Exploring Bidirectional Relationships: Child Sleep Duration, Child Behavior Problems, and Parenting Stress in Families of Children with Autism Spectrum Disorder.

Background: Youth with Autism Spectrum Disorder (ASD) are at-risk for sleep and behavior problems, and their parents are at-risk for high stress. Child sleep duration, behavior problems, and parenting stress are interrelated; however, directionality of these associations is unclear and research including youth with ASD is lacking. Using a day-to-day, within-person design, this study explores the directionality of these relationships in families of children with ASD. Method: Twenty-six children (ages 3-5, 73.1% male, 65.4% Hispanic/Latino) with ASD and their mothers participated in a 14-day study. Child sleep duration (parent-report and actigraphy), behavior problems, and parenting stress were measured daily. Constructs were decomposed into their within- and between-person components and analyzed with random intercept cross-lagged panel models. Results: While between-person relationships were directionally expected in that shorter sleep, more behavior problems, and greater parenting stress were associated, within-person relationships were complicated. Better-than-average child behavior was associated with less next-day parenting stress, yet more parenting stress than average was associated with better next-day child behavior. As expected, longer-than-average child sleep was associated with less next-day parenting stress, while greater child behavior problems were associated with less sleep that night. Conclusions: Understanding the directionality of associations between child and parent factors allows for the optimization of interventions to improve the quality of life for families of children with ASD. Interventions that target child behavior and/or help parents manage stress while maintaining effective parenting strategies for sleep and behavior may be useful.

Altered Thalamocortical Connectivity in 6-Week-Old Infants at High Familial Risk for Autism Spectrum Disorder.

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here, we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and low-risk controls (LR). Resting-state functional connectivity and diffusion tensor imaging data were acquired in 52 6-week-old infants. Functional connectivity was examined between 6 cortical seeds-prefrontal, motor, somatosensory, temporal, parietal, and occipital regions-and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared with LR infants. Notably, aberrant connectivity indices at 6 weeks predicted atypical social development between 9 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as 6 weeks of age, providing a possible early marker of risk for ASD.

Social cognition in 22q11.2 deletion syndrome and idiopathic developmental neuropsychiatric disorders.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is a common recurrent neurogenetic condition associated with elevated risk for developmental neuropsychiatric disorders and intellectual disability. Children and adults with 22q11DS often exhibit marked social impairment as well as neurocognitive deficits, and have elevated rates of both autism spectrum disorder (ASD) and psychosis. However, the relationship between the basic processes of social cognition and cognitive ability has not been well studied in 22q11DS. Here, we examined differences in social cognition in 22q11DS, relative to multiple groups of idiopathic neuropsychiatric disorders, and typically developing healthy controls (HC). Additionally, we examined differences in intellectual functioning and its relationship to social cognitive abilities. Finally, we examined the relationship between social cognitive abilities and real-world social behavior. METHODS: We examined social cognition and intellectual functioning in 273 participants (mean age = 17.74 ± 5.18% female = 44.3%): 50 with 22q11DS, 49 youth with first episode psychosis (FEP), 48 at clinical high-risk (CHR) for psychosis, 24 participants with ASD, and 102 HC. Social cognition was assessed using The Awareness of Social Inference Test (TASIT), while reciprocal social behavior was assessed via parent/caregiver ratings on the Social Responsiveness Scale (SRS). Participants were also administered the Wechsler Abbreviated Scale of Intelligence, 2nd edition (WASI-II) to assess intellectual functioning. RESULTS: The 22q11DS group exhibited significantly lower social cognitive abilities compared to CHR, FEP, and HC groups after controlling for intellectual functioning, but not in comparison to the ASD group. Significant positive correlations were found between social cognition, as measured by the TASIT and IQ across groups. In contrast, no significant relationships were found between TASIT and real-world social behavior (SRS) for any group. CONCLUSIONS: Our findings indicate social cognitive deficits are more prominent in 22q11DS than idiopathic neuropsychiatric conditions across the age range, even after adjusting for global intellectual function. These results contribute to our understanding of the intellectual and social vulnerabilities of 22q11DS in comparison to idiopathic neuropsychiatric disorders. Our findings of robust associations between intellectual ability and social cognition emphasizes the importance of accounting for neurocognitive deficits in social skills interventions and tailoring these existing treatment models for 22q11DS and other populations with intellectual impairment.

Neurophysiologic evidence for increased retrieval suppression among negative ruminators.

INTRODUCTION: Events (e.g., seeing a familiar face) may initiate retrieval of associated information (e.g., person's name), but not all cue-initiated memory retrieval is welcome (e.g., trauma). Retrieval suppression refers to the ability to halt unwanted retrieval, and any erosion of memory associations in response to repeatedly excluding a memory from consciousness. The current study sought to examine event-related potential (ERP, averaged scalp electrical recordings) correlates of inhibitory cognitive control of memory retrieval and any linkage of such control to ruminative memory styles. METHODS: Participants (N = 23) first learned face-picture pairings. ERPs were then recorded as they viewed face cues while either bringing the associated picture to mind (think trial), or not allowing the associated picture to come to mind (no-think trial). RESULTS: Emotional valence of learned pictures (negative versus neutral) modulated a posterior (P1, 100-150 ms) ERP associated with attention to the face cue. Memory strategy (think versus no-think) modulated a frontal (P3, 350-450 ms) associated with alerting of the need to control retrieval. Both valence and strategy worked in combination to modulate a late posterior (LC, 450-550 ms) ERP associated with successful memory retrieval. Brooding, a negative form of rumination, was found to be positively correlated with the LC ERP. CONCLUSION: The results suggest early separation of emotional and strategic control of retrieval, but later combined control over access to working memory. Moreover, the positive correlation of brooding and the LC suggest that individuals who are high in application of perseverative strategies to memory retrieval will show greater modulation of the retrieval-related LC ERP.

A Review of Default Mode Network Connectivity and Its Association With Social Cognition in Adolescents With Autism Spectrum Disorder and Early-Onset Psychosis.

Recent studies have demonstrated substantial phenotypic overlap, notably social impairment, between autism spectrum disorder (ASD) and schizophrenia. However, the neural mechanisms underlying the pathogenesis of social impairments across these distinct neuropsychiatric disorders has not yet been fully examined. Most neuroimaging studies to date have focused on adults with these disorders, with little known about the neural underpinnings of social impairments in younger populations. Here, we present a narrative review of the literature available through April 2020 on imaging studies of adolescents with either ASD or early-onset psychosis (EOP), to better understand the shared and unique neural mechanisms of social difficulties across diagnosis from a developmental framework. We specifically focus on functional connectivity studies of the default mode network (DMN), as the most extensively studied brain network relevant to social cognition across both groups. Our review included 29 studies of DMN connectivity in adolescents with ASD (Mean age range = 11.2-21.6 years), and 14 studies in adolescents with EOP (Mean age range = 14.2-24.3 years). Of these, 15 of 29 studies in ASD adolescents found predominant underconnectivity when examining DMN connectivity. In contrast, findings were mixed in adolescents with EOP, with five of 14 studies reporting DMN underconnectivity, and an additional six of 14 studies reporting both under- and over-connectivity of the DMN. Specifically, intra-DMN networks were more frequently underconnected in ASD, but overconnected in EOP. On the other hand, inter-DMN connectivity patterns were mixed (both under- and over-connected) for each group, especially DMN connectivity with frontal, sensorimotor, and temporoparietal regions in ASD, and with frontal, temporal, subcortical, and cerebellar regions in EOP. Finally, disrupted DMN connectivity appeared to be associated with social impairments in both groups, less so with other features distinct to each condition, such as repetitive behaviors/restricted interests in ASD and hallucinations/delusions in EOP. Further studies on demographically well-matched groups of adolescents with each of these conditions are needed to systematically explore additional contributing factors in DMN connectivity patterns such as clinical heterogeneity, pubertal development, and medication effects that would better inform treatment targets and facilitate prediction of outcomes in the context of these developmental neuropsychiatric conditions.

Repetitive behaviors in autism are linked to imbalance of corticostriatal connectivity: a functional connectivity MRI study.

The neural underpinnings of repetitive behaviors (RBs) in autism spectrum disorders (ASDs), ranging from cognitive to motor characteristics, remain unknown. We assessed RB symptomatology in 50 ASD and 52 typically developing (TD) children and adolescents (ages 8-17 years), examining intrinsic functional connectivity (iFC) of corticostriatal circuitry, which is important for reward-based learning and integration of emotional, cognitive and motor processing, and considered impaired in ASDs. Connectivity analyses were performed for three functionally distinct striatal seeds (limbic, frontoparietal and motor). Functional connectivity with cortical regions of interest was assessed for corticostriatal circuit connectivity indices and ratios, testing the balance of connectivity between circuits. Results showed corticostriatal overconnectivity of limbic and frontoparietal seeds, but underconnectivity of motor seeds. Correlations with RBs were found for connectivity between the striatal motor seeds and cortical motor clusters from the whole-brain analysis, and for frontoparietal/limbic and motor/limbic connectivity ratios. Division of ASD participants into high (n = 17) and low RB subgroups (n = 19) showed reduced frontoparietal/limbic and motor/limbic circuit ratios for high RB compared to low RB and TD groups in the right hemisphere. Results suggest an association between RBs and an imbalance of corticostriatal iFC in ASD, being increased for limbic, but reduced for frontoparietal and motor circuits.

Patterns of Atypical Functional Connectivity and Behavioral Links in Autism Differ Between Default, Salience, and Executive Networks.

Autism spectrum disorder (ASD) is characterized by atypical brain network organization, but findings have been inconsistent. While methodological and maturational factors have been considered, the network specificity of connectivity abnormalities remains incompletely understood. We investigated intrinsic functional connectivity (iFC) for four "core" functional networks-default-mode (DMN), salience (SN), and left (lECN) and right executive control (rECN). Resting-state functional MRI data from 75 children and adolescents (37 ASD, 38 typically developing [TD]) were included. Functional connectivity within and between networks was analyzed for regions of interest (ROIs) and whole brain, compared between groups, and correlated with behavioral scores. ROI analyses showed overconnectivity (ASD > TD), especially between DMN and ECN. Whole-brain results were mixed. While predominant overconnectivity was found for DMN (posterior cingulate seed) and rECN (right inferior parietal seed), predominant underconnectivity was found for SN (right anterior insula seed) and lECN (left inferior parietal seed). In the ASD group, reduced SN integrity was associated with sensory and sociocommunicative symptoms. In conclusion, atypical connectivity in ASD is network-specific, ranging from extensive overconnectivity (DMN, rECN) to extensive underconnectivity (SN, lECN). Links between iFC and behavior differed between groups. Core symptomatology in the ASD group was predominantly related to connectivity within the salience network.

Under-reactive but easily distracted: An fMRI investigation of attentional capture in autism spectrum disorder.

For individuals with autism spectrum disorder (ASD), salient behaviorally-relevant information often fails to capture attention, while subtle behaviorally-irrelevant details commonly induce a state of distraction. The present study used functional magnetic resonance imaging (fMRI) to investigate the neurocognitive networks underlying attentional capture in sixteen high-functioning children and adolescents with ASD and twenty-one typically developing (TD) individuals. Participants completed a rapid serial visual presentation paradigm designed to investigate activation of attentional networks to behaviorally-relevant targets and contingent attention capture by task-irrelevant distractors. In individuals with ASD, target stimuli failed to trigger bottom-up activation of the ventral attentional network and the cerebellum. Additionally, the ASD group showed no differences in behavior or occipital activation associated with contingent attentional capture. Rather, results suggest that to-be-ignored distractors that shared either task-relevant or irrelevant features captured attention in ASD. Results indicate that individuals with ASD may be under-reactive to behaviorally-relevant stimuli, unable to filter irrelevant information, and that both top-down and bottom-up attention networks function atypically in ASD. Lastly, deficits in target-related processing were associated with autism symptomatology, providing further support for the hypothesis that non-social attentional processes and their neurofunctional underpinnings may play a significant role in the development of sociocommunicative impairments in ASD.

Regional specificity of aberrant thalamocortical connectivity in autism.

Preliminary evidence suggests aberrant (mostly reduced) thalamocortical (TC) connectivity in autism spectrum disorder (ASD), but despite the crucial role of thalamus in sensorimotor functions and its extensive connectivity with cerebral cortex, relevant evidence remains limited. We performed a comprehensive investigation of region-specific TC connectivity in ASD. Resting-state functional MRI and diffusion tensor imaging (DTI) data were acquired for 60 children and adolescents with ASD (ages 7-17 years) and 45 age, sex, and IQ-matched typically developing (TD) participants. We examined intrinsic functional connectivity (iFC) and anatomical connectivity (probabilistic tractography) with thalamus, using 68 unilateral cerebral cortical regions of interest (ROIs). For frontal and parietal lobes, iFC was atypically reduced in the ASD group for supramodal association cortices, but was increased for cingulate gyri and motor cortex. Temporal iFC was characterized by overconnectivity for auditory cortices, but underconnectivity for amygdalae. Occipital iFC was broadly reduced in the ASD group. DTI indices (such as increased radial diffusion) for regions with group differences in iFC further indicated compromised anatomical connectivity, especially for frontal ROIs, in the ASD group. Our findings highlight the regional specificity of aberrant TC connectivity in ASD. Their overall pattern can be largely accounted for by functional overconnectivity with limbic and sensorimotor regions, but underconnectivity with supramodal association cortices. This could be related to comparatively early maturation of limbic and sensorimotor regions in the context of early overgrowth in ASD, at the expense of TC connectivity with later maturing cortical regions.

Diagnostic classification of intrinsic functional connectivity highlights somatosensory, default mode, and visual regions in autism.

Despite consensus on the neurological nature of autism spectrum disorders (ASD), brain biomarkers remain unknown and diagnosis continues to be based on behavioral criteria. Growing evidence suggests that brain abnormalities in ASD occur at the level of interconnected networks; however, previous attempts using functional connectivity data for diagnostic classification have reached only moderate accuracy. We selected 252 low-motion resting-state functional MRI (rs-fMRI) scans from the Autism Brain Imaging Data Exchange (ABIDE) including typically developing (TD) and ASD participants (n = 126 each), matched for age, non-verbal IQ, and head motion. A matrix of functional connectivities between 220 functionally defined regions of interest was used for diagnostic classification, implementing several machine learning tools. While support vector machines in combination with particle swarm optimization and recursive feature elimination performed modestly (with accuracies for validation datasets <70%), diagnostic classification reached a high accuracy of 91% with random forest (RF), a nonparametric ensemble learning method. Among the 100 most informative features (connectivities), for which this peak accuracy was achieved, participation of somatosensory, default mode, visual, and subcortical regions stood out. Whereas some of these findings were expected, given previous findings of default mode abnormalities and atypical visual functioning in ASD, the prominent role of somatosensory regions was remarkable. The finding of peak accuracy for 100 interregional functional connectivities further suggests that brain biomarkers of ASD may be regionally complex and distributed, rather than localized.

Cerebro-cerebellar Resting-State Functional Connectivity in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: The cerebellum plays important roles in sensori-motor and supramodal cognitive functions. Cellular, volumetric, and functional abnormalities of the cerebellum have been found in autism spectrum disorders (ASD), but no comprehensive investigation of cerebro-cerebellar connectivity in ASD is available. METHODS: We used resting-state functional connectivity magnetic resonance imaging in 56 children and adolescents (28 subjects with ASD, 28 typically developing subjects) 8-17 years old. Partial and total correlation analyses were performed for unilateral regions of interest (ROIs), distinguished in two broad domains as sensori-motor (premotor/primary motor, somatosensory, superior temporal, and occipital) and supramodal (prefrontal, posterior parietal, and inferior and middle temporal). RESULTS: There were three main findings: 1) Total correlation analyses showed predominant cerebro-cerebellar functional overconnectivity in the ASD group; 2) partial correlation analyses that emphasized domain specificity (sensori-motor vs. supramodal) indicated a pattern of robustly increased connectivity in the ASD group (compared with the typically developing group) for sensori-motor ROIs but predominantly reduced connectivity for supramodal ROIs; and 3) this atypical pattern of connectivity was supported by significantly increased noncanonical connections (between sensori-motor cerebral and supramodal cerebellar ROIs and vice versa) in the ASD group. CONCLUSIONS: Our findings indicate that sensori-motor intrinsic functional connectivity is atypically increased in ASD, at the expense of connectivity supporting cerebellar participation in supramodal cognition.

The Influence of Task Difficulty and Participant Age on Balance Control in ASD.

Impairments in sensorimotor integration are reported in Autism Spectrum Disorder (ASD). Poor control of balance in challenging balance tasks is one suggested manifestation of these impairments, and is potentially related to ASD symptom severity. Reported balance and symptom severity relationships disregard age as a potential covariate, however, despite its involvement in balance development. We tested balance control during increasingly difficult balance conditions in children with ASD and typically developing peers, and investigated relationships between balance control and diagnostic/symptom severity metrics for participants with ASD, including age as a covariate. Balance deficits in ASD were exacerbated by stance alterations, but were not related to symptom severity when age was considered. These findings support impaired balance in ASD, especially in challenging conditions, but question a link between balance and symptom severity.

Impact of methodological variables on functional connectivity findings in autism spectrum disorders.

Growing evidence suggests that Autism Spectrum Disorder (ASD) involves abnormalities of multiple functional networks. Neuroimaging studies of ASD have therefore increasingly focused on connectivity. Many functional connectivity (fcMRI) studies have reported network underconnectivity in children and adults with ASD. However, there are notable inconsistencies, with some studies reporting overconnectivity. A previous literature survey suggested that a few methodological factors play a crucial role in differential fcMRI outcomes. Using three ASD data sets (two task-related, one resting state) from 54 ASD and 51 typically developing (TD) participants (ages 9-18 years), we examined the impact of four methodological factors: type of pipeline (co-activation vs. intrinsic analysis, related to temporal filtering and removal of task-related effects), seed selection, field of view (whole brain vs. limited ROIs), and dataset. Significant effects were found for type of pipeline, field of view, and dataset. Notably, for each dataset results ranging from robust underconnectivity to robust overconnectivity were detected, depending on the type of pipeline, with intrinsic fcMRI analyses (low bandpass filter and task regressor) predominantly yielding overconnectivity in ASD, but co-activation analyses (no low bandpass filter or task removal) mostly generating underconnectivity findings. These results suggest that methodological variables have dramatic impact on group differences reported in fcMRI studies. Improved awareness of their implications appears indispensible in fcMRI studies when inferences about "underconnectivity" or "overconnectivity" in ASD are made. In the absence of a gold standard for functional connectivity, the combination of different methodological approaches promises a more comprehensive understanding of connectivity in ASD.

Local functional overconnectivity in posterior brain regions is associated with symptom severity in autism spectrum disorders.

Although growing evidence indicates atypical long-distance connectivity in autism spectrum disorder (ASD), much less is known about local connectivity, despite conjectures that local overconnectivity may be causally involved in the disorder. Using functional connectivity MRI and graph theory, we found that local functional connectivity was atypically increased in adolescents with ASD in temporo-occipital regions bilaterally. Posterior overconnectivity was found to be associated with higher ASD symptom severity, whereas an ASD subsample with low severity showed frontal underconnectivity. The findings suggest links between symptomatology and local connectivity, which vary within the autism spectrum.

Approaches to local connectivity in autism using resting state functional connectivity MRI.

While the literature on aberrant long-distance connectivity in autism spectrum disorder (ASD) has grown fast over the past decade, little is known about local connectivity. We used regional homogeneity and local density approaches at different spatial scales to examine local connectivity in 29 children and adolescents with ASD and 29 matched typically developing participants, using resting state functional magnetic resonance imaging data. Across a total of 12 analysis pipelines, the gross pattern of between-group findings was overall stable, with local overconnectivity in the ASD group in occipital and posterior temporal regions and underconnectivity in middle/posterior cingulate, and medial prefrontal regions. This general pattern was confirmed in secondary analyses for low-motion subsamples (n = 20 per group), in which time series segments with >0.25 mm head motion were censored, as well as in an analysis including global signal regression. Local overconnectivity in visual regions appears consistent with preference for local over global visual processing previously reported in ASD, whereas cingulate and medial frontal underconnectivity may relate to aberrant function within the default mode network.

Impaired thalamocortical connectivity in autism spectrum disorder: a study of functional and anatomical connectivity.

The thalamus plays crucial roles in the development and mature functioning of numerous sensorimotor, cognitive and attentional circuits. Currently limited evidence suggests that autism spectrum disorder may be associated with thalamic abnormalities, potentially related to sociocommunicative and other impairments in this disorder. We used functional connectivity magnetic resonance imaging and diffusion tensor imaging probabilistic tractography to study the functional and anatomical integrity of thalamo-cortical connectivity in children and adolescents with autism spectrum disorder and matched typically developing children. For connectivity with five cortical seeds (prefontal, parieto-occipital, motor, somatosensory and temporal), we found evidence of both anatomical and functional underconnectivity. The only exception was functional connectivity with the temporal lobe, which was increased in the autism spectrum disorders group, especially in the right hemisphere. However, this effect was robust only in partial correlation analyses (partialling out time series from other cortical seeds), whereas findings from total correlation analyses suggest that temporo-thalamic overconnectivity in the autism group was only relative to the underconnectivity found for other cortical seeds. We also found evidence of microstructural compromise within the thalamic motor parcel, associated with compromise in tracts between thalamus and motor cortex, suggesting that the thalamus may play a role in motor abnormalities reported in previous autism studies. More generally, a number of correlations of diffusion tensor imaging and functional connectivity magnetic resonance imaging measures with diagnostic and neuropsychological scores indicate involvement of abnormal thalamocortical connectivity in sociocommunicative and cognitive impairments in autism spectrum disorder.

Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: a Diffusion Tensor Imaging study.

BACKGROUND: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI). METHODS: We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). RESULTS: The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p<0.05, corrected). We found significantly lower FA in right and left ATR, CC, left UF and right and left ILF and significantly higher MD values of the CC in the ASD group in region of interest-based analyses. We also observed significantly higher RD values of right and left ATR, CC, left UF, left ILF in subjects with ASD compared to typically developing boys and significantly lower AD values of both ILF. Right ATR and right UF FA was significantly negatively correlated with total SRS score within the ASD group (r=-.56, p=.02). CONCLUSIONS: Our preliminary findings support evidence implicating disturbances in the thalamo-frontal connections in autism. These findings highlight the role of hypoconnectivity between the frontal cortex and thalamus in ASD.