Dysfunction In Autism Spectrum Disorder Research Articles

Mechanisms underlying auditory processing deficits in Fragile X syndrome.

Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.

5-aminoisoquinolinone attenuates social behavior deficits and immune abnormalities in the BTBR T+ Itpr3tf/J mouse model for autism

Autism spectrum disorder (ASD) is diagnosed by core symptoms including impaired social communication and the presence of repetitive and stereotypical behaviors. There is also evidence for immune dysfunction in individuals with ASD, but it is a disease that is still insufficiently controlled by current treatment strategies. The use of 5-aminoisoquinolinone (5-AIQ) ameliorates several immune-mediated symptoms including rheumatoid arthritis and colitis, and has neuroprotective properties; however, its role in ASD is not yet characterized. In this study, we investigated the effect of 5-AIQ on sociability tests, self-grooming, marble burying, and locomotor activities in BTBR T+ Itpr3tf/J (BTBR) mice, which serve as an ASD animal model. We further investigated the possible molecular mechanism of 5-AIQ administration on CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3+ T cells isolated from the spleens of treated mice. We also explored its effects on mRNA expression in brain tissue. Our results showed that in BTBR mice, 5-AIQ treatment significantly prevented self-grooming and marble burying behaviors and enhanced social interactions without any adverse effects on locomotor activity/anxiety level. Additionally, 5-AIQ treatment substantially decreased CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3+ T cells in the spleen. Furthermore, 5-AIQ treatment decreased CXCR4, IFN-γ, IL-22, STAT1, and RORγT mRNA expression levels in brain tissue. Our findings demonstrated that 5-AIQ improved behavioral and immune abnormalities associated with ASD, which supports the hypothesis that 5-AIQ has important therapeutic potential for the treatment of behavioral and neuroimmune dysfunctions in ASD.

Coactivation pattern analysis reveals altered salience network dynamics in children with autism spectrum disorder.

Brain connectivity studies of autism spectrum disorder (ASD) have historically relied on static measures of functional connectivity. Recent work has focused on identifying transient configurations of brain activity, yet several open questions remain regarding the nature of specific brain network dynamics in ASD. We used a dynamic coactivation pattern (CAP) approach to investigate the salience/midcingulo-insular (M-CIN) network, a locus of dysfunction in ASD, in a large multisite resting-state fMRI dataset collected from 172 children (ages 6–13 years; n = 75 ASD; n = 138 male). Following brain parcellation by using independent component analysis, dynamic CAP analyses were conducted and k-means clustering was used to determine transient activation patterns of the M-CIN. The frequency of occurrence of different dynamic CAP brain states was then compared between children with ASD and typically developing (TD) children. Dynamic brain configurations characterized by coactivation of the M-CIN with central executive/lateral fronto-parietal and default mode/medial fronto-parietal networks appeared less frequently in children with ASD compared with TD children. This study highlights the utility of time-varying approaches for studying altered M-CIN function in prevalent neurodevelopmental disorders. We speculate that altered M-CIN dynamics in ASD may underlie the inflexible behaviors commonly observed in children with the disorder.

A Descriptive Review on the Prevalence of Gastrointestinal Disturbances and Their Multiple Associations in Autism Spectrum Disorder.

Background and Objectives: Gastrointestinal disturbances have been frequently, but not unanimously, reported in autism spectrum disorder (ASD) individuals. Thus, digestive symptoms, such as constipation, diarrhea, abdominal bloating, and pain have been reported to correlate to the various maladaptive behaviors in ASD children, such as irritability, social withdrawal, stereotypy, hyperactivity, and even language regression. In this context, the present study provides an overview on the prevalence of the gastrointestinal (GI) disorders in ASD and the correlation between these and ASD symptoms and comorbidities and subsequently discusses the metabolic and microbiome factors underlying the effects of GI disorders in ASD. Materials and Methods: For our analysis of GI symptoms in children with ASD, we have searched peer-reviewed journals from 2005 to 2017 in PubMed databases that addressed the specificity of GI symptoms in ASD and included correlations of GI and ASD symptoms. The criteria for inclusion were clear quantitative mentioning of GI modifications, GI symptoms correlation with specific ASD symptoms or comorbidities, an appropriate methodology for defining ASD, and larger size samples. For this topic, only studies on human patients and original research were considered. A subsequent search in PubMed databases in journals from 2000 to 2017 we analyzed 13 articles on the mechanisms underlying the impact of GI dysfunctions in ASD, including gut microbial dysbiosis, immune reactivity, genetics, and altered neurotransmitters on the gut–brain axis. Results: In the 18 original research studies that we selected out of an initial 327 studies, despite the different methodology, a predominant 83% highlighted the increased prevalence of GI symptoms in ASD patients. Constipation was most frequently cited, appearing in 12 of the studies (80%), followed by diarrhea reports in eight studies (53%). The association between cognitive and behavioral deficits and GI disorders was suggested in certain groups of ASD individuals. Conclusion: The evidence presented so far by numerous studies seems to indicate that GI dysfunctions are of particular relevance in ASD, underlined by various abnormalities along the nervous connections between the central nervous system and the gut, such as impaired parasympathetic activity and increased endocrine stress response. Sufficiently large size samples and standardized methodology are required for future studies to clarify the complex interactions between GI disturbances and ASD symptoms.

Stress-Induced Neuron Remodeling Reveals Differential Interplay Between Neurexin and Environmental Factors in Caenorhabditis elegans.

Neurexins are neuronal adhesion molecules important for synapse maturation, function, and plasticity. Neurexins have been genetically associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) and schizophrenia, but can have variable penetrance and phenotypic severity. Heritability studies indicate that a significant percentage of risk for ASD and schizophrenia includes environmental factors, highlighting a poorly understood interplay between genetic and environmental factors. The singular Caenorhabditis elegans ortholog of human neurexins, nrx-1, controls experience-dependent morphologic remodeling of a GABAergic neuron in adult males. Here, I show remodeling of this neuron's morphology in response to each of three environmental stressors (nutritional, heat, or genotoxic stress) when applied specifically during sexual maturation. Increased outgrowth of axon-like neurites following adolescent stress is the result of an altered morphologic plasticity in adulthood. Despite remodeling being induced by each of the three stressors, only nutritional stress affects downstream behavior and is dependent on neurexin/nrx-1 Heat or genotoxic stress in adolescence does not alter behavior despite inducing GABAergic neuron remodeling, in a neurexin/nrx-1 independent fashion. Starvation-induced remodeling is also dependent on neuroligin/nlg-1, the canonical binding partner for neurexin/nrx-1, and the transcription factors FOXO/daf-16 and HSF1/hsf-1hsf-1 and daf-16, in addition, each have unique roles in remodeling induced by heat and UV stress. The differential molecular mechanisms underlying GABAergic neuron remodeling in response to different stressors, and the disparate effects of stressors on downstream behavior, are a paradigm for understanding how genetics, environmental exposures, and plasticity may contribute to brain dysfunction in ASDs and schizophrenia.

Dorsal-movement and ventral-form regions are functionally connected during visual-speech recognition.

Faces convey social information such as emotion and speech. Facial emotion processing is supported via interactions between dorsal‐movement and ventral‐form visual cortex regions. Here, we explored, for the first time, whether similar dorsal–ventral interactions (assessed via functional connectivity), might also exist for visual‐speech processing. We then examined whether altered dorsal–ventral connectivity is observed in adults with high‐functioning autism spectrum disorder (ASD), a disorder associated with impaired visual‐speech recognition. We acquired functional magnetic resonance imaging (fMRI) data with concurrent eye tracking in pairwise matched control and ASD participants. In both groups, dorsal‐movement regions in the visual motion area 5 (V5/MT) and the temporal visual speech area (TVSA) were functionally connected to ventral‐form regions (i.e., the occipital face area [OFA] and the fusiform face area [FFA]) during the recognition of visual speech, in contrast to the recognition of face identity. Notably, parts of this functional connectivity were decreased in the ASD group compared to the controls (i.e., right V5/MT—right OFA, left TVSA—left FFA). The results confirmed our hypothesis that functional connectivity between dorsal‐movement and ventral‐form regions exists during visual‐speech processing. Its partial dysfunction in ASD might contribute to difficulties in the recognition of dynamic face information relevant for successful face‐to‐face communication.

Microbiota and gut-brain axis dysfunction in autism spectrum disorder: Evidence for functional gastrointestinal disorders.

The high frequency of functional gastrointestinal disorders (FGIDs) in autism spectrum disorders (ASD) has drawn attention to the composition of gut microbiota as a possible factor in ASD pathogenesis. However, characterization of a distinctive ASD microbial pattern is still unclear. To conduct a narrative review on ASD microbial profile and diversity changes relative to NT children and FGID comorbidity and ASD pathogenesis. First, we searched the PubMed database in peer-reviewed journals for evidence regarding the current epidemiological evidence on FGID comorbidity. For the identification of a microbial profile in ASD children, only original studies examining gut bacterial and fungal abundances and diversity in ASD children and adolescents were included. Lastly, research on the role of microbial dysbiosis as an interface between genetic and environmental risk factors in the pathogenesis of neuropsychiatric disorders, and specifically ASD, was examined. Prevalence and risk of FGIDs is significantly higher in ASD children and correlates with the severity of ASD. Bacterial and fungal diversity differ between ASD and NT children, indicating a difference in taxonomic abundance profiles, which have been reported at all bacterial phylogenetic levels. However, studies analyzing gut microbiota have a heterogeneous methodology and several limitations that could account for the variety of findings for each taxon. Also, covariate analysis reveals influence of demographics, diet, disease severity, GI comorbidity and allergies. Integration of these findings with changes in metabolome and genetic risk factors allowed for a better understanding of microbiota involvement in ASD pathogenesis for future research.

Antineuronal antibodies and 8-OHdG an indicator of cerebellar dysfunction in autism spectrum disorder: a case–control study

ABSTRACTObjectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder, that starts in early childhood and presents with deficiencies in social-communicational domains along with restr...

The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when NaV1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.

Beyond the brain: A multi-system inflammatory subtype of autism spectrum disorder.

An immune-mediated subtype of autism spectrum disorder (ASD) has long been hypothesized. This article reviews evidence from family history studies of autoimmunity, immunogenetics, maternal immune activation, neuroinflammation, and systemic inflammation, which suggests immune dysfunction in ASD. Individuals with ASD have higher rates of co-morbid medical illness than the general population. Major medical co-morbidities associated with ASD are discussed by body system. Mechanisms by which FDA-approved and emerging treatments for ASD act upon the immune system are then reviewed. We conclude by proposing the hypothesis of an immune-mediated subtype of ASD which is characterized by systemic, multi-organ inflammation or immune dysregulation with shared mechanisms that drive both the behavioral and physical illnesses associated with ASD. Although gaps in evidence supporting this hypothesis remain, benefits of this conceptualization include framing future research questions that will help define a clinically meaningful subset of patients and focusing clinical interactions on early detection and treatment of high-risk medical illnesses as well as interfering behavioral signs and symptoms across the lifespan.

Mitochondrial Dysfunction Is Inducible in Lymphoblastoid Cell Lines From Children With Autism and May Involve the TORC1 Pathway.

We previously developed a lymphoblastoid cell line (LCL) model of mitochondrial dysfunction in autism spectrum disorder (ASD); some individuals with ASD showed mitochondrial dysfunction (AD-A) while other individuals (AD-N) demonstrated mitochondrial respiration similar to controls (CNT). To test the hypothesis that mitochondrial dysfunction could be a consequence of environmental exposures through chronic elevations in reactive oxygen species (ROS), we exposed LCLs to prolonged ROS. We also examined expression of metabolic regulatory genes and the modulating effect of the mechanistic target of rapamycin (mTOR) pathway. Prolonged ROS exposure induced or worsened mitochondrial dysfunction in all LCL groups. Expression of genes associated with ROS protection was elevated in both AD-N and AD-A LCLs, but mitochondrial fission/fusion and mitoplasticity gene expression was only increased in AD-N LCLs. Partial least squares discriminant analysis showed that mTOR, UCP2 (uncoupling protein 2), SIRT1 (sirtuin 1), and MFN2 (mitofusin-2) gene expression differentiated LCL groups. Low-dose rapamycin (0.1 nM) normalized respiration with the magnitude of this normalization greater for AD-A LCLs, suggesting that the mammalian target of rapamycin complex 1 (mTORC1) pathway may have a different dynamic range for regulating mitochondrial activity in individuals with ASD with and without mitochondrial dysfunction, potentially related to S6K1 (S6 kinase beta-1) regulation. Understanding pathways that underlie mitochondrial dysfunction in ASD may lead to novel treatments.

Citalopram attenuates social behavior deficits in the BTBR T+Itpr3tf/J mouse model of autism

Autism spectrum disorder (ASD) is diagnosed by two core symptoms: impaired social communication and the presence of repetitive, stereotyped behaviors and/or restricted interests. Alterations in serotonergic signaling are involved in the genesis of ASD. Selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce repetitive behaviors and rescue social deficits in ASD mouse models and patients. In the present study, we examined the potential of citalopram (a representative selective serotonin reuptake inhibitor) on sociability and repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse model of ASD. We found that the deficits of sociability in the BTBR mice were reversed by a 20 mg/kg dose of citalopram treatment without any adverse effects on locomotor activity or anxiety level. In addition, both high (20 mg/kg) and low (10 mg/kg) doses decreased the repetitive behavior of marble burying but did not affect self-grooming behavior. Furthermore, both doses were shown to have antidepressant-like activity in both the B6 and the BTBR mice in the tail suspension test. Taken together, these findings further demonstrate that citalopram can alleviate behavioral abnormalities in the BTBR autism model and lend support to the hypothesis that SSRIs may be potential therapeutic drugs for the treatment of behavioral dysfunctions in ASD.

Atypical event-related potentials revealed during the passive parts of a Go-NoGo task in autism spectrum disorder: a case-control study

BackgroundThe core features of autism spectrum disorder (ASD) are easily recognizable in non-structured clinical and real-life situations. The features are often difficult to capture in structured laboratory settings, and the results from tests do not necessarily reflect symptom severity. We investigated neurophysiological processing in the passive parts of a cued Go-NoGo task, using the active parts of the test as a comparator.MethodsForty-nine adolescents diagnosed with ASD and 49 typically developing (TD) adolescents (age 12–21 years) were included. Daily life executive function was assessed with the Behavior Rating Inventory of Executive Function (BRIEF). We applied a visual cued Go-NoGo task and recorded event-related potentials (ERPs). We investigated occipital N1, a component related to early perception of visual stimuli, and P3a, a fronto-central component related to switching of attention, in the passive and active parts of the test.ResultsDuring the passive parts, the ASD group had statistically significantly longer N1 latency (p < 0.001, Cohens d = 0.75) and enhanced amplitude of P3a (p = 0.002, Cohens d = 0.64) compared to the TD, while no significant differences were observed in the active parts. Both components correlated significantly with the Behavioral Regulation Index of the BRIEF (partial correlation r = 0.35, p = 0.003).ConclusionDelayed N1 response, indicating altered visual perception, and enhanced P3a response, indicating increased neural activation related to attention allocation, were found during the passive parts of a Go-NoGo task in ASD participants. These abnormal ERP signals in the non-structured settings were associated with everyday executive function, suggesting that neurophysiolocal measures related to atypical control of alertness and “hyper-awareness” underlie daily life dysfunction in ASD. Assessments during passive settings have a potential to reveal core neurobiological substrates of ASD.

Structural and Functional Aberrations of the Auditory Brainstem in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with difficulties in the social, communicative, and behavioral domains. Most cases of ASD arise from an unknown etiologic process, but there are numerous risk factors, including comorbidities and maternal exposures. Although it is not part of the diagnostic criteria, hearing difficulties ranging from deafness to hyperacusis are present in the majority of persons with ASD. High-functioning children with ASD have been found to have significantly slower and asymmetric auditory brainstem reflexes. Additionally, histopathological studies of postmortem brainstems in decedents who had ASD have consistently revealed significantly fewer neurons in auditory nuclei compared with those in people who did not have ASD. The authors review the literature implicating auditory dysfunction in ASD along with results from human study participants and postmortem human brain tissue. Together, these results implicate significant structural and functional abnormalities in the auditory brainstem in ASD and support the utility of auditory testing to screen for ASD.

Therapeutic responses to a frontal/executive programme in autism spectrum disorder: Comparison with schizophrenia.

IntroductionStudies on autism spectrum disorder in recent years have controversially indicated similarities with schizophrenia. Cognitive dysfunction is present in both disorders, and while there is a rich array of interventions for cognitive dysfunction in schizophrenia, there are few such treatments for autism spectrum disorder. In this study, we have investigated a potentially useful approach in autism spectrum disorder by comparing autism spectrum disorder with schizophrenia in regard to the characteristics of cognitive dysfunction and therapeutic response to cognitive remediation therapy.MethodWe studied seven patients with autism spectrum disorder and eight patients with schizophrenia, using a frontal/executive programme as the intervention. The characteristics of cognitive dysfunction in autism spectrum disorder before frontal/executive programme and the therapeutic response to frontal/executive programme in autism spectrum disorder patients were compared with those in schizophrenia patients, based on evaluation of cognitive function and social function. The changes in cognitive and social function after treatment in each patient group were compared using the Mann–Whitney’s U test.ResultsThe severity of cognitive dysfunction did not differ significantly between autism spectrum disorder and schizophrenia. Frontal/executive programme was effective in autism spectrum disorder, with subjects showing about the same therapeutic response as in schizophrenia.ConclusionFrontal/executive programme appears to be useful for patients with autism spectrum disorder. Furthermore, the similarities in cognitive dysfunction and therapeutic response between autism spectrum disorder and schizophrenia are highly relevant to the recent debate concerning the similarity between these two disease concepts.

Dynamic functional connectivity analysis reveals decreased variability of the default-mode network in developing autistic brain.

Accumulating neuroimaging evidence suggests that abnormal functional connectivity of the default mode network (DMN) contributes to the social-cognitive deficits of autism spectrum disorder (ASD). Although most previous studies relied on conventional functional connectivity methods, which assume that connectivity patterns remain constant over time, understanding the temporal dynamics of functional connectivity during rest may provide new insights into the dysfunction of the DMN in ASD. In this work, dynamic functional connectivity analysis based on sliding time window correlation was applied to the resting-state functional magnetic resonance imaging data of 28 young children with ASD (age range: 3-7 years) and 29 matched typically developing controls (TD group). In addition, k-means cluster analysis was performed to identify distinct temporal states based on the spatial similarity of each functional connectivity pattern. Compared with the TD group, young children with ASD showed decreased dynamic functional connectivity variance between the posterior cingulate cortex (PCC) and the right precentral gyrus, which is negatively correlated with social motivation and social relating. Cluster analysis revealed significant differences in functional connectivity patterns between the ASD and TD groups in discrete temporal states. Our findings reveal that atypical dynamic interactions between the PCC and sensorimotor cortex are associated with social deficits in ASD. Results also highlight the critical role of PCC in the social-cognitive deficits of ASD and support the concept that understanding the dynamic neural interactions among brain regions can provide insights into functional abnormalities in ASD. Autism Research 2018, 11: 1479-1493. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Social cognitive dysfunction in autism spectrum disorder (ASD) is associated with dysfunction of the default mode network (DMN), a set of brain areas involved in various domains of social processing. We found that decreases in the dynamic functional connectivity variance between the posterior cingulate cortex and the sensorimotor cortex are associated with deficits in social motivation and social relating in young children with ASD. This result suggests that aberrations in the DMN and its dynamic interactions with other networks contribute to atypical integration of information with respect to self and others.

Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects ~ 2% of children in the United States. The etiology of ASD likely involves environmental factors triggering physiological abnormalities in genetically sensitive individuals. One of these major physiological abnormalities is mitochondrial dysfunction, which may affect a significant subset of children with ASD. Here we systematically review the literature on human studies of mitochondrial dysfunction related to ASD. Clinical aspects of mitochondrial dysfunction in ASD include unusual neurodevelopmental regression, especially if triggered by an inflammatory event, gastrointestinal symptoms, seizures, motor delays, fatigue and lethargy. Traditional biomarkers of mitochondrial disease are widely reported to be abnormal in ASD, but appear non-specific. Newer biomarkers include buccal cell enzymology, biomarkers of fatty acid metabolism, non-mitochondrial enzyme function, apoptosis markers and mitochondrial antibodies. Many genetic abnormalities are associated with mitochondrial dysfunction in ASD, including chromosomal abnormalities, mitochondrial DNA mutations and large-scale deletions, and mutations in both mitochondrial and non-mitochondrial nuclear genes. Mitochondrial dysfunction has been described in immune and buccal cells, fibroblasts, muscle and gastrointestinal tissue and the brains of individuals with ASD. Several environmental factors, including toxicants, microbiome metabolites and an oxidized microenvironment are shown to modulate mitochondrial function in ASD tissues. Investigations of treatments for mitochondrial dysfunction in ASD are promising but preliminary. The etiology of mitochondrial dysfunction and how to define it in ASD is currently unclear. However, preliminary evidence suggests that the mitochondria may be a fruitful target for treatment and prevention of ASD. Further research is needed to better understand the role of mitochondrial dysfunction in the pathophysiology of ASD.

Interhemispheric alpha-band hypoconnectivity in children with autism spectrum disorder

•Diverse genetic and environmental etiologies converge onto circuit level brain dysfunction in autism spectrum disorder (ASD), manifesting at a macroscopic level as aberrant neural connectivity. Previous studies have described atypical patterns of decreased short range and increased long range connectivity in ASD [1]. However, it remains unclear whether group level features of circuit dysfunction are consistently present across the range of cognitive function seen in the autism spectrum.•The dynamics of neural oscillations in the alpha range (6–12 Hz) are exquisitely sensitive to healthy development of functional and structural connectivity. Alpha-band coherence, measured with high temporal-precision electroencephalography (EEG) therefore represents an ideal tool for studying neural connectivity in developmental populations.•Here we examined spontaneous alpha phase coherence in a heterogeneous sample of 59 children with ASD and 39 age matched typically developing children. Using a data driven approach, we conducted an unbiased examination of all possible atypical connectivity patterns across all cortical regions.•Long-range hypoconnectivity was present in children with ASD compared to typically developing children, with temporal interhemispheric connectivity showing the largest difference between the two groups.•Decreased long range alpha coherence distinguishes a heterogeneous group of ASD children from typically developing children. Interhemispheric temporal hypoconnectivity represents a fundamental functional difference in children with ASD across a wide cognitive and age range that may reflect white matter disturbances or increased signal variability at temporal sites in ASD.

Genetic and clinical evidence of mitochondrial dysfunction in autism spectrum disorder and intellectual disability.

Clinical conditions commonly associated with mitochondrial disorders (CAMDs) are often present in autism spectrum disorders (ASD) and intellectual disability (ID). Therefore, the mitochondrial dysfunction hypothesis has been proposed as a transversal mechanism that may function in both disorders. Here, we investigated the presence of conditions associated with mitochondrial disorders and mitochondrial DNA (mtDNA) alterations in 122 subjects who presented ASD with ID (ASD group), 115 subjects who presented ID but not ASD (ID group) and 112 healthy controls (HC group). We assessed in the three study groups the presence of the clinical conditions through a questionnaire and the mtDNA content of two mitochondrial genes, MT-ND1 and MT-ND4, by qPCR. The mtDNA sequences of 98 ASD and 95 ID subjects were obtained by mtDNA-targeted next generation sequencing and analysed through the MToolBox pipeline to identify mtDNA mutations. Subjects with ASD and ID showed higher frequencies of constipation, edema, seizures, vision alterations, strabismus and sphincter incontinence than HCs subjects. ASD and ID subjects showed significantly lower mtDNA content than HCs in both MT-ND1 and MT-ND4 genes. In addition, we identified 49 putative pathogenic variants with a heteroplasmy level higher than 60%: 8 missense, 29 rRNA and 12 tRNA variants. A total of 28.6% of ASD and 30.5% of ID subjects carried at least one putative pathogenic mtDNA mutation. The high frequency of CAMDs, the low mtDNA content and the presence of putative pathogenic mtDNA mutations observed in both ASD and ID subjects are evidence of mitochondrial dysfunction in ASD and ID.

Rethinking the role of music in the neurodevelopment of autism spectrum disorder

Music has played a prominent role in the clinical and research literature on autism spectrum disorder (ASD) in regard to diagnosis, therapy, and behavioral observations of exceptional artistic abilities in this population. Music as therapy for ASD has traditionally focused on social interaction, communication skills, and social-emotional behaviors. However, recently, there has been an increased research focus on the role of motor and attention functions as part of the hallmark features of ASD, which may have significant implications for the role of music as an intervention for individuals with autism. The purpose of this article is to provide a critical appraisal of new research developments for therapists and researchers to potentially reassess the role of music as intervention to support healthy neurodevelopment in individuals with ASD and expand the current clinical scope of practice in music therapy for autism. Our argument is based upon compelling research evidence indicating that motor and attention deficits are deeply implicated in the healthy neurodevelopment of socio-communication skills and may be key indicators of structural and functional brain dysfunction in ASD. In light of this evidence, we suggest that music-based developmental training for attention and motor control may receive a critical new functional role in the treatment of autism due to the significant effect of auditory-motor entrainment on motor and attention functions and brain connectivity.