Relationships between tryptophan-related gut metabolites, brain activity, and autism symptomatology.

Gut microbial metabolites have been theorized to play a causative role in the pathophysiology of autism spectrum disorder (ASD). This hypothesis is based on results from mechanistic preclinical studies and several correlational studies showing differences in gut microbial composition between ASD subjects and neurotypical (NT) controls. However, alterations in how the human brain interacts with the gut microbiome in ASD have not been examined. In this cross-sectional, case-control observational study, fecal metabolomics, task-based functional magnetic resonance imaging (fMRI), and behavioral assessments were obtained from 43 ASD and 41 NT children aged 8-17. The fMRI tasks were based on socio-emotional and sensory paradigms that commonly show strong evoked brain differences in ASD participants. General linear models and mediational modeling were applied to examine the links between tryptophan metabolism and evoked brain activity and behavior. Results indicated that fecal levels of specific tryptophan-related metabolites were associated with: 1) brain activity atypicalities in regions previously implicated in ASD (i.e., insula and cingulate); and 2) ASD severity and symptomatology (i.e., ADOS scores, disgust propensity, and sensory sensitivities). Importantly, activity in the mid-insula and mid-cingulate significantly mediated relationships between the microbial tryptophan metabolites, indolelactate and tryptophan betaine, and ASD severity and disgust sensitivity. To our knowledge, this is the first study to elucidate how interactions between gut metabolites and brain activity may impact autism symptomatology, particularly in functional brain pathways associated with vagal and interoceptive/emotion processing.

Correction: Raman et al. Relationships between Affect Recognition, Empathy, Alexithymia, and Co-Occurring Conditions in Autism. Brain Sci. 2023, 13, 1161.

In the original publication [...].

Caregiver and youth inter-rater assessment agreement in autism spectrum disorder, developmental coordination disorder, and typical development.

Youth diagnosed with autism spectrum disorder (ASD) and those with developmental coordination disorder (DCD) are at heightened risk for co-occurring mental health diagnoses, especially anxiety and attention-deficit/hyperactivity disorder (ADHD). However, caregiver-child agreement on presence of related symptoms in populations with neurodevelopmental conditions is not well understood. Here, we examine the extent to which 37 ASD, 26 DCD, and 40 typically developing children and their caregivers agree on the degree of the child's symptoms of anxiety and ADHD. All caregiver-child dyads completed the Screen for Child Anxiety Related Emotional Disorders and Conners 3 ADHD Index. Across groups, intraclass correlations indicated generally poor agreement on anxiety and ADHD symptomatology. Although youth generally reported greater internalizing symptoms (i.e., anxiety), caregivers tended to report more observable externalizing behaviors (i.e., ADHD). Together, the results of this study support the need for a multi-informant approach in assessments of anxiety and ADHD in youth with neurodevelopmental disorders.

Motor Signature Differences Between Autism Spectrum Disorder and Developmental Coordination Disorder, and Their Neural Mechanisms.

Autism spectrum disorder (ASD) and Developmental Coordination Disorder (DCD) are distinct clinical groups with overlapping motor features. We attempted to (1) differentiate children with ASD from those with DCD, and from those typically developing (TD) (ages 8-17; 18 ASD, 16 DCD, 20 TD) using a 5-min coloring game on a smart tablet and (2) identify neural correlates of these differences. We utilized standardized behavioral motor assessments (e.g. fine motor, gross motor, and balance skills) and video recordings of a smart tablet task to capture any visible motor, behavioral, posture, or engagement differences. We employed machine learning analytics of motor kinematics during a 5-min coloring game on a smart tablet. Imaging data was captured using functional magnetic resonance imaging (fMRI) during action production tasks. While subject-rated motor assessments could not differentiate the two clinical groups, machine learning computational analysis provided good predictive discrimination: between TD and ASD (76% accuracy), TD and DCD (78% accuracy), and ASD and DCD (71% accuracy). Two kinematic markers which strongly drove categorization were significantly correlated with cerebellar activity. Findings demonstrate unique neuromotor patterns between ASD and DCD relate to cerebellar function and present a promising route for computational techniques in early identification. These are promising preliminary results that warrant replication with larger samples.

Connectivity differences between inferior frontal gyrus and mentalizing network in autism as compared to developmental coordination disorder and non-autistic youth.

Prior studies have compared neural connectivity during mentalizing tasks in autism (ASD) to non-autistic individuals and found reduced connectivity between the inferior frontal gyrus (IFG) and mentalizing regions. However, given that the IFG is involved in motor processing, and about 80% of autistic individuals have motor-related difficulties, it is necessary to explore if these differences are specific to ASD or instead similar across other developmental motor disorders, such as developmental coordination disorder (DCD). Participants (29 ASD, 20 DCD, 31 typically developing [TD]; ages 8-17) completed a mentalizing task in the fMRI scanner, where they were asked to think about why someone was performing an action. Results indicated that the ASD group, as compared to both TD and DCD groups, showed significant functional connectivity differences when mentalizing about other's actions. The left IFG seed revealed ASD connectivity differences with the: bilateral temporoparietal junction (TPJ), left insular cortex, and bilateral dorsolateral prefrontal cortex (DLPFC). Connectivity differences using the right IFG seed revealed ASD differences in the: left insula, and right DLPFC. These results indicate that connectivity differences between the IFG, mentalizing regions, emotion and motor processing regions are specific to ASD and not a result of potentially co-occurring motor differences.

Relationships between Affect Recognition, Empathy, Alexithymia, and Co-Occurring Conditions in Autism.

Prior studies show differences in empathy and affect-recognition ability between those with autism spectrum disorder (ASD) and typically developing (TD) individuals. Autistic individuals also exhibit increased behavioral, gastrointestinal, and sleep issues. In the current study, we explored the differences in empathy and affect recognition between the ASD and TD groups; and we investigated their associations with conditions co-occurring in ASD. A total of 54 TD and 56 ASD children (8-17 years) were included. As compared to the TD group, the ASD group showed lower scores for affect recognition and perspective taking (PT) and higher scores for personal distress (PD). Interestingly, results from hierarchical linear regressions suggested that disparities in the PD and PT between the groups were primarily attributable to attenuated levels of alexithymia, rather than being mediated by the presence of an autism diagnosis. Differences in affect-recognition ability, however, were mediated by both an autism diagnosis and alexithymia. We also found significant correlations between empathy and affect recognition and measures of related conditions common in ASD. Alexithymia, hence, contributes to difficulties in empathy while both alexithymia and autism are associated with affect-recognition ability in ASD. Additionally, the association between affect recognition and empathic ability with co-occurring conditions in ASD needs to be considered during assessments and interventions.

The relationship between alexithymia, interoception, and neural functional connectivity during facial expression processing in autism spectrum disorder.

Neural processing differences of emotional facial expressions, while common in autism spectrum disorder (ASD), may be related to co-occurring alexithymia and interoceptive processing differences rather than autism per se. Here, we investigate relationships between alexithymia, interoceptive awareness of emotions, and functional connectivity during observation of facial expressions in youth (aged 8-17) with ASD (n = 28) compared to typically developing peers (TD; n = 37). Behaviorally, we found no significant differences between ASD and TD groups in interoceptive awareness of emotions, though alexithymia severity was significantly higher in the ASD group. In the ASD group, increased alexithymia was significantly correlated with lower interoceptive sensation felt during emotion. Using psycho-physiological interaction (PPI) analysis, the ASD group showed higher functional connectivity between the left ventral anterior insula and the left lateral prefrontal cortex than the TD group when viewing facial expressions. Further, alexithymia was associated with reduced left anterior insula-right precuneus connectivity and reduced right dorsal anterior insula-left ventral anterior insula connectivity when viewing facial expressions. In the ASD group, the degree of interoceptive sensation felt during emotion was positively correlated with left ventral anterior insula-right IFG connectivity when viewing facial expressions. However, across all participants, neither alexithymia nor interoceptive awareness of emotions predicted connectivity between emotion-related brain regions when viewing emotional facial expressions. To summarize, we found that in ASD compared to TD: 1) there is stronger connectivity between the insula and lateral prefrontal cortex; and 2) differences in interhemispheric and within left hemisphere connectivity between the insula and other emotion-related brain regions are related to individual differences in interoceptive processing and alexithymia. These results highlight complex relationships between alexithymia, interoception, and brain processing in ASD.

Relationships between alexithymia, interoception, and emotional empathy in autism spectrum disorder.

LAY ABSTRACT: Empathy, the ability to understand and share the emotions of others, is a necessary skill for social functioning and can be categorized into cognitive and emotional empathy. There is evidence to suggest that individuals with autism spectrum disorder have difficulties with cognitive empathy, the ability to imagine how another person is thinking or feeling. However, it is unclear if individuals with autism spectrum disorder struggle with emotional empathy, the ability to share and feel emotions others are experiencing. Self-report and interview data were collected to explore the relationships between interoception (individuals' self-reported awareness of sensation from their body such as thirst, heartbeat, etc.), alexithymia (an individual's ability to describe and distinguish between their own emotions), and emotional empathy in 35 youth with autism spectrum disorder and 40 typically developing youth. Greater personal distress to others' emotions and greater difficulty describing and recognizing self-emotions were associated with reporting fewer physical sensations in the body when experiencing emotion in the autism spectrum disorder group. The results of this study suggest that while autism spectrum disorder youth with concomitant alexithymia may experience emotional empathy differently, it should not be characterized as an absence of a capacity for emotional empathy.

Differences in Praxis Errors in Autism Spectrum Disorder Compared to Developmental Coordination Disorder.

This study aimed to better understand how autism spectrum disorder (ASD) and developmental coordination disorder (DCD) differ in types of praxis errors made on the Florida Apraxia Battery Modified (FAB-M) and the potential relationships between praxis errors and social deficits in ASD. The ASD group made significantly more timing sequencing errors in imitation of meaningful gestures, as well as more body-part-for-tool errors during gesture-to-command compared to the other two groups. In the ASD group, increased temporal errors in meaningful imitation were significantly correlated with poorer affect recognition and less repetitive behaviors. Thus, in ASD, aspects of imitation ability are related to socioemotional skills and repetitive behaviors.

Specific tractography differences in autism compared to developmental coordination disorder.

About 85% of children with autism spectrum disorder (ASD) experience comorbid motor impairments, making it unclear whether white matter abnormalities previously found in ASD are related to social communication deficits, the hallmark of ASD, or instead related to comorbid motor impairment. Here we aim to understand specific white matter signatures of ASD beyond those related to comorbid motor impairment by comparing youth (aged 8-18) with ASD (n = 22), developmental coordination disorder (DCD; n = 16), and typically developing youth (TD; n = 22). Diffusion weighted imaging was collected and quantitative anisotropy, radial diffusivity, mean diffusivity, and axial diffusivity were compared between the three groups and correlated with social and motor measures. Compared to DCD and TD groups, diffusivity differences were found in the ASD group in the mid-cingulum longitudinal and u-fibers, the corpus callosum forceps minor/anterior commissure, and the left middle cerebellar peduncle. Compared to the TD group, the ASD group had diffusivity differences in the right inferior frontal occipital/extreme capsule and genu of the corpus callosum. These diffusion differences correlated with emotional deficits and/or autism severity. By contrast, children with DCD showed unique abnormality in the left cortico-spinal and cortico-pontine tracts.Trial Registration All data are available on the National Institute of Mental Health Data Archive: https://nda.nih.gov/edit_collection.html?id=2254 .

Sensory Modulation in Children with Developmental Coordination Disorder Compared to Autism Spectrum Disorder and Typically Developing Children.

Developmental Coordination Disorder (DCD) is one of the least studied and understood developmental disorders. One area that has been minimally investigated in DCD is potential issues with sensory modulation. Further, in other neurodevelopmental disorders (e.g., autism spectrum disorder (ASD)) sensory modulation is related to many other challenges (e.g., social issues, repetitive behaviors, anxiety); however, such potential relationships in children with DCD have been largely unexplored. The purpose of this study is to explore sensory modulation differences in DCD and to understand the relationships between sensory modulation and social emotional measures, behavior, and motor skills in DCD in comparison to ASD and typically developing (TD) peers. Participants (aged 8-17) and their caregivers (DCD, N = 26; ASD, N = 57; and TD, N = 53) completed behavioral and clinical measures. The results indicated that 31% of the DCD group showed sensory modulation difficulties, with the DCD group falling between the ASD and TD groups. In the DCD group, sensory modulation was significantly associated with anxiety, empathic concern, repetitive behaviors, and motor skills. Data are compared to patterns seen in ASD and TD groups and implications for interventions are discussed.

Motor performance, praxis, and social skills in autism spectrum disorder and developmental coordination disorder.

Previous research has shown that individuals with autism spectrum disorder (ASD) and developmental coordination disorder (DCD) may have overlapping social and motor skill impairments. This study compares ASD, DCD, and typically developing (TD) youth on a range of social, praxis and motor skills, and investigates the relationship between these skills in each group. Data were collected on participants aged 8-17 (n = 33 ASD, n = 28 DCD, n = 35 TD). Overall, the clinical groups showed some similar patterns of social and motor impairments but diverged in praxis impairments, cognitive empathy, and Theory of Mind ability. When controlling for both social and motor performance impairments, the ASD group showed significantly lower accuracy on imitation of meaningful gestures and gesture to command, indicating a prominent deficit in these praxis skills in ASD. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) and developmental coordination disorder (DCD) have social and motor skill impairments to varying degrees. This study compares ASD, DCD, and typically developing (TD) youth on a range of social, praxis, and motor skills. ASD and DCD shared similar patterns of gross and fine motor skills, but differed in skills related to making gestures. Specifically, our results also suggest that ASD has a prominent deficit in gesture performance and meaningful imitation compared to TD and DCD groups.

The Brain-Gut-Microbiome System: Pathways and Implications for Autism Spectrum Disorder.

Gastrointestinal dysfunction is one of the most prevalent physiological symptoms of autism spectrum disorder (ASD). A growing body of largely preclinical research suggests that dysbiotic gut microbiota may modulate brain function and social behavior, yet little is known about the mechanisms that underlie these relationships and how they may influence the pathogenesis or severity of ASD. While various genetic and environmental risk factors have been implicated in ASD, this review aims to provide an overview of studies elucidating the mechanisms by which gut microbiota, associated metabolites, and the brain interact to influence behavior and ASD development, in at least a subgroup of individuals with gastrointestinal problems. Specifically, we review the brain-gut-microbiome system and discuss findings from current animal and human studies as they relate to social-behavioral and neurological impairments in ASD, microbiota-targeted therapies (i.e., probiotics, fecal microbiota transplantation) in ASD, and how microbiota may influence the brain at molecular, structural, and functional levels, with a particular interest in social and emotion-related brain networks. A deeper understanding of microbiome-brain-behavior interactions has the potential to inform new therapies aimed at modulating this system and alleviating both behavioral and physiological symptomatology in individuals with ASD.

Motor and sensory features successfully decode autism spectrum disorder and combine with the original RDoC framework to boost diagnostic classification.

Sensory processing and motor coordination atypicalities are not commonly identified as primary characteristics of autism spectrum disorder (ASD), nor are they well captured in the NIMH's original Research Domain Criteria (RDoC) framework. Here, motor and sensory features performed similarly to RDoC features in support vector classification of 30 ASD youth against 33 typically developing controls. Combining sensory with RDoC features boosted classification performance, achieving a Matthews Correlation Coefficient (MCC) of 0.949 and balanced accuracy (BAcc) of 0.971 (p = 0.00020, calculated against a permuted null distribution). Sensory features alone successfully classified ASD (MCC = 0.565, BAcc = 0.773, p = 0.0222) against a clinically relevant control group of 26 youth with Developmental Coordination Disorder (DCD) and were in fact required to decode against DCD above chance. These findings highlight the importance of sensory and motor features to the ASD phenotype and their relevance to the RDoC framework.

Unique deficit in embodied simulation in autism: An fMRI study comparing autism and developmental coordination disorder.

A deficit in pre-cognitively mirroring other people's actions and experiences may be related to the social impairments observed in autism spectrum disorder (ASD). However, it is unclear whether such embodied simulation deficits are unique to ASD or instead are related to motor impairment, which is commonly comorbid with ASD. Here we aim to disentangle how, neurologically, motor impairments contribute to simulation deficits and identify unique neural signatures of ASD. We compare children with ASD (N = 30) to children with Developmental Coordination Disorder (DCD; N = 23) as well as a typically developing group (N = 33) during fMRI tasks in which children observe, imitate, and mentalize about other people's actions. Results indicate a unique neural signature in ASD: during action observation, only the ASD group shows hypoactivity in a region important for simulation (inferior frontal gyrus, pars opercularis, IFGop). However, during a motor production task (imitation), the IFGop is hypoactive for both ASD and DCD groups. For all tasks, we find correlations across groups with motor ability, even after controlling for age, IQ, and social impairment. Conversely, across groups, mentalizing ability is correlated with activity in the dorsomedial prefrontal cortex when controlling for motor ability. These findings help identify the unique neurobiological basis of ASD for aspects of social processing. Furthermore, as no previous fMRI studies correlated brain activity with motor impairment in ASD, these findings help explain prior conflicting reports in these simulation networks.

Impact of Sensory Processing on School Performance Outcomes in High Functioning Individuals with Autism Spectrum Disorder.

Difficulty processing sensory information may impede progress in school for students with autism spectrum disorder (ASD). We explore the relationship between sensory processing and school performance in 26 high-functioning youths with ASD and 26 controls (age 8-14) using measures of sensory, social, cognitive, and academic functioning. In the ASD group, bivariate Pearson correlations indicated a significant positive relationship between intelligence quotient (IQ) and the School Competence Scale (SCS) of the Child Behavior Checklist (CBCL), and a significant negative relationship between Dunn's Sensory Processing Framework and SCS scores. Final hierarchical multiple linear regression model accounting for SCS scores in ASD included IQ, ADHD symptoms, and sensory features. An interaction between increased sensory sensitivity with reduced sensory avoidance behaviors explained the greatest amount of variance in SCS, meaning school performance is lowest for children with greater hypersensitivity and fewer avoidance behaviors. Results indicate a strong impact of sensory processing on school performance in ASD.

Ayres Theories of Autism and Sensory Integration Revisited: What Contemporary Neuroscience Has to Say.

Abnormal sensory-based behaviors are a defining feature of autism spectrum disorders (ASD). Dr. A. Jean Ayres was the first occupational therapist to conceptualize Sensory Integration (SI) theories and therapies to address these deficits. Her work was based on neurological knowledge of the 1970's. Since then, advancements in neuroimaging techniques make it possible to better understand the brain areas that may underlie sensory processing deficits in ASD. In this article, we explore the postulates proposed by Ayres (i.e., registration, modulation, motivation) through current neuroimaging literature. To this end, we review the neural underpinnings of sensory processing and integration in ASD by examining the literature on neurophysiological responses to sensory stimuli in individuals with ASD as well as structural and network organization using a variety of neuroimaging techniques. Many aspects of Ayres' hypotheses about the nature of the disorder were found to be highly consistent with current literature on sensory processing in children with ASD but there are some discrepancies across various methodological techniques and ASD development. With additional characterization, neurophysiological profiles of sensory processing in ASD may serve as valuable biomarkers for diagnosis and monitoring of therapeutic interventions, such as SI therapy.

A Review of Functional and Structural Neurobiology of the Action Observation Network in Autism Spectrum Disorder and Developmental Coordination Disorder.

Recent research has reported motor impairment similarities between children with developmental coordination disorder (DCD) and a subgroup of individuals with autism spectrum disorder (ASD). However, there is a debate as to whether DCD is a co-occurring diagnosis in individuals with ASD and motor impairments (ASDd), or if motor impairments in ASD are distinct from DCD. However, the etiology of motor impairments is not well understood in either disorder. Clarifying comorbidities in ASD is important to determine different etiopathological phenotyping clusters in ASD and to understand the variety of genetic and environmental factors that contribute to the disorder. Furthermore, this distinction has important therapeutic relevance. Here we explore the current neuroimaging findings in ASD and DCD and discusses possible neural mechanisms that underlie similarities and differences between the disorders.

Understanding Activation Patterns in Shared Circuits: Toward a Value Driven Model.

Over the past decade many studies indicate that we utilize our own motor system to understand the actions of other people. This mirror neuron system (MNS) has been proposed to be involved in social cognition and motor learning. However, conflicting findings regarding the underlying mechanisms that drive these shared circuits make it difficult to decipher a common model of their function. Here we propose adapting a "value-driven" model to explain discrepancies in the human mirror system literature and to incorporate this model with existing models. We will use this model to explain discrepant activation patterns in multiple shared circuits in the human data, such that a unified model may explain reported activation patterns from previous studies as a function of value.

Developmental trajectories of cerebral blood flow and oxidative metabolism at baseline and during working memory tasks.

The neurobiological interpretation of developmental BOLD fMRI findings remains difficult due to the confounding issues of potentially varied baseline of brain function and varied strength of neurovascular coupling across age groups. The central theme of the present research is to study the development of brain function and neuronal activity through in vivo assessments of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) both at baseline and during the performance of a working memory task in a cohort of typically developing children aged 7 to 18years. Using a suite of 4 emerging MRI technologies including MR blood oximetry, phase-contrast MRI, pseudo-continuous arterial spin labeling (pCASL) perfusion MRI and concurrent CBF/BOLD fMRI, we found: 1) At baseline, both global CBF and CMRO2 showed an age related decline while global OEF was stable across the age group; 2) During the working memory task, neither BOLD nor CBF responses showed significant variations with age in the activated fronto-parietal brain regions. Nevertheless, detailed voxel-wise analyses revealed sub-regions within the activated fronto-parietal regions that show significant decline of fractional CMRO2 responses with age. These findings suggest that the brain may become more "energy efficient" with age during development.