 146). To measure anxiety and motivation across domains, we paired existing measures of math anxiety and reading motivation with researcher-developed analogs for reading anxiety and math motivation. Participants completed standardized assessments of mathematics and reading, anxiety and motivation surveys for math and reading, and a measure of nonverbal cognitive ability. Results showed high internal consistency for all anxiety and motivation scales (Cronbach's alpha = 0.76-0.91). Pearson correlations showed that within and across domains, participants with higher competence had lower anxiety and higher motivation. Higher anxiety was also associated with lower motivation. Regression analyses showed that for both math and reading, within-domain motivation was a stronger predictor of competence than anxiety. There was a unidirectional across-domain relation: socio-emotional characteristics for reading predicted math competence, after accounting for nonverbal cognitive ability, age, gender, and within-domain anxiety and motivation. Results contribute to knowledge of the socio-emotional characteristics of children with and without learning difficulties in association with reading and math activities. Implications of a unidirectional socio-emotional link between the two domains can advance research and theory of the relations among socio-emotional characteristics and competence for academically-diverse learners.

Neuroimaging Markers of Resiliency in Youth at Clinical High Risk for Psychosis: A Qualitative Review.

Psychotic disorders are highly debilitating and constitute a major public health burden. Identifying markers of psychosis risk and resilience is a necessary step toward understanding etiology and informing prevention and treatment efforts in individuals at clinical high risk (CHR) for psychosis. In this context, it is important to consider that neural risk markers have been particularly useful in identifying mechanistic determinants along with predicting clinical outcomes. Notably, despite a growing body of supportive literature and the promise of recent findings identifying potential neural markers, the current work on CHR resilience markers has received little attention. The present review provides a brief overview of brain-based risk markers with a focus on predicting symptom course. Next, the review turns to protective markers, examining research from nonpsychiatric and schizophrenia fields to build an understanding of framing, priorities, and potential, applying these ideas to contextualizing a small but informative body of resiliency-relevant CHR research. Four domains (neurocognition, emotion regulation, allostatic load, and sensory and sensorimotor function) were identified and are discussed in terms of behavioral and neural markers. Taken together, the literature suggests significant predictive value for brain-based markers for individuals at CHR for psychosis, and the limited but compelling resiliency work highlights the critical importance of expanding this promising area of inquiry.

Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders.

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R2 = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

Image acquisition and quality assurance in the Boston Adolescent Neuroimaging of Depression and Anxiety study.

The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14-17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and differences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA).