Examining the latent structure and correlates of sensory reactivity in autism: a multi-site integrative data analysis by the autism sensory research consortium.

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these "supra-modal" traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a "general response pattern" factor for each supra-modal construct and determine the added value of "modality-specific response pattern" scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ωH = .800) but not a supra-modal HYPO construct (ωH = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ωH = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many "real-world" sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

Cognitive Sparing in Proton versus Photon Radiotherapy for Pediatric Brain Tumor Is Associated with White Matter Integrity: An Exploratory Study.

Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging >7 years post-radiotherapy. A healthy comparison group (n = 23) was also recruited. Participants completed age-appropriate measures of intellectual functioning, visual-motor integration, and motor coordination. Tractography was conducted using automated fiber quantification (AFQ). Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 12 tracts of interest. Overall, both white matter integrity (FA) and neuropsychological performance were lower in XRT patients while PRT patients were similar to healthy control participants with respect to both FA and cognitive functioning. These findings support improved long-term outcomes in PRT versus XRT. This exploratory study is the first to directly support for white matter integrity as a mechanism of cognitive sparing in PRT.

Comparison of neurocognitive and quality-of-life outcomes in pediatric craniopharyngioma patients treated with partial resection and radiotherapy versus gross-total resection only.

OBJECTIVE: The optimal management of pediatric craniopharyngioma patients remains controversial, shifting from radical resection (gross-total resection [GTR]) to a more conservative approach with partial resection/biopsy followed by radiotherapy (PR+RT). To the authors' knowledge, no previous studies have compared neurocognitive and quality-of-life (QOL) outcomes between the two main treatments. In this study, the authors compared changes in intellectual, adaptive, and QOL scores in children treated for craniopharyngioma with GTR and those treated with PR+RT. METHODS: Patients underwent annual neurocognitive and QOL evaluations for up to 10 years posttreatment, including the Full-Scale IQ, Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI). Child- and parent-reported QOL scores and adaptive behavior in different domains were assessed. General linear mixed models were used to examine change in scores over time by treatment group with adjustment for significant covariates. RESULTS: Scores from 43 patients treated between 2009 and 2019 (21 GTR, 22 PR+RT) were examined. Within the PR+RT group, 9 patients had intensity-modulated RT and 13 had proton beam therapy. The treatment groups were similar in sex (44% male) and age (median 7.3 years). There were no significant differences in the trajectory of intellectual functioning or QOL scale scores between the two groups. However, patients who underwent GTR exhibited significant improvement over time in overall adaptive behavior (p = 0.04) and conceptual skills (p = 0.01), which was not observed in patients treated with PR+RT. CONCLUSIONS: Long-term pediatric craniopharyngioma survivors treated with GTR and PR+RT have similar intellectual function and QOL. Larger studies are needed to explore small but clinically significant differences between the two groups.

Examining the Latent Structure and Correlates of Sensory Reactivity in Autism: A Multi-site Integrative Data Analysis by the Autism Sensory Research Consortium.

Background Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these "supra-modal" traits in the autistic population. Methods Leveraging a combined sample of 3,868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a "general response pattern" factor for each supra-modal construct and determine the added value of "modality-specific response pattern" scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO and SEEK (sub)constructs. Results All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses unambiguously supported the validity of a supra-modal HYPER construct (ω H = .800), whereas a coherent supra-modal HYPO construct was not supported (ω H = .611), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ω H = .799; 4/7 modalities). Within each sensory construct, modality-specific subscales demonstrated substantial added value beyond the supra-modal score. Meta-analytic correlations varied by construct, although sensory features tended to correlate most strongly with other domains of core autism features and co-occurring psychiatric symptoms. Certain subconstructs within the HYPO and SEEK domains were also associated with lower adaptive behavior scores. Limitations: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to parent-report of observable behaviors and excluded multisensory items that reflect many "real-world" sensory experiences. Conclusion Psychometric issues may limit the degree to which some measures of supra-modal HYPO/SEEK can be interpreted. Depending on the research question at hand, modality-specific response pattern scores may represent a valid alternative method of characterizing sensory reactivity in autism.

Superior verbal learning and memory in pediatric brain tumor survivors treated with proton versus photon radiotherapy.

OBJECTIVE: Radiotherapy for pediatric brain tumor has been associated with late cognitive effects. Compared to conventional photon radiotherapy (XRT), proton radiotherapy (PRT) delivers lower doses of radiation to healthy brain tissue. PRT has been associated with improved long-term cognitive outcomes compared to XRT. However, there is limited research comparing the effects of XRT and PRT on verbal memory. METHOD: Survivors of pediatric brain tumor treated with either XRT (n = 29) or PRT (n = 51) completed neuropsychological testing > 1 year following radiotherapy. Performance on neuropsychological measures was compared between treatment groups using analysis of covariance. Chi-squared tests of independence were used to compare the frequency of encoding, retrieval, and intact memory profiles between treatment groups. Associations between memory performance and other neurobehavioral measures were examined using Pearson correlation. RESULTS: Overall, patients receiving PRT demonstrated superior verbal learning and recall compared to those treated with XRT. Encoding and retrieval deficits were more common in the XRT group than the PRT group, with encoding problems being most prevalent. The PRT group was more likely to engage in semantic clustering strategies, which predicted better encoding and retrieval. Encoding ability was associated with higher intellectual and adaptive functioning, and fewer parent-reported concerns about day-to-day attention and cognitive regulation. CONCLUSION: Results suggest that PRT is associated with verbal memory sparing, driven by effective encoding and use of learning strategies. Future work may help to clarify underlying neural mechanisms associated with verbal memory decline, which will better inform treatment approaches. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Reduced asymmetry of the hand knob area and decreased sensorimotor u-fiber connectivity in middle-aged adults with autism.

Individuals with autism spectrum disorder (ASD) frequently present with impairments in motor skills (e.g., limb coordination, handwriting and balance), which are observed across the lifespan but remain largely untreated. Many adults with ASD may thus experience adverse motor outcomes in aging, when physical decline naturally occurs. The 'hand knob' of the sensorimotor cortex is an area that is critical for motor control of the fingers and hands. However, this region has received little attention in ASD research, especially in adults after midlife. The hand knob area of the precentral (PrChand) and postcentral (PoChand) gyri was semi-manually delineated in 49 right-handed adults (25 ASD, 24 typical comparison [TC] participants, aged 41-70 years). Using multimodal (T1-weighted, diffusion-weighted, and resting-state functional) MRI, we examined the morphology, ipsilateral connectivity and laterality of these regions. We also explored correlations between hand knob measures with motor skills and autism symptoms, and between structural and functional connectivity measures. Bayesian analyses indicated moderate evidence of group effects with greater right PrChand volume and reduced leftward laterality of PrChand and PoChand volume in the ASD relative to TC group. Furthermore, the right PoC-PrChand u-fibers showed increased mean diffusivity in the ASD group. In the ASD group, right u-fiber volume positively correlated with corresponding functional connectivity but did not survive multiple comparisons correction. Correlations of hand knob measures and behavior were observed in the ASD group but did not survive multiple comparisons correction. Our findings suggest that morphological laterality and u-fiber connectivity of the sensorimotor network, putatively involved in hand motor/premotor function, may be diminished in middle-aged adults with ASD, perhaps rendering them more vulnerable to motor decline in old age. The altered morphology may relate to atypical functional motor asymmetries found in ASD earlier in life, possibly reflecting altered functional asymmetries over time.

Blood Oxygen Level-Dependent Lag Patterns Differ Between Rest and Task Conditions, but Are Largely Typical in Autism.

Background/Introduction: Autism spectrum disorder (ASD) is characterized by atypical functional connectivity (FC) within and between distributed brain networks. However, FC findings have often been inconsistent, possibly due to a focus on static FC rather than brain dynamics. Lagged connectivity analyses aim at evaluating temporal latency, and presumably neural propagation, between regions. This approach may, therefore, reveal a more detailed picture of network organization in ASD than traditional FC methods. Methods: The current study evaluated whole-brain lag patterns in adolescents with ASD (n = 28) and their typically developing peers (n = 22). Functional magnetic resonance imaging data were collected during rest and during a lexico-semantic decision task. Optimal lag was calculated for each pair of regions of interest by using cross-covariance, and mean latency projections were calculated for each region. Results: Latency projections did not regionally differ between groups, with the same regions emerging among the "earliest" and "latest." Although many of the longest absolute latencies were preserved across resting-state and task conditions, lag patterns overall were affected by condition, as many regions shifted toward zero-lag during task performance. Lag structure was also strongly associated with literature-derived estimates of arterial transit time. Discussion: Results suggest that lag patterns are broadly typical in ASD but undergo changes during task performance. Moreover, lag patterns appear to reflect a combination of neural and vascular sources, which should be carefully considered when interpreting lagged FC. Impact statement Altered brain dynamics have been proposed in autism spectrum disorder (ASD). Lagged functional connectivity analysis uses cross-correlation between functional magnetic resonance imaging (fMRI) time series to determine regional latency. Few studies have examined blood oxygen level-dependent (BOLD) lag in ASD, and findings have been inconsistent. Using multi-echo fMRI data with improved artifact detection and removal, we find differences in lag structure between task and rest states, but not between adolescents with ASD and typically developing peers. Additional analyses exploring links with arterial transit time, however, highlight the impact of vascular organization on BOLD lag patterns and its potential to confound measures of neural dynamics.

Multifaceted empathy differences in children and adults with autism.

Although empathy impairments have been reported in autistic individuals, there is no clear consensus on how emotional valence influences this multidimensional process. In this study, we use the Multifaceted Empathy Test for juveniles (MET-J) to interrogate emotional and cognitive empathy in 184 participants (ages 8-59 years, 83 autistic) under the robust Bayesian inference framework. Group comparisons demonstrate previously unreported interaction effects between: (1) valence and autism diagnosis in predictions of emotional resonance, and (2) valence and age group in predictions of arousal to images portraying positive and negative facial expressions. These results extend previous studies using the MET by examining differential effects of emotional valence in a large sample of autistic children and adults with average or above-average intelligence. We report impaired cognitive empathy in autism, and subtle differences in emotional empathy characterized by less distinction between emotional resonance to positive vs. negative facial expressions in autism compared to neurotypicals. Reduced emotional differentiation between positive and negative affect in others could be a mechanism for diminished social reciprocity that poses a universal challenge for people with autism. These component- and valence- specific findings are of clinical relevance for the development and implementation of target-specific social interventions in autism.

Cortical Morphology in Autism: Findings from a Cortical Shape-Adaptive Approach to Local Gyrification Indexing.

It has been challenging to elucidate the differences in brain structure that underlie behavioral features of autism. Prior studies have begun to identify patterns of changes in autism across multiple structural indices, including cortical thickness, local gyrification, and sulcal depth. However, common approaches to local gyrification indexing used in prior studies have been limited by low spatial resolution relative to functional brain topography. In this study, we analyze the aforementioned structural indices, utilizing a new method of local gyrification indexing that quantifies this index adaptively in relation to specific sulci/gyri, improving interpretation with respect to functional organization. Our sample included n = 115 autistic and n = 254 neurotypical participants aged 5-54, and we investigated structural patterns by group, age, and autism-related behaviors. Differing structural patterns by group emerged in many regions, with age moderating group differences particularly in frontal and limbic regions. There were also several regions, particularly in sensory areas, in which one or more of the structural indices of interest either positively or negatively covaried with autism-related behaviors. Given the advantages of this approach, future studies may benefit from its application in hypothesis-driven examinations of specific brain regions and/or longitudinal studies to assess brain development in autism.

Sex-related patterns of intrinsic functional connectivity in children and adolescents with autism spectrum disorders.

LAY SUMMARY: We investigated whether children and adolescents with autism spectrum disorders show sex-specific patterns of brain function (using functional magnetic resonance imaging) that are well documented in typically developing males and females. We found, unexpectedly, that boys and girls with autism do not differ in their brain functional connectivity, whereas typically developing boys and girls showed differences in a brain network involved in thinking about self and others (the default mode network). Results suggest that autism may be characterized by a lack of brain sex differentiation.

Elevated Thresholds for Light Touch in Children With Autism Reflect More Conservative Perceptual Decision-Making Rather Than a Sensory Deficit.

Individuals with autism spectrum disorder (ASD) are often behaviorally hyper-reactive to light touch, but it is unclear to what degree this arises from a fundamental sensory difference vs. higher order systems for attention or emotion processing. Thus far, experimental findings for light touch detection are mixed, and few previous studies have independently considered sensitivity (the ability to discriminate signal from noise) and decision criterion (the overall response bias or tendency to answer "yes" or "no" in a detection task). We tested a large sample of children, adolescents, and adults with ASD (n = 88) and with neurotypical (NT) development (n = 59) using von Frey filaments to derive light touch thresholds at the palm. We calculated signal detection metrics for sensitivity (Az) and response criterion (c) from hit and false alarm rates. Both metrics exhibited significant group differences, such that the ASD group was less sensitive, but had a much more conservative response criterion. We used a best subset model selection procedure in three separate ordinal regressions for the whole group, adults, and children/adolescents. In all selected models, c was by far the most significant predictor of threshold, supplanting effects of diagnostic group that were significant in the baseline models. In contrast, Az was not a significant predictor of threshold in any of the models. Mean values of c were similar for adults with and without autism and for children/adolescents with ASD, but lower (more liberal) in neurotypical children/adolescents. This suggests that children with ASD exhibit a conservatism in their perceptual decision-making that differs from their NT peers but resembles that of adults. Across the sample, the value of c was significantly and positively correlated with age and with autism symptoms (SRS-2 total score), in addition to thresholds. The results of this study suggest that, rather than a sensory difference in detection of light touch, there is a difference in response bias such that children with ASD are more conservative/likely to report "no" if unsure, than their young NT peers. Future work should consider the implications of conservative response criterion in ASD for commonly used forced-choice psychophysical paradigms.

Neural Correlates of Cardiac Interoceptive Focus Across Development: Implications for Social Symptoms in Autism Spectrum Disorder.

Interoception involves the processing of sensory information relevant to physiological functioning and is integral to building self-awareness, emotional states, and modulating social behaviors. With the role of interoception in emotional processing and social functioning, there is growing interest in characterizing interoception in autism spectrum disorder (ASD), yet, there are mixed results regarding cardiac interoceptive accuracy in ASD. In this study, we explored the neural basis of cardiac interoception using an fMRI heartbeat-counting task in order to assess neural correlates of primary interoception. We predicted that interoceptive-specific response in the insula, a "hub" for interoception, would be related to ASD symptomatology. We investigated the relationship of insula responses during cardiac interoceptive focus and a self/caregiver-reported autism-related symptom scale (Social Responsiveness Scale-2 (SRS)). Participants included 46 individuals with autism spectrum disorder (ASD) (age 8-54, mean = 19.43 ± 10.68 years) and 54 individuals with typical development for comparison (TC, age 8-53, mean = 21.43 ± 10.41 years). We found no significant difference in cardiac interoceptive accuracy or neural response to cardiac interoception focus in ASD. Several insula subdivisions had a curvilinear relationship to age, peaking in early adulthood. Interoceptive-specific insula response was associated with adult self-report SRS scores; this association differed by diagnostic group and was not present for caregiver-reported scores. This work suggests that (a) there is no global deficit in cardiac interoception in ASD, but integrating interoceptive cues with social information may distinguish individuals with ASD, and (b) there is a developmental trajectory for interoceptive processing in the insula that may be relevant for socio-emotional health. Autism Res 2020, 13: 908-920. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We use internal sensory information from the body, such as signals from the heart, to understand our emotional response to the external world. We measured how accurately people with autism feel their heartbeat and how the brain responds to this type of information. We found no differences between the autism and comparison groups in how the brain senses heartbeats, or in how accurately people feel their heartbeats. However, for people with autism, brain responses while sensing heartbeats were related to social difficulties. This work suggests people with autism may use internal and external information in a different way.

Brief Report: A Gaming Approach to the Assessment of Attention Networks in Autism Spectrum Disorder and Typical Development.

Attentional impairments are among the earliest identifiable features of autism spectrum disorders (ASDs). Three attention networks have been extensively studied using the attention network test (ANT), but this long and repetitive task may pose challenges for individuals with ASDs. The AttentionTrip was developed as a more engaging measure of attention network efficiency. In 20 adults with ASDs and 20 typically developing controls, both tasks produced typical network scores (all p < .003, all Cohen's d > 0.78). Reaction time was less variable in the AttentionTrip than the ANT, possibly reflecting improved task engagement. Although the AttentionTrip elicited more consistent responses throughout an experimental session, anomalously low split-half reliability for its executive control network suggests that some changes may be needed.

Atypical Relationships Between Spontaneous EEG and fMRI Activity in Autism.

Autism spectrum disorders (ASDs) have been linked to atypical communication among distributed brain networks. However, despite decades of research, the exact nature of these differences between typically developing (TD) individuals and those with ASDs remains unclear. ASDs have been widely studied using resting-state neuroimaging methods, including both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). However, little is known about how fMRI and EEG measures of spontaneous brain activity are related in ASDs. In the present study, two cohorts of children and adolescents underwent resting-state EEG (n = 38 per group) or fMRI (n = 66 ASD, 57 TD), with a subset of individuals in both the EEG and fMRI cohorts (n = 17 per group). In the EEG cohort, parieto-occipital EEG alpha power was found to be reduced in ASDs. In the fMRI cohort, blood oxygen level-dependent (BOLD) power was regionally increased in right temporal regions and there was widespread overconnectivity between the thalamus and cortical regions in the ASD group relative to the TD group. Finally, multimodal analyses indicated that while TD children showed consistently positive relationships between EEG alpha power and regional BOLD power, these associations were weak or negative in ASDs. These findings suggest atypical links between alpha rhythms and regional BOLD activity in ASDs, possibly implicating neural substrates and processes that coordinate thalamocortical regulation of the alpha rhythm.

Transient states of network connectivity are atypical in autism: A dynamic functional connectivity study.

There is ample evidence of atypical functional connectivity (FC) in autism spectrum disorders (ASDs). However, transient relationships between neural networks cannot be captured by conventional static FC analyses. Dynamic FC (dFC) approaches have been used to identify repeating, transient connectivity patterns ("states"), revealing spatiotemporal network properties not observable in static FC. Recent studies have found atypical dFC in ASDs, but questions remain about the nature of group differences in transient connectivity, and the degree to which states persist or change over time. This study aimed to: (a) describe and relate static and dynamic FC in typical development and ASDs, (b) describe group differences in transient states and compare them with static FC patterns, and (c) examine temporal stability and flexibility between identified states. Resting-state functional magnetic resonance imaging (fMRI) data were collected from 62 ASD and 57 typically developing (TD) children and adolescents. Whole-brain, data-driven regions of interest were derived from group independent component analysis. Sliding window analysis and k-means clustering were used to explore dFC and identify transient states. Across all regions, static overconnnectivity and increased variability over time in ASDs predominated. Furthermore, significant patterns of group differences emerged in two transient states that were not observed in the static FC matrix, with group differences in one state primarily involving sensory and motor networks, and in the other involving higher-order cognition networks. Default mode network segregation was significantly reduced in ASDs in both states. Results highlight that dynamic approaches may reveal more nuanced transient patterns of atypical FC in ASDs.

Distinct Patterns of Atypical Functional Connectivity in Lower-Functioning Autism.

BACKGROUND: Functional magnetic resonance imaging research on autism spectrum disorders (ASDs) has been largely limited to individuals with near-average intelligence. Although cognitive impairment is common in ASDs, functional network connectivity in this population remains poorly understood. Specifically, it remains unknown whether lower-functioning individuals exhibit exacerbated connectivity abnormalities similar to those previously detected in higher-functioning samples or specific divergent patterns of connectivity. METHODS: Resting-state functional magnetic resonance imaging data from 88 children (44 ASD, 44 typically developing; average age: 11 years) were included. Based on IQ, individuals with ASDs were assigned to either a lower-functioning group (mean IQ = 77 ± 6) or a higher-functioning group (mean IQ = 123 ± 8). Two typically developing comparison groups were matched to these groups on head motion, handedness, and age. Seeds in the medial prefrontal cortex, posterior cingulate cortex, posterior superior temporal sulcus, insula, and amygdala were used to contrast whole-brain functional connectivity across groups. RESULTS: Lower-functioning ASD participants (compared with higher-functioning ASD participants) showed significant underconnectivity within the default mode network and the ventral visual stream. Higher-functioning ASD participants (compared with matched typically developing participants) showed significantly decreased anticorrelations among default mode, salience, and task-positive regions. Effect sizes of detected differences were large (Cohen's d > 1.46). CONCLUSIONS: Lower- and higher-functioning individuals with ASDs demonstrated distinct patterns of atypical connectivity. Findings suggest a gross pattern of predominantly reduced network integration in lower-functioning ASDs (affecting default mode and visual networks) and predominantly reduced network segregation in higher-functioning ASDs. Results indicate the need for stratification by general functional level in studies of functional connectivity in ASDs.

Multimodal approaches to functional connectivity in autism spectrum disorders: An integrative perspective.

Atypical functional connectivity has been implicated in autism spectrum disorders (ASDs). However, the literature to date has been largely inconsistent, with mixed and conflicting reports of hypo- and hyper-connectivity. These discrepancies are partly due to differences between various neuroimaging modalities. Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG) measure distinct indices of functional connectivity (e.g., blood-oxygenation level-dependent [BOLD] signal vs. electrical activity). Furthermore, each method has unique benefits and disadvantages with respect to spatial and temporal resolution, vulnerability to specific artifacts, and practical implementation. Thus far, functional connectivity research on ASDs has remained almost exclusively unimodal; therefore, interpreting findings across modalities remains a challenge. Multimodal integration of fMRI, EEG, and MEG data is critical in resolving discrepancies in the literature, and working toward a unifying framework for interpreting past and future findings. This review aims to provide a theoretical foundation for future multimodal research on ASDs. First, we will discuss the merits and shortcomings of several popular theories in ASD functional connectivity research, using examples from the literature to date. Next, the neurophysiological relationships between imaging modalities, including their relationship with invasive neural recordings, will be reviewed. Finally, methodological approaches to multimodal data integration will be presented, and their future application to ASDs will be discussed. Analyses relating transient patterns of neural activity ("states") are particularly promising. This strategy provides a comparable measure across modalities, captures complex spatiotemporal patterns, and is a natural extension of recent dynamic fMRI research in ASDs. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 456-473, 2018.

Associations Between Interoceptive Cognition and Age in Autism Spectrum Disorder and Typical Development.

Interoceptive awareness is linked to emotional and social cognition, which are impaired in individuals with autism spectrum disorder (ASD). It is unknown how this ability is associated with age in either typical or atypical development. We used a standard test of interoceptive accuracy (IA) to investigate these questions in children and adults with and without ASD. Perceived number of heartbeats over 4 time intervals was compared with actual heart rate to determine IA. Effects of group, age, IQ, heart rate, and mental counting ability on accuracy were assessed using multiple regression. Post hoc correlations were performed to clarify significant interactions. Age was unrelated to IA in both groups when IQ ≥115. When IQ <115, this relationship was positive in typical development and negative in ASD. These results suggest that cognitive ability moderates the effect of age on IA differently in autism and typical development.

Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial.

OBJECTIVE: No drug is yet approved to treat the core symptoms of autism spectrum disorder (ASD). Low-dose suramin was effective in the maternal immune activation and Fragile X mouse models of ASD. The Suramin Autism Treatment-1 (SAT-1) trial was a double-blind, placebo-controlled, translational pilot study to examine the safety and activity of low-dose suramin in children with ASD. METHODS: Ten male subjects with ASD, ages 5-14 years, were matched by age, IQ, and autism severity into five pairs, then randomized to receive a single, intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes were ADOS-2 comparison scores and Expressive One-Word Picture Vocabulary Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist, autism treatment evaluation checklist, repetitive behavior questionnaire, and clinical global impression questionnaire. RESULTS: Blood levels of suramin were 12 ± 1.5 µmol/L (mean ± SD) at 2 days and 1.5 ± 0.5 µmol/L after 6 weeks. The terminal half-life was 14.7 ± 0.7 days. A self-limited, asymptomatic rash was seen, but there were no serious adverse events. ADOS-2 comparison scores improved by -1.6 ± 0.55 points (n = 5; 95% CI = -2.3 to -0.9; Cohen's d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo group. EOWPVT scores did not change. Secondary outcomes also showed improvements in language, social interaction, and decreased restricted or repetitive behaviors. INTERPRETATION: The safety and activity of low-dose suramin showed promise as a novel approach to treatment of ASD in this small study.

A functional neuroimaging study of fusiform response to restricted interests in children and adolescents with autism spectrum disorder.

BACKGROUND: While autism spectrum disorder (ASD) is characterized by both social communication deficits and restricted and repetitive patterns of behavior and interest, literature examining possible neural bases of the latter class of symptoms is limited. The fusiform face area (FFA) is a region in the ventral temporal cortex that not only shows preferential responsiveness to faces but also responds to non-face objects of visual expertise. Because restricted interests in ASD are accompanied by high levels of visual expertise, the objective of this study was to determine the extent to which this region responds to images related to restricted interests in individuals with ASD, compared to individuals without ASD who have a strong hobby or interest. METHODS: Children and adolescents with and without ASD with hobbies or interests that consumed a pre-determined minimum amount of time were identified, and the intensity, frequency, and degree of interference of these interests were quantified. Each participant underwent functional magnetic resonance imaging (fMRI) while viewing images related to their personal restricted interests (in the ASD group) or strong interest or hobby (in the comparison group). A generalized linear model was used to compare the intensity and spatial extent of fusiform gyrus response between groups, controlling for the appearance of faces in the stimuli. RESULTS: Images related to interests and expertise elicited response in FFA in both ASD and typically developing individuals, but this response was more robust in ASD. CONCLUSIONS: These findings add neurobiological support to behavioral observations that restricted interests are associated with enhanced visual expertise in ASD, above and beyond what would be expected for simply a strong interest. Further, the results suggest that brain regions associated with social functioning may not be inherently less responsive in ASD, but rather may be recruited by different environmental stimuli. This study contributes to our understanding of the neural basis of restricted interests in ASD and may provide clues toward developing novel interventions.