Neurobiology Of Autism Spectrum Disorder Research Articles

Abnormalities in both stimulus-induced and baseline MEG alpha oscillations in the auditory cortex of children with Autism Spectrum Disorder.

The neurobiology of Autism Spectrum Disorder (ASD) is hypothetically related to the imbalance between neural excitation (E) and inhibition (I). Different studies have revealed that alpha-band (8-12Hz) activity in magneto- and electroencephalography (MEG and EEG) may reflect E and I processes and, thus, can be of particular interest in ASD research. Previous findings indicated alterations in event-related and baseline alpha activity in different cortical systems in individuals with ASD, and these abnormalities were associated with core and co-occurring conditions of ASD. However, the knowledge on auditory alpha oscillations in this population is limited. This MEG study investigated stimulus-induced (Event-Related Desynchronization, ERD) and baseline alpha-band activity (both periodic and aperiodic) in the auditory cortex and also the relationships between these neural activities and behavioral measures of children with ASD. Ninety amplitude-modulated tones were presented to two groups of children: 20 children with ASD (5 girls, Mage = 10.03, SD = 1.7) and 20 typically developing controls (9 girls, Mage = 9.11, SD = 1.3). Children with ASD had a bilateral reduction of alpha-band ERD, reduced baseline aperiodic-adjusted alpha power, and flattened aperiodic exponent in comparison to TD children. Moreover, lower raw baseline alpha power and aperiodic offset in the language-dominant left auditory cortex were associated with better language skills of children with ASD measured in formal assessment. The findings highlighted the alterations of E / I balance metrics in response to basic auditory stimuli in children with ASD and also provided evidence for the contribution of low-level processing to language difficulties in ASD.

Autism-associated brain differences can be observed in utero using MRI.

Developmental changes that occur before birth are thought to be associated with the development of autism spectrum disorders. Identifying anatomical predictors of early brain development may contribute to our understanding of the neurobiology of autism spectrum disorders and allow for earlier and more effective identification and treatment of autism spectrum disorders. In this study, we used retrospective clinical brain magnetic resonance imaging data from fetuses who were diagnosed with autism spectrum disorders later in life (prospective autism spectrum disorders) in order to identify the earliest magnetic resonance imaging-based regional volumetric biomarkers. Our results showed that magnetic resonance imaging-based autism spectrum disorder biomarkers can be found as early as in the fetal period and suggested that the increased volume of the insular cortex may be the most promising magnetic resonance imaging-based fetal biomarker for the future emergence of autism spectrum disorders, along with some additional, potentially useful changes in regional volumes and hemispheric asymmetries.

Neurobiological Correlation Between Autism Spectrum Disorder and Anorexia Nervosa in Children

IntroductionAnorexia Nervosa (AN) is common in adolescents and has a high mortality and morbidity rate with a lifetime prevalence of 0.5% to 2%.1,2 We aim to review the neurobiology correlation of Anorexia Nervosa in Autism Spectrum Disorder as they are often associated together.Objectives1. Understand the correlation between the neurobiology of Autism Spectrum Disorder (ASD) and Anorexia Nervosa.2. Assess the association and prevalence of Anorexia nervosa in the ASD population.3. To focus on the implications for the pathogenesis of Anorexia Nervosa and treatment of this disorder in the ASD population.MethodsWe searched PubMed, APA PscyINFO, Embase, CINAHL, and Google scholar databases with the keywords Autism Spectrum Disorder AND Anorexia Nervosa and included 6 relevant human studies out of 187 published in English.ResultsNeilson et al. studied the outcome of ASD in teenage onset AN, and a statistically significant negative dose-response relationship is found in all the 3 Morgan-Russell Outcome Assessment Schedule (MROAS) domains in stable ASD over time, and the results on the subscales ‘mental state,’ ‘psychosexual state’ and ‘socio-economic state, “personal contacts,’ ‘social activities’ and ‘employment record.’3 The outcome of AN onset in adolescence is generally favorable regarding mortality and the persistence of eating disorders in adulthood. A study by Pruccoli et al. noted a high prevalence of ASD traits in a group of young AN patients, predominantly seen in 4 specific EDI-3 subscales and independent of BMI.4 Margari et al. found only AN diagnosis had a statistically significant difference (p = 0.04) in females vs. males when comparing sex differences for comorbidities.5ConclusionsMorphological changes in brain areas are linked to social cognition and increase the risk of eating disorders in ASD. We recommend future studies with robust study design to explore the full spectrum of pathogenesis and association of AN in ASD.Disclosure of InterestNone Declared

Exercise in the Treatment of Repetitive, Self-Injurious, and Aggressive Behavior in Adults with Autism Spectrum Disorder: A Neurobiological Analysis

Objective: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by markedly impaired social interaction and restricted/ repetitive patterns of behavior, interests, and activities. Maladaptive behaviors associated with ASD can include stereotyped, self-injurious, and aggressive behaviors. Current evidence-based interventions for ASD involve specialist availability, financial, time, and side effect constraints. Physical exercise has received increasing attention in the treatment of children with ASD, but research in adults is comparatively scarce. The purpose of this paper is to explore possible mechanisms by which exercise can reduce repetitive, self-injurious, and aggressive behaviors in adults with ASD. Methods: The literature on the neurobiology of exercise is reviewed and compared with the literature on the neurobiology of ASD. Information from this comparison is then used to formulate possible mechanisms by which exercise may reduce maladaptive behaviors in adults with ASD. Results: Plausible mechanisms for an exercise-induced beneficial effect on maladaptive behaviors in adults with ASD include modulation of neurotransmitter release and function, facilitation of endocannabinoid release, increased expression of neurotrophic factors, improved functional connectivity in higher-level cognitive networks, reduced oxidative stress, improved HPA axis function, treatment of comorbid depression, and reduction in amyloid beta deposition in cortical GABAergic neurons and subcortical structures. Conclusions: Future research should attempt to confirm the efficacy of exercise in reducing maladaptive behaviors in adults with ASD as well as the proposed mechanisms for such a relationship. Verification of these issues would have major implications in terms of supporting an evidence-based, inexpensive, widely available, and broadly beneficial treatment for adults with ASD.

Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder

Evidence from cross-sectional human studies, and preliminary microbial-based intervention studies, have implicated the microbiota-gut-brain axis in the neurobiology of autism spectrum disorder (ASD). Using a prospective longitudinal study design, we investigated the developmental profile of the fecal microbiota and metabolome in infants with (n = 16) and without (n = 19) a family history of ASD across the first 36 months of life. In addition, the general developmental levels of infants were evaluated using the Mullen Scales of Early Learning (MSEL) test at 5 and 36 months of age, and with ADOS-2 at 36 months of age. At 5 months of age, infants at elevated-likelihood of ASD (EL) harbored less Bifidobacterium and more Clostridium and Klebsiella species compared to the low-likelihood infants (LL). Untargeted metabolic profiling highlighted that LL infants excreted a greater amount of fecal γ-aminobutyric acid (GABA) at 5 months, which progressively declined with age. Similar age-dependent patterns were not observed in the EL group, with GABA being consistently low across all timepoints. Integrated microbiome-metabolome analysis showed a positive correlation between GABA and Bifidobacterium species and negative associations with Clostridium species. In vitro experiments supported these observations demonstrating that bifidobacteria can produce GABA while clostridia can consume it. At the behavioral level, there were no significant differences between the EL and LL groups at 5 months. However, at 36 months of age, the EL group had significantly lower MSEL and ADOS-2 scores compared to the LL group. Taken together, the present results reveal early life alterations in gut microbiota composition and functionality in infants at elevated-likelihood of ASD. These changes occur before any behavioral impairments can be detected, supporting a possible role for the gut microbiota in emerging behavioral variability later in life.

Exploring the correlation between genetic transcription and multi-temporal developmental autism spectrum disorder using resting-state functional magnetic resonance imaging.

The present investigation aimed to explore the neurodevelopmental trajectory of autism spectrum disorder (ASD) by identifying the changes in brain function and gene expression associated with the disorder. Previous studies have indicated that ASD is a highly inherited neurodevelopmental disorder of the brain that displays symptom heterogeneity across different developmental periods. However, the transcriptomic changes underlying these developmental differences remain largely unknown. To address this gap in knowledge, our study employed resting-state functional magnetic resonance imaging (rs-fMRI) data from a large sample of male participants across four representative age groups to stratify the abnormal changes in brain function associated with ASD. Partial least square regression (PLSr) was utilized to identify unique changes in gene expression in brain regions characterized by aberrant functioning in ASD. Our results revealed that ASD exhibits distinctive developmental trajectories in crucial brain regions such as the default mode network (DMN), temporal lobe, and prefrontal lobes during critical periods of neurodevelopment when compared to the control group. These changes were also associated with genes primarily located in synaptic tissues. The findings of this study suggest that the neurobiology of ASD is uniquely heterogeneous across different ages and may be accompanied by distinct molecular mechanisms related to gene expression.

Glutamate levels of the right and left anterior cingulate cortex in autistics adults

BackgroundThe neurobiology of Autism Spectrum Disorder (ASD) is still unknown. Alteration in glutamate metabolism might translate into an imbalance of the excitation/inhibition equilibrium of cortical networks that in turn are related to autistic symptoms, but previous studies using voxel located in bilateral anterior cingulate cortex (ACC) failed to show abnormalities in total glutamate level. Due to the functional differences in the right and left ACC, we sought to determine whether a difference between right and left ACC glutamate levels could be found when comparing ASD patients and control subjects. MethodsUsing single-voxel proton magnetic resonance spectroscopy (1H-MRS), we analyzed the glutamate + glutamine (Glx) concentrations in the left and right ACC of 19 ASD patients with normal IQs and 25 matched control subjects. ResultsNo overall group differences in Glx were shown, in the left ACC (p = 0.24) or in the right ACC (p = 0.11). ConclusionsNo significant alterations in Glx levels were detected in the left and right ACC in high-functioning autistic adults. In the excitatory/inhibitory imbalance framework, our data reinforce the critical need to analyze the GABAergic pathway, for better understanding of basic neuropathology in autism.

The neurobiology of autism spectrum disorder as it relates to twice exceptionality

There is a long-standing association between exceptional cognitive abilities of various sorts and neuropsychiatric illness, but it has historically largely been investigated in an exploratory and non-systematic way. One group in which this association has been investigated with more rigor is in subjects who have been identified as twice exceptional; an educational term describing subjects who are both gifted and diagnosed with a neuropsychiatric disorder. This term covers multiple conditions, but is of specific interest in particular in the study of autism spectrum disorder. Recent findings have led to the development of a hypothesis that a certain degree of the neurobiology associated with autism might even be advantageous for individuals and could lead to high giftedness, while becoming disadvantageous, once a certain threshold is surpassed. In this model, the same neurobiological mechanisms confer an increasing advantage up to a certain threshold, but become pathological past that point. Twice-exceptional individuals would be exactly at the inflection point, being highly gifted, but also symptomatic at the same time. Here, we review how existing neuroimaging literature on autism spectrum disorder can inform research on twice exceptionality specifically. We propose to study key neural networks with a robust implication in ASD to identify the neurobiology underlying twice-exceptionality. A better understanding of the neural mechanisms of twice exceptionality should help to better understand resilience and vulnerability to neurodevelopmental disorders and to.further support affected individuals.

Serum Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Potential Diagnostic Biomarkers in Autism Spectrum Disorders: A Preliminary Study.

Autism spectrum disorder (ASD) is one of the most common neurodevelopment disorders, characterized by a multifactorial etiology based on the interaction of genetic and environmental factors. Recent evidence supports the neurobiological hypothesis based on neuroinflammation theory. To date, there are no sufficiently validated diagnostic and prognostic biomarkers for ASD. Therefore, we decided to investigate the potential diagnostic role for ASD of two biomarkers well known for other neurological inflammatory conditions: the glial fibrillary acidic protein (GFAP) and the neurofilament (Nfl). Nfl and GFAP serum levels were analyzed using SiMoA technology in a group of ASD patients and in a healthy control group (CTRS), age- and gender-matched. Then we investigated the distribution, frequency, and correlation between serum Nfl and GFAP levels and clinical data among the ASD group. The comparison of Nfl and GFAP serum levels between ASD children and the control group showed a mean value of these two markers significantly higher in the ASD group (sNfL mean value ASD pt 6.86 pg/mL median value ASD pt 5.7 pg/mL; mean value CTRS 3.55 pg/mL; median value CTRS 3.1 pg; GFAP mean value ASD pt 205.7 pg/mL median value ASD pt 155.4 pg/mL; mean value CTRS 77.12 pg/mL; median value CTRS 63.94 pg/mL). Interestingly, we also found a statistically significant positive correlation between GFAP levels and hyperactivity symptoms (p-value <0.001). Further investigations using larger groups are necessary to confirm our data and to verify in more depth the potential correlation between these biomarkers and ASD clinical features, such as the severity of the core symptoms, the presence of associated symptoms, and/or the evaluation of a therapeutic intervention. However, these data not only might shed a light on the neurobiology of ASD, supporting the neuroinflammation and neurodegeneration hypothesis, but they also might support the use of these biomarkers in the early diagnosis of ASD, to longitudinally monitor the disease activity, and even more as future prognostic biomarkers.

Fetal Amygdala Functional Connectivity Relates to Autism Spectrum Disorder Traits at Age 3

Autism spectrum disorder (ASD) is a highly prevalent developmental disorder. There is notable disparity in occurrence rates between males and females, with males being 4.5 times as likely as their female counterparts to be diagnosed with the disease. A major objective for improving functional outcomes in ASD is to isolate biomarkers for earlier detection; an area as yet unexplored is whether biomarkers of future ASD symptomology may be observable in the fetal brain. Here, we focus on the amygdala, which shows sex-differential patterns of development and has been implicated in the neurobiology of ASD.

Adaptive and Maladaptive Bodily Awareness: Distinguishing Interoceptive Sensibility and Interoceptive Attention from Anxiety-Induced Somatization in Autism and Alexithymia.

There is growing interest in "interoception" (i.e., detection and interpretation of internal body signals) as a relevant mechanism contributing to certain symptoms and features of autism spectrum disorder (ASD) and alexithymia. However, inconsistent measurement and operationalization of interoception has led to confusion and inconsistent findings in the literature. In this commentary, we present alternative interpretations of findings from existing studies to demonstrate that ASD and alexithymia are conditions associated with reduced adaptive forms of interoceptive attention (i.e., attention toward bodily signals) but heightened maladaptive forms of interoceptive attention related to anxiety-induced somatization. Differentiating adaptive and maladaptive forms of interoceptive attention reveals a clearer pattern of findings in the research literature for further investigation of interoceptive processes that are involved in the neurobiology of ASD. However, interoception is a complex and multi-faceted construct that requires continual refinement in conceptualization and operationalization. Interoception research may benefit from self-report measures that clearly differentiate adaptive and maladaptive forms of bodily awareness. LAY SUMMARY: Some research suggests that autistic people have difficulty understanding bodily feelings such as hunger, illness, or emotions, whereas some studies have reported the opposite pattern of findings. We argue that this latter subset of studies reached false conclusions from using measures of bodily awareness that largely measure physical symptoms of anxiety. While attention to unpleasant bodily signals is an important ability necessary for maintaining healthy bodily functioning, excessive attention, and worry toward bodily signals can increase anxiety and be harmful.

Autism Spectrum Disorder Symptoms are Associated with Connectivity Between Large-Scale Neural Networks and Brain Regions Involved in Social Processing.

The neurobiology of autism spectrum disorder remains poorly understood. The present study addresses this knowledge gap by examining the relationship between functional brain connectivity and Autism Diagnostic Observation Schedule (ADOS) scores using publicly available data from the Autism Brain Imaging Data Exchange (ABIDE) database (N = 107). This relationship was tested across all brain voxels, without a priori assumptions, using a novel statistical approach. ADOS scores were primarily associated with decreased connectivity to right temporoparietal junction, right anterior insula, and left fusiform gyrus (p < 0.05, corrected). Seven large-scale brain networks influenced these associations. Findings largely encompassed brain regions involved in processing socially relevant information, highlighting the importance of these processes in autism spectrum disorder.

Sex Differences in the Amygdala Resting-State Connectome of Children With Autism Spectrum Disorder

BackgroundMultifactorial liability models predict greater dissimilarity in the neural phenotype of autism spectrum disorder (ASD) in female individuals than in male individuals, while gender incoherence and extreme male brain models predict attenuated sex differences in ASD. The amygdala is an informative target to explore these models because it is implicated in both the neurobiology of ASD and sex differences in typical development. MethodsThis study investigated amygdala resting-state functional connectivity in a cohort of 116 children with ASD (36 female) and 58 typically developing children (27 female) 2 to 7 years of age during natural sleep. First, multivariate distance matrix regression assessed global sex and diagnostic differences across the amygdala connectome. Second, univariate general linear models identified regions with mean connectivity differences. ResultsMultivariate distance matrix regression revealed greater differences between typically developing children and those with ASD in females than in males, consistent with multifactorial liability models, and attenuated sex differences in the left amygdala connectome of children with ASD in a pattern consistent with the gender incoherence model. Univariate analysis identified similar sex differences in dorsomedial and ventral prefrontal cortices, lingual gyrus, and posterior cingulate cortex, but also noted that lower amygdala connectivity with superior temporal sulcus is observed across sexes. ConclusionsThis study provides evidence that compared with sex-matched control subjects, ASD manifests differently in the brain at the time of diagnosis and prior to the influence of compensatory mechanisms in male and female children, consistent with multifactorial liability models, and that ASD is associated with reduced sex differences in a pattern consistent with gender incoherence models.

Frontal lobe metabolic alterations in autism spectrum disorder: a 1H-magnetic resonance spectroscopy study.

PurposeRecently, neuroimaging studies were performed using 1H-magnetic resonance spectroscopy (1H-MRS), revealing a quantitative alteration of neurochemicals (such as neurotransmitters and metabolites) in several brain regions of patients with autism spectrum disorder (ASD). The involvement of the frontal lobe in the neurobiology of ASD has long been documented in the literature. Therefore, the aim of this study was to analyze the alterations of N-acetylaspartate/creatine (NAA/Cr) and choline/Cr (Cho/Cr) ratios in the frontal lobe subcortical white matter (WM) in ASD patients, in order to reveal any alteration of metabolites that might be the expression of specific clinical features of the disorder.Patients and methodsAn 1H-MRS study of the frontal lobe subcortical WM was performed in 75 children with ASD and in 50 age-matched controls to evaluate the functional activity of this brain region.ResultsNAA/Cr and Cho/Cr ratios were significantly altered in ASD, compared to control subjects. Moreover, in the ASD group, NAA/Cr was significantly lower in patients with a cognitive impairment.ConclusionResults from this study confirm the existence of brain metabolites’ alterations in frontal lobe WM in children with ASD, supporting the relevance of this brain region in the clinical expressions of this disorder, including its role in the cognitive impairment. Further 1H-MRS investigations will allow to comprehensively explain the relationship between metabolic alteration in a specific brain region and specific clinical features of ASD.

Neurobiology of autism spectrum disorders

Autism Spectrum Disorders (ASD) is a group of neurodevelopmental disorders with heterogeneous etiology characterized by deficits in social cognition, communication, and behavioral flexibility. Disturbances on molecular and cellular level in early brain development incl. intercellular communication, an unbalanced ratio between certain neuronal populations and maturation/differentiation process, oxidative stress, happening in embryonal stages, might be promising candidates to explain the development of autistic symptoms.In order to get a deeper understanding of these processes, valid “disease models” are pivotal. A new cutting edge technique, named brain organoids, has been highlighted as a promising candidate for obtaining a better “disease model”.Brain organoids derived from patients induced pluripotent stem cells (iPSC) follow in vivo timeline development; they also have the ability to recreate the right complexity of the brains, developmental stages. On the cellular and gene expression level, organoids demonstrate a high similarity to the developing brain in vivo and can therefore recapitulate early stages of the neurogenesis. To date organoids are the most relevant cellular in vitro platform for the understanding of the mechanisms behind ADS pathology. Investigations of “mini brains” at different time points in their development will give a wider and more detailed picture of the disease dynamic and thus the development of therapeutic and prevention strategies. It is a tool that can be used for effective high throughput screening of chemical compounds as potential drugs (“in sphero” drug testing). Organoids are a good modeling system for elucidating the role of epigenetic and environmental factors for development of ASD.Disclosure of interestThe authors declare that they have no competing interest.

The neuroanatomy of autism spectrum disorder: An overview of structural neuroimaging findings and their translatability to the clinical setting.

Autism spectrum disorder is a complex neurodevelopmental disorder, which is accompanied by differences in brain anatomy, functioning and brain connectivity. Due to its neurodevelopmental character, and the large phenotypic heterogeneity among individuals on the autism spectrum, the neurobiology of autism spectrum disorder is inherently difficult to describe. Nevertheless, significant progress has been made in characterizing the neuroanatomical underpinnings of autism spectrum disorder across the human life span, and in identifying the molecular pathways that may be affected in autism spectrum disorder. Moreover, novel methodological frameworks for analyzing neuroimaging data are emerging that make it possible to characterize the neuroanatomy of autism spectrum disorder on the case level, and to stratify individuals based on their individual phenotypic make up. While these approaches are increasingly more often employed in the research setting, their applicability in the clinical setting remains a vision for the future. The aim of the current review is to (1) provide a general overview of recent structural neuroimaging findings examining the neuroanatomy of autism spectrum disorder across the human life span, and in males and females with the condition, (2) highlight potential neuroimaging (bio)markers that may in the future be used for the stratification of autism spectrum disorder individuals into biologically homogeneous subgroups and (3) inform treatment and intervention strategies.

Oxidative stress – A promising candidate in explaining the neurobiology of autism spectrum disorders

IntroductionThe diagnoses of autism spectrum disorders (ASDs) are based on a phenotype, characterized by impaired social interaction and communication and by repetitive and restricted interests. However, this might not represent a single clinical entity, but a behavioral manifestation of different neurodevelopmental deficits with a multifactorial etiology. Small studies have shown elevated levels of oxidative stress and lower levels of anti-oxidants in patients with ASD, and correlations with the severity of ASD. Therapies targeting oxidative stress have shown improvements regarding behavior, social interaction and verbal communication in patients with ASD, supporting the oxidative stress theory.ObjectivesTo evaluate the importance of oxidative stress in the neurobiology of adults with ASD.AimsThere is a need to understand the neurobiology of ASD, therefore this study analyzes the level of oxidative stress in a larger cohort of patients with ASD and compares to controls.MethodsThe study includes 350 patients over 18 years of age diagnosed with ICD-10 diagnoses F84.0, F84.1, F84.5 or F84.8 and compared to gender and age matched neurotypical controls. The included probands will have their serum and plasma analyzed for levels of oxidative stress (superoxide dismutase 1 and 2, catalase, glutathioneperoxidase, malonialdehyde, thiobarbituric acid reactive substances and xanthinoxidase).ResultsThe preliminary results will be presented at the EPA in March 2016 in Madrid.ConclusionWith this study we aim to elucidate some of the neurobiology in ASD. This could lead to new potential targets for treatment and prevention of the disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Multimodal imaging in autism: an early review of comprehensive neural circuit characterization.

There is accumulating evidence that the neurobiology of autism spectrum disorders (ASD) is linked to atypical neural communication and connectivity. This body of work emphasizes the need to characterize the function of multiple regions that comprise neural circuits rather than focusing on singular regions as contributing to deficits in ASD. Multimodal neuroimaging - the formal combination of multiple functional and structural measures of the brain - is extremely promising as an approach to understanding neural deficits in ASD. This review provides an overview of the multimodal imaging approach, and then provides a snapshot of how multimodal imaging has been applied in the study of ASD to date. This body of work is separated into two categories: one concerning whole brain connectomics and the other focused on characterizing neural circuits implicated as altered in ASD. We end this review by highlighting emerging themes from the existing body of literature, and new resources that will likely influence future multimodal imaging studies.

Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders.

BackgroundGABRB3 is a position candidate gene at chromosome 15q12 that has been implicated in the neurobiology of autism spectrum disorders (ASD). The aim of this study was to examine the genetic association of GABRB3 with ASD.MethodsThe sample consisted of 356 patients with clinical diagnosis of ASD according to the DSM-IV diagnostic criteria and confirmed by the Autism Diagnostic Interview-Revised and 386 unrelated controls. We searched for mutations at all the exonic regions and 1.6 Kb of the 5′ region of GABRB3 in the genomic DNA of all the participants using the Sanger sequencing. We implemented a case-control association analysis of variants detected in this sample, and conducted a reporter gene assay to assess the functional impact of variants at the 5′ regulatory region.ResultsWe detected six known common SNPs; however, they were not associated with ASD. Besides, a total of 22 rare variants (12 at 5′ regulatory, 4 at intronic, and 6 at exonic regions) were detected in 18 patients and 6 controls. The frequency of rare variants was significantly higher in the patient group than in the control group (18/356 versus 6/386, odds ratio = 3.37, P = 0.007). All the 12 rare variants at the 5′ regulatory region were only detected in 7 patients, but not in any of the controls (7/356 versus 0/386, Fisher’s exact test, P = 0.006). Two patients carried multiple rare variants. Family studies showed that most of these rare variants were transmitted from their parents. Reporter gene assays revealed that four rare variants at the 5′ regulatory region and 1 at exon 1a untranslated region had elevated reporter gene activities compared to two wild type alleles.ConclusionsOur data suggest rare variants of GABRB3 might be associated with ASD, and increased GABRB3 expression may contribute to the pathogenesis of ASD in some patients.Trial registrationClinical trial registration Identifier: NCT00494754

Autism Spectrum Disorder as Early Neurodevelopmental Disorder: Evidence from the Brain Imaging Abnormalities in 2–3 Years Old Toddlers

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships in adolescents and adults with ASD, literature is still limited in information about the neurobiology of ASD in the early age of life. Brain images of 50 toddlers with ASD and 28 age, gender, and developmental quotient matched toddlers with developmental delay (DD) (control group) between ages 2 and 3 years were captured using combined magnetic resonance-based structural imaging and diffusion tensor imaging (DTI). Structural magnetic resonance imaging was applied to assess overall gray matter (GM) and white matter (WM) volumes, and regional alterations were assessed by voxel-based morphometry. DTI was used to investigate the white matter tract integrity. Compared with DD, significant increases were observed in ASD, primarily in global GM and WM volumes and in right superior temporal gyrus regional GM and WM volumes. Higher fractional anisotropy value was also observed in the corpus callosum, posterior cingulate cortex, and limbic lobes of ASD. The converging findings of structural and white matter abnormalities in ASD suggest that alterations in neural-anatomy of different brain regions may be involved in behavioral and cognitive deficits associated with ASD, especially in an early age of 2–3 years old toddlers.