Salience network connectivity is altered in 6-week-old infants at heightened likelihood for developing autism.

Converging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network - an early-emerging neural network involved in orienting attention to the most salient aspects of one's internal and external environment - may predict the development of ASD symptoms such as reduced social attention and atypical sensory processing. Six-week-old infants at high likelihood of developing ASD based on family history exhibited stronger Salience Network connectivity with sensorimotor regions; infants at typical likelihood of developing ASD demonstrated stronger Salience Network connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in Salience Network connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with vulnerability to ASD.

Altered intra- and inter-network brain functional connectivity associated with prolonged screen time in pre-school children with autism spectrum disorder.

Prolonged screen time (ST) has adverse effects on autistic characteristics and language development. However, the mechanisms underlying the effects of prolonged ST on the neurodevelopment of children with autism spectrum disorder (ASD) remain unclear. Neuroimaging technology may help to further explain the role of prolonged ST in individuals with ASD. This study included 164 cases, all cases were divided into low-dose ST exposure (LDE group 108 cases) and high-dose ST exposure (HDE group 56 cases) based on the average ST of all subjects. Spatial independent component analysis (ICA) was used to identify resting state networks (RSNs) and investigate intra- and inter-network alterations in ASD children with prolonged ST. We found that the total Childhood Autism Rating Scale (CARS) scores in the HDE group were significantly higher than those in the LDE group (36.2 ± 3.1 vs. 34.6 ± 3.9, p = 0.008). In addition, the developmental quotient (DQ) of hearing and language in the HDE group were significantly lower than those in the LDE group (31.5 ± 13.1 vs. 42.5 ± 18.5, p < 0.001). A total of 13 independent components (ICs) were identified. Between-group comparison revealed that the HDE group exhibited decreased functional connectivity (FC) in the left precuneus (PCUN) of the default mode network (DMN), the right middle temporal gyrus (MTG) of the executive control network (ECN), and the right median cingulate and paracingulate gyri (MCG) of the attention network (ATN), compared with the LDE group. Additionally, there was an increase in FC in the right orbital part of the middle frontal gyrus (ORBmid) of the salience network (SAN), compared with the LDE group. The inter-network analysis revealed increased FC between the visual network (VN) and basal ganglia (BG) and decreased FC between the sensorimotor network (SMN) and DMN, SMN and ATN, SMN and auditory network (AUN), and DMN and SAN in the HDE group, compared with the LDE group. There was a significant negative correlation between altered FC values in MTG and total CARS scores in subjects (r = - 0.18, p = 0.018).  Conclusion: ASD children with prolonged ST often exhibit lower DQ of language development and more severe autistic characteristics. The alteration of intra- and inter-network FC may be a key neuroimaging feature of the effect of prolonged ST on neurodevelopment in ASD children.  Clinical trial registration: ChiCTR2100051141. What is Known: • Prolonged ST has adverse effects on autistic characteristics and language development. • Neuroimaging technology may help to further explain the role of prolonged ST in ASD. What is New: • This is the first study to explore the impact of ST on intra- and inter-network FC in children with ASD. • ASD children with prolonged ST have atypical changes in intra- and inter-brain network FC.

Sex shapes gut-microbiota-brain communication and disease.

Research into the microbiota-gut-brain axis (MGBA) has entered a golden age, raising the hope that therapeutics acting on it may offer breakthroughs in the treatment of many illnesses. However, most of this work overlooks a fundamental, yet understudied, biological variable: sex. Sex differences exist at every level of the MGBA. Sex steroids shape the structure of the gut microbiota, and these microbes in turn regulate levels of bioactive sex steroids. These hormones and microbes act on gut sensory enteroendocrine cells, which modulate downstream activity in the enteric nervous system, vagus nerve, and brain. We examine recent advances in this field, and discuss the scientific and moral imperative to include females in biomedical research, using autism spectrum disorder (ASD) as an example.

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats. METHODS: Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1ß, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum. KEY FINDINGS: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1ß, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage. CONCLUSIONS: Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

Atypical facial mimicry for basic emotions in children with autism spectrum disorder.

During social encounters, people tend to reproduce the facial expressions of others, termed "facial mimicry," which is believed to underlie many important social cognitive functions. Clinically, atypical mimicry is closely associated with serious social dysfunction. However, findings regarding the facial mimicry ability of children with autism spectrum disorder (ASD) are inconsistent; it is necessary to test whether deficits in facial mimicry are core defects of autism and explore the potential mechanism underlying this process. Using quantitative analysis, this study investigated voluntary and automatic facial mimicry performance of six basic expressions in children with and without ASD. There was no significant group difference in mimicry accuracy, but children with ASD showed less intensity in voluntary and automatic mimicry than typically developing children; they also presented less voluntary mimicry intensity for happy, sad, and fearful expressions. Performance on voluntary and automatic mimicry was significantly correlated with the level of autistic symptoms (r >-.43) and theory of mind (r >.34). Furthermore, theory of mind mediated the relationship between autistic symptoms and the intensity of facial mimicry. These results suggest that individuals with ASD show atypical facial mimicry (i.e., less intensity for both voluntary and automatic mimicry, mainly for voluntary mimicry of happiness, sadness, and fear), which might offer a potential cognitive marker for quantifying syndrome manifestations in children with ASD. These findings suggest that theory of mind plays a mediating role in facial mimicry, which may provide insight into the theoretical mechanism of social dysfunction in children with autism.

A generalizable connectome-based marker of in-scan sustained attention in neurodiverse youth.

Difficulty with attention is an important symptom in many conditions in psychiatry, including neurodiverse conditions such as autism. There is a need to better understand the neurobiological correlates of attention and leverage these findings in healthcare settings. Nevertheless, it remains unclear if it is possible to build dimensional predictive models of attentional state in a sample that includes participants with neurodiverse conditions. Here, we use 5 datasets to identify and validate functional connectome-based markers of attention. In dataset 1, we use connectome-based predictive modeling and observe successful prediction of performance on an in-scan sustained attention task in a sample of youth, including participants with a neurodiverse condition. The predictions are not driven by confounds, such as head motion. In dataset 2, we find that the attention network model defined in dataset 1 generalizes to predict in-scan attention in a separate sample of neurotypical participants performing the same attention task. In datasets 3-5, we use connectome-based identification and longitudinal scans to probe the stability of the attention network across months to years in individual participants. Our results help elucidate the brain correlates of attentional state in youth and support the further development of predictive dimensional models of other clinically relevant phenotypes.

Motor networks in children with autism spectrum disorder: a systematic review on EEG studies.

Motor disturbance and altered motor networks are commonly reported in individuals with autism spectrum disorder (ASD). It has been suggested that electroencephalogram (EEG) can be used to provide exquisite temporal resolution for understanding motor control processes in ASD. However, the variability of study design and EEG approaches can impact our interpretation. Here, we conducted a systematic review on recent 11 EEG studies that involve motor observation and/or execution tasks and evaluated how these findings help us understand motor difficulties in ASD. Three behavior paradigms with different EEG analytic methods were demonstrated. The main findings were quite mixed: children with ASD did not always show disrupted neuronal activity during motor observation. Additionally, they might have intact ability for movement execution but have more difficulties in neuronal modulation during movement preparation. We would like to promote discussions on how methodological selections of behavioral tasks and data analytic approaches impact our interpretation of motor deficits in ASD. Future EEG research addressing the inconsistency across methodological approaches is necessary to help us understand neurophysiological mechanism of motor abnormalities in ASD.

The importance of nutritional management and education in the treatment of autism.

Autism spectrum disorders (ASDs) are an early-onset neurodevelopmental disorders. The key symptoms of ASD include social deficits, verbal and non-verbal communication deficits, and restricted, repetitive patterns of behaviour, interests, or activities. Dietary patterns have been evidenced to be related to maternal nutritional status that might lead to different metabolic conditions, and maternal metabolic dysfunction has been observed to be associated with ASD. Furthermore growing evidence suggests that the gut microbiota has a role in the pathophysiology of ASD. Differences in composition of the gastrointestinal (GI) microbiota in children with ASD compared to unaffected siblings and/or healthy unrelated controls have been reported in various studies. The above-mentioned ASD factors and symptoms can be regulated by proper nutrition. The importance of nutrition and its possible impact on ASD patients is key to integral therapy. According to numerous research studies, various nutritional approaches succeeded in reducing the severity of patients' core ASD symptoms. The numerous options for diet that is used in the ASD therapy, as described in the scientific literature, are related to the problem of choosing an appropriate nutritional treatment. Each nutrition programme needs to be personalised and tailored to an individual patient. The aim of the paper is to review the available literature on dietary interventions in children with ASD and provide up-to-date evidence.

Circadian Responses to Light in the BTBR Mouse.

Animals with altered freerunning periods are valuable in understanding properties of the circadian clock. Understanding the relationship between endogenous clock properties, entrainment, and influence of light in terms of parametric and non-parametric models can help us better understand how different populations adapt to external light cycles. Many clinical populations often show significant changes in circadian properties that in turn cause sleep and circadian problems, possibly exacerbating their underlying clinical condition. BTBR T+Itpr3tf/J (BTBR) mice are a model commonly used for the study of autism spectrum disorders (ASD). Adults and adolescents with ASD frequently exhibit profound sleep and circadian disruptions, including increased latency to sleep, insomnia, advanced and delayed sleep phase disorders, and sleep fragmentation. Here, we investigated the circadian phenotype of BTBR mice in freerunning and light-entrained conditions and found that this strain of mice showed noticeably short freerunning periods (~22.75 h). In addition, when compared to C57BL/6J controls, BTBR mice also showed higher levels of activity even though this activity was compressed into a shorter active phase. Phase delays and phase advances to light were significantly larger in BTBR mice. Despite the short freerunning period, BTBR mice exhibited normal entrainment in light-dark cycles and accelerated entrainment to both advanced and delayed light cycles. Their ability to entrain to skeleton photoperiods of 1 min suggests that this entrainment cannot be attributed to masking. Period differences were also correlated with differences in the number of vasoactive intestinal polypeptide-expressing cells in the suprachiasmatic nucleus (SCN). Overall, the BTBR model, with their unique freerunning and entrainment properties, makes an interesting model to understand the underlying circadian clock.

Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish.

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.

Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

Intersecting kinematic encoding and readout of intention in autism.

Observers with autism spectrum disorders (ASDs) find it difficult to read intentions from movements. However, the computational bases of these difficulties are unknown. Do these difficulties reflect an intention readout deficit, or are they more likely rooted in kinematic (dis-)similarities between typical and ASD kinematics? We combined motion tracking, psychophysics, and computational analyses to uncover single-trial intention readout computations in typically developing (TD) children (n = 35) and children with ASD (n = 35) who observed actions performed by TD children and children with ASD. Average intention discrimination performance was above chance for TD observers but not for ASD observers. However, single-trial analysis showed that both TD and ASD observers read single-trial variations in movement kinematics. TD readers were better able to identify intention-informative kinematic features during observation of TD actions; conversely, ASD readers were better able to identify intention-informative features during observation of ASD actions. Crucially, while TD observers were generally able to extract the intention information encoded in movement kinematics, those with autism were unable to do so. These results extend existing conceptions of mind reading in ASD by suggesting that intention reading difficulties reflect both an interaction failure, rooted in kinematic dissimilarity between TD and ASD kinematics (at the level of feature identification), and an individual readout deficit (at the level of information extraction), accompanied by an overall reduced sensitivity of intention readout to single-trial variations in movement kinematics.

Cortical signatures of auditory object binding in children with autism spectrum disorder are anomalous in concordance with behavior and diagnosis.

Organizing sensory information into coherent perceptual objects is fundamental to everyday perception and communication. In the visual domain, indirect evidence from cortical responses suggests that children with autism spectrum disorder (ASD) have anomalous figure-ground segregation. While auditory processing abnormalities are common in ASD, especially in environments with multiple sound sources, to date, the question of scene segregation in ASD has not been directly investigated in audition. Using magnetoencephalography, we measured cortical responses to unattended (passively experienced) auditory stimuli while parametrically manipulating the degree of temporal coherence that facilitates auditory figure-ground segregation. Results from 21 children with ASD (aged 7-17 years) and 26 age- and IQ-matched typically developing children provide evidence that children with ASD show anomalous growth of cortical neural responses with increasing temporal coherence of the auditory figure. The documented neurophysiological abnormalities did not depend on age, and were reflected both in the response evoked by changes in temporal coherence of the auditory scene and in the associated induced gamma rhythms. Furthermore, the individual neural measures were predictive of diagnosis (83% accuracy) and also correlated with behavioral measures of ASD severity and auditory processing abnormalities. These findings offer new insight into the neural mechanisms underlying auditory perceptual deficits and sensory overload in ASD, and suggest that temporal-coherence-based auditory scene analysis and suprathreshold processing of coherent auditory objects may be atypical in ASD.

Associations among autistic traits, cognitive and affective empathy, and personality traits in adults with autism spectrum disorder and no intellectual disability.

Reported empathy deficits in autism spectrum disorder (ASD) could be attributable to other ASD-related features. We evaluated 28 ASD adults with no intellectual disability and 24 age-matched non-ASD control subjects using the Autism-Spectrum Quotient (AQ), Questionnaire of Cognitive and Affective Empathy (QCAE), Interpersonal Reactivity Index (IRI), and NEO Personality Inventory-Revised (NEO). Compared to the controls, ASD participants showed lower scores for perspective taking, online simulation, cognitive empathy, and peripheral responsivity on the QCAE, and lower scores for perspective taking and empathic concern on the IRI. Within the ASD group, the AQ scores showed significant relationships with perspective taking, online simulation and cognitive empathy on the QCAE, and perspective taking on the IRI. The ASD group also showed higher scores for neuroticism and lower scores for extraversion on the NEO compared to the controls. However, there were no relationships between AQ scores and NEO factors within the ASD group. Multiple regression analysis with stepwise linear regression demonstrated that perspective taking score on the QCAE and extraversion score on the NEO were good predictor variables to autistic traits on the AQ. These findings help us to understand empathy and personality traits in ASD adults with no intellectual disability.

Stride-level analysis of mouse open field behavior using deep-learning-based pose estimation.

Gait and posture are often perturbed in many neurological, neuromuscular, and neuropsychiatric conditions. Rodents provide a tractable model for elucidating disease mechanisms and interventions. Here, we develop a neural-network-based assay that adopts the commonly used open field apparatus for mouse gait and posture analysis. We quantitate both with high precision across 62 strains of mice. We characterize four mutants with known gait deficits and demonstrate that multiple autism spectrum disorder (ASD) models show gait and posture deficits, implying this is a general feature of ASD. Mouse gait and posture measures are highly heritable and fall into three distinct classes. We conduct a genome-wide association study to define the genetic architecture of stride-level mouse movement in the open field. We provide a method for gait and posture extraction from the open field and one of the largest laboratory mouse gait and posture data resources for the research community.

Deep learning-based school attendance prediction for autistic students.

Autism Spectrum Disorder is a neurodevelopmental disorder characterized by deficits in social communication and interaction as well as the presence of repetitive, restricted patterns of behavior, interests, or activities. Many autistic students experience difficulty with daily functioning at school and home. Given these difficulties, regular school attendance is a primary source for autistic students to receive an appropriate range of needed educational and therapeutic interventions. Moreover, school absenteeism (SA) is associated with negative consequences such as school drop-out. Therefore, early SA prediction would help school districts to intervene properly to ameliorate this issue. Due to its heterogeneity, autistic students show within-group differences concerning their SA. A comprehensive statistical analysis performed by the authors shows that the individual and demographic characteristics of the targeted population are not predictive factors of SA. So, we used the students' recent previous attendance to predict their future attendance. We introduce a deep learning-based framework for predicting short-and long-term SA of autistic students using the Long Short-Term Memory (LSTM) and Multilayer Perceptron (MLP) algorithms. The adopted algorithms outperform other machine learning algorithms. In detail, LSTM increased the accuracy and recall of short-term SA prediction by 20% and 13%, while the same scores of long-term SA prediction increased by 5% using MLP.

Differences in cortical processing of facial emotions in broader autism phenotype.

Autism Spectrum Disorder (ASD) is a heterogeneous condition that affects face perception. Evidence shows that there are differences in face perception associated with the processing of low spatial frequency (LSF) and high spatial frequency (HSF) of visual stimuli between non-symptomatic relatives of individuals with autism (broader autism phenotype, BAP) and typically developing individuals. However, the neural mechanisms involved in these differences are not fully understood. Here we tested whether face-sensitive event related potentials could serve as neuronal markers of differential spatial frequency processing, and whether these potentials could differentiate non-symptomatic parents of children with autism (pASD) from parents of typically developing children (pTD). To this end, we performed electroencephalographic recordings of both groups of parents while they had to recognize emotions of face pictures composed of the same or different emotions (happiness or anger) presented in different spatial frequencies. We found no significant differences in the accuracy between groups but lower amplitude modulation in the Late Positive Potential activity in pASD. Source analysis showed a difference in the right posterior part of the superior temporal region that correlated with ASD symptomatology of the child. These results reveal differences in brain processing of recognition of facial emotion in BAP that could be a precursor of ASD.

Sleep Problems and Circadian Functioning in Children and Adolescents With Autism Spectrum Disorder.

BACKGROUND: Sleep problems are a prevalent comorbidity in autism spectrum disorder (ASD) with a multifactorial basis in which circadian misalignment has been described. METHODS: A cross-sectional study was conducted including 52 children and adolescents with ASD (9.85 ± 3.07) and 27 children and adolescent controls with normal intellectual functioning (8.81 ± 2.14). They were matched for age, sex, and body mass index, and all were drug-naïve. An ambulatory circadian monitoring device was used to record temperature and motor, body position, sleep, and light intensity. RESULTS: Individuals with ASD presented longer sleep-onset latency, lower sleep efficiency, and decreased total sleep time and tended to be more sedentary and have less exposure to light. They also showed lower amplitude, low interdaily stability, and a different pattern of wrist temperature across the day, with a midpoint of sleep that did not concur with sleep midpoint indicated by the rest of circadian parameters. CONCLUSIONS: The sleep problems observed in this sample resemble those reported previously, with the exception of nocturnal awakenings which did not show differences. The ambulatory circadian monitoring device enabled measurement of circadian parameters such as temperature which, until now, were scarcely described in children with ASD and could be used to better understand sleep and circadian system in ASD.