Altered Network Topologies and Hub Organization in Adults with Autism: A Resting-State fMRI Study

Recent functional magnetic resonance imaging (fMRI) studies on autism spectrum condition (ASC) have identified dysfunctions in specific brain networks involved in social and non-social cognition that persist into adulthood. Although increasing numbers of fMRI studies have revealed atypical functional connectivity in the adult ASC brain, such functional alterations at the network level have not yet been fully characterized within the recently developed graph-theoretical framework. Here, we applied a graph-theoretical analysis to resting-state fMRI data acquired from 46 adults with ASC and 46 age- and gender-matched controls, to investigate the topological properties and organization of autistic brain network. Analyses of global metrics revealed that, relative to the controls, participants with ASC exhibited significant decreases in clustering coefficient and characteristic path length, indicating a shift towards randomized organization. Furthermore, analyses of local metrics revealed a significantly altered organization of the hub nodes in ASC, as shown by analyses of hub disruption indices using multiple local metrics and by a loss of “hubness” in several nodes (e.g., the bilateral superior temporal sulcus, right dorsolateral prefrontal cortex, and precuneus) that are critical for social and non-social cognitive functions. In particular, local metrics of the anterior cingulate cortex consistently showed significant negative correlations with the Autism-Spectrum Quotient score. Our results demonstrate altered patterns of global and local topological properties that may underlie impaired social and non-social cognition in ASC.     

Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory

Mutations in the Autism susceptibility candidate 2 gene (AUTS2) have been associated with a broad range of psychiatric illnesses including autism spectrum disorders, intellectual disability and schizophrenia. We previously demonstrated that the cytoplasmic AUTS2 acts as an upstream factor for the Rho family small GTPase Rac1 and Cdc42 that regulate the cytoskeletal rearrangements in neural cells. Moreover, genetic ablation of the Auts2 gene in mice has resulted in defects in neuronal migration and neuritogenesis in the developing cerebral cortex caused by inactivation of Rac1-signaling pathway, suggesting that AUTS2 is required for neural development. In this study, we conducted a battery of behavioral analyses on Auts2 heterozygous mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction. Furthermore, the capability for novel object recognition and cued associative memory were impaired in Auts2 mutant mice. Social behavior and sensory motor gating functions were, however, normal in the mutant mice as assessed by the three-chamber test and prepulse inhibition test, respectively. Together, our findings indicate that AUTS2 is critical for the acquisition of neurocognitive function.     

Cerebellar Oxidative DNA Damage and Altered DNA Methylation in the BTBR T+tf/J Mouse Model of Autism and Similarities with Human Post Mortem Cerebellum

The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of OGG1 alterations in pathogenesis of autism.     

精神障碍的神经电生理循证医学证据

寻找客观标记物是精神医学研究最重要的课题之一,近期融合了循证医学的神经电生理研究为此提供了重要的途径,并取得了较为可观的研究成果,然而现有的研究结果仍然存在较多争议,难以取得一致共识.本文全面总结和归纳了结合以元分析(meta-analysis)为代表的循证医学方法和以脑电图(electroencephalography)为代表的神经电生理技术的精神障碍相关脑电研究成果,将事件相关电位划分为早期和晚期成分,并结合定量EEG分析,从感知加工、认知控制、情绪反应和社会认知等不同认知过程出发,系统分析和评述了精神障碍患者及高危人群的神经认知功能异常情况.我们发现:精神分裂症患者存在从早期到晚期的各种感知、情感和社会认知方面的缺陷,注意缺陷/多动障碍(ADHD)患者存在从早期到晚期的认知控制缺陷,焦虑和强迫障碍患者则存在早期的认知控制缺陷,而孤独症谱系障碍(ASD)患者则存在早期的感知加工和社会认知缺陷.此外,反映注意资源分配和认知加工速度的P300异常特征跨越了多个诊断类型,这表明该脑电成分可能反映了精神障碍的一般性认知缺陷.未来研究可利用多中心大样本数据库探寻精神疾病的神经电生理客观标记物,并融合先进的多模态精神影像技术和机器学习等人工智能方法,进一步增强精神障碍生物标记物的可靠性和有效性.     

Interactive Social Neuroscience to Study Autism Spectrum Disorder

Individuals with autism spectrum disorder (ASD) demonstrate difficulty with social interactions and relationships, but the neural mechanisms underlying these difficulties remain largely unknown. While social difficulties in ASD are most apparent in the context of interactions with other people, most neuroscience research investigating ASD have provided limited insight into the complex dynamics of these interactions. The development of novel, innovative “interactive social neuroscience” methods to study the brain in contexts with two interacting humans is a necessary advance for ASD research. Studies applying an interactive neuroscience approach to study two brains engaging with one another have revealed significant differences in neural processes during interaction compared to observation in brain regions that are implicated in the neuropathology of ASD. Interactive social neuroscience methods are crucial in clarifying the mechanisms underlying the social and communication deficits that characterize ASD.     

The Integration of Prosodic Speech in High Functioning Autism: A Preliminary fMRI Study

Background

Autism is a neurodevelopmental disorder characterized by a specific triad of symptoms such as abnormalities in social interaction, abnormalities in communication and restricted activities and interests. While verbal autistic subjects may present a correct mastery of the formal aspects of speech, they have difficulties in prosody (music of speech), leading to communication disorders. Few behavioural studies have revealed a prosodic impairment in children with autism, and among the few fMRI studies aiming at assessing the neural network involved in language, none has specifically studied prosodic speech. The aim of the present study was to characterize specific prosodic components such as linguistic prosody (intonation, rhythm and emphasis) and emotional prosody and to correlate them with the neural network underlying them.

Methodology/Principal Findings

We used a behavioural test (Profiling Elements of the Prosodic System, PEPS) and fMRI to characterize prosodic deficits and investigate the neural network underlying prosodic processing. Results revealed the existence of a link between perceptive and productive prosodic deficits for some prosodic components (rhythm, emphasis and affect) in HFA and also revealed that the neural network involved in prosodic speech perception exhibits abnormal activation in the left SMG as compared to controls (activation positively correlated with intonation and emphasis) and an absence of deactivation patterns in regions involved in the default mode.

Conclusions/Significance

These prosodic impairments could not only result from activation patterns abnormalities but also from an inability to adequately use the strategy of the default network inhibition, both mechanisms that have to be considered for decreasing task performance in High Functioning Autism.     

It’s All in the Eyes: Subcortical and Cortical Activation during Grotesqueness Perception in Autism

Atypical face processing plays a key role in social interaction difficulties encountered by individuals with autism. In the current fMRI study, the Thatcher illusion was used to investigate several aspects of face processing in 20 young adults with high-functioning autism spectrum disorder (ASD) and 20 matched neurotypical controls. “Thatcherized” stimuli were modified at either the eyes or the mouth and participants discriminated between pairs of faces while cued to attend to either of these features in upright and inverted orientation. Behavioral data confirmed sensitivity to the illusion and intact configural processing in ASD. Directing attention towards the eyes vs. the mouth in upright faces in ASD led to (1) improved discrimination accuracy; (2) increased activation in areas involved in social and emotional processing; (3) increased activation in subcortical face-processing areas. Our findings show that when explicitly cued to attend to the eyes, activation of cortical areas involved in face processing, including its social and emotional aspects, can be enhanced in autism. This suggests that impairments in face processing in autism may be caused by a deficit in social attention, and that giving specific cues to attend to the eye-region when performing behavioral therapies aimed at improving social skills may result in a better outcome.     

Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder

Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.     

Genetic architecture,epigenetic influence and environment exposure in the pathogenesis of Autism

Autism spectrum disorder(ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.     

Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats

Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.     

Functional Organization of the Action Observation Network in Autism: A Graph Theory Approach

Background

The ability to recognize, understand and interpret other’s actions and emotions has been linked to the mirror system or action-observation-network (AON). Although variations in these abilities are prevalent in the neuro-typical population, persons diagnosed with autism spectrum disorders (ASD) have deficits in the social domain and exhibit alterations in this neural network.

Method

Here, we examined functional network properties of the AON using graph theory measures and region-to-region functional connectivity analyses of resting-state fMRI-data from adolescents and young adults with ASD and typical controls (TC).

Results

Overall, our graph theory analyses provided convergent evidence that the network integrity of the AON is altered in ASD, and that reductions in network efficiency relate to reductions in overall network density (i.e., decreased overall connection strength). Compared to TC, individuals with ASD showed significant reductions in network efficiency and increased shortest path lengths and centrality. Importantly, when adjusting for overall differences in network density between ASD and TC groups, participants with ASD continued to display reductions in network integrity, suggesting that also network-level organizational properties of the AON are altered in ASD.

Conclusion

While differences in empirical connectivity contributed to reductions in network integrity, graph theoretical analyses provided indications that also changes in the high-level network organization reduced integrity of the AON.     

Developing Neuroimaging Phenotypes of the Default Mode Network in PTSD: Integrating the Resting State,Working Memory,and Structural Connectivity

Complementary structural and functional neuroimaging techniques used to examine the Default Mode Network (DMN) could potentially improve assessments of psychiatric illness severity and provide added validity to the clinical diagnostic process. Recent neuroimaging research suggests that DMN processes may be disrupted in a number of stress-related psychiatric illnesses, such as posttraumatic stress disorder (PTSD).Although specific DMN functions remain under investigation, it is generally thought to be involved in introspection and self-processing. In healthy individuals it exhibits greatest activity during periods of rest, with less activity, observed as deactivation, during cognitive tasks, e.g., working memory. This network consists of the medial prefrontal cortex, posterior cingulate cortex/precuneus, lateral parietal cortices and medial temporal regions.Multiple functional and structural imaging approaches have been developed to study the DMN. These have unprecedented potential to further the understanding of the function and dysfunction of this network. Functional approaches, such as the evaluation of resting state connectivity and task-induced deactivation, have excellent potential to identify targeted neurocognitive and neuroaffective (functional) diagnostic markers and may indicate illness severity and prognosis with increased accuracy or specificity. Structural approaches, such as evaluation of morphometry and connectivity, may provide unique markers of etiology and long-term outcomes. Combined, functional and structural methods provide strong multimodal, complementary and synergistic approaches to develop valid DMN-based imaging phenotypes in stress-related psychiatric conditions. This protocol aims to integrate these methods to investigate DMN structure and function in PTSD, relating findings to illness severity and relevant clinical factors.     

Gene-Network Analysis Identifies Susceptibility Genes Related to Glycobiology in Autism

The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.     

Autism spectrum disorder: seeing is not understanding

Impairments in social and emotional skills are a defining feature of autism spectrum disorder. Recent research shows that structural and functional abnormalities within the neural system that matches observation and execution of actions--the mirror neuron system--may explain the social aspects of the pathophysiology of autism spectrum disorder.     

A Neurosemantic Theory of Concrete Noun Representation Based on the Underlying Brain Codes

This article describes the discovery of a set of biologically-driven semantic dimensions underlying the neural representation of concrete nouns, and then demonstrates how a resulting theory of noun representation can be used to identify simple thoughts through their fMRI patterns. We use factor analysis of fMRI brain imaging data to reveal the biological representation of individual concrete nouns like apple, in the absence of any pictorial stimuli. From this analysis emerge three main semantic factors underpinning the neural representation of nouns naming physical objects, which we label manipulation, shelter, and eating. Each factor is neurally represented in 3–4 different brain locations that correspond to a cortical network that co-activates in non-linguistic tasks, such as tool use pantomime for the manipulation factor. Several converging methods, such as the use of behavioral ratings of word meaning and text corpus characteristics, provide independent evidence of the centrality of these factors to the representations. The factors are then used with machine learning classifier techniques to show that the fMRI-measured brain representation of an individual concrete noun like apple can be identified with good accuracy from among 60 candidate words, using only the fMRI activity in the 16 locations associated with these factors. To further demonstrate the generativity of the proposed account, a theory-based model is developed to predict the brain activation patterns for words to which the algorithm has not been previously exposed. The methods, findings, and theory constitute a new approach of using brain activity for understanding how object concepts are represented in the mind.     

Structural Alterations of the Social Brain: A Comparison between Schizophrenia and Autism

Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.     

Assessment of Techniques for Teaching School Children with Autism

BackgroundIn the modern era, researchers are facing a big challenge in diagnosing autism disorders. According to the Center for Disease Control and Prevention 2014 report, the prevalence of autism among children in the United States is approximately 1 out of 88 children; whereas, in South Korea, the prevalence is 1 out of 38. In India, most of the children with autism are yet to be diagnosed partly due to the lack of self-screening test compared to the other countries. Currently, no data is available for analyzing the prevalence of autism in India. In order to improve the behavior, the social interaction, and the verbal communication of these children, scientists are using various kinds of teaching methods.ObjectivesThe objectives of this work were to screen the level of autism among school children using Gilliam Autism Rating Scale (GARS-2) questionnaire and evaluate the effects of various teaching methods on social behavior of school children with autism.Methods and resultsNinety children in the age group between 3 – 16 years from three schools (S1 – 30, S2 – 30 and S3 – 30) with autism are participated in this study. In S1, the autistic children are trained with horseback riding and yoga therapy; whereas in the S2, the children are trained with normal teaching using blackboard and in the S3, the children are trained with cue cards. The GARS-2 questionnaire was used for assessing the communication, the stereotype behavior and the social interaction with the help of parents or the caregivers.ConclusionResults of our study revealed that raw and the standard scores of stereotyped behaviors was notably (p<0.05) low in S1 school children when collated with the other two (S2 and S3) schools. Similarly, the raw and the standard score of communication, the socially interaction sub-score was notably (p<0.05) low for the children in S3 when collated with the children in the other two schools. The study concluded that the horseback riding, the yoga therapy and the cue cards-based teaching methods improve the stereotyped behavior, increase concentration power and also helps in maintaining the children's mind stability.     

Neural basis of self and other representation in autism: an FMRI study of self-face recognition

Background

Autism is a developmental disorder characterized by decreased interest and engagement in social interactions and by enhanced self-focus. While previous theoretical approaches to understanding autism have emphasized social impairments and altered interpersonal interactions, there is a recent shift towards understanding the nature of the representation of the self in individuals with autism spectrum disorders (ASD). Still, the neural mechanisms subserving self-representations in ASD are relatively unexplored.

Methodology/Principal Findings

We used event-related fMRI to investigate brain responsiveness to images of the subjects'' own face and to faces of others. Children with ASD and typically developing (TD) children viewed randomly presented digital morphs between their own face and a gender-matched other face, and made “self/other” judgments. Both groups of children activated a right premotor/prefrontal system when identifying images containing a greater percentage of the self face. However, while TD children showed activation of this system during both self- and other-processing, children with ASD only recruited this system while viewing images containing mostly their own face.

Conclusions/Significance

This functional dissociation between the representation of self versus others points to a potential neural substrate for the characteristic self-focus and decreased social understanding exhibited by these individuals, and suggests that individuals with ASD lack the shared neural representations for self and others that TD children and adults possess and may use to understand others.     

Toxicological Status of Children with Autism vs. Neurotypical Children and the Association with Autism Severity

This study investigates both the level of toxic metals in children with autism and the possible association of those toxic metals with autism severity. This study involved 55 children with autism ages 5–16 years compared to 44 controls with similar age and gender. The study included measurements of toxic metals in whole blood, red blood cells (RBC), and urine. The autism group had higher levels of lead in RBC (+41 %, p?=?0.002) and higher urinary levels of lead (+74 %, p?=?0.02), thallium (+77 %, p?=?0.0001), tin (+115 %, p?=?0.01), and tungsten (+44 %, p?=?0.00005). However, the autism group had slightly lower levels of cadmium in whole blood (?19 %, p?=?0.003). A stepwise, multiple linear regression analysis found a strong association of levels of toxic metals with variation in the degree of severity of autism for all the severity scales (adjusted R ² of 0.38–0.47, p?<?0.0003). Cadmium (whole blood) and mercury (whole blood and RBC) were the most consistently significant variables. Overall, children with autism have higher average levels of several toxic metals, and levels of several toxic metals are strongly associated with variations in the severity of autism for all three of the autism severity scales investigated.