Typically Developing Subjects Research Articles

Autonomic and hedonic response to affective touch in autism spectrum disorder.

Interpersonal touch plays a crucial role in shaping relationships and encouraging social connections. Failure in processing tactile input or abnormal tactile sensitivity may hamper social behaviors and have severe consequences in individuals' relational lives. Autism Spectrum Disorder (ASD) is characterized by both sensory disruptions and social impairments, making affective touch an ideal meeting point for understanding these features in ASD individuals. By integrating behavioral and physiological measures, we investigated the effects of affective touch on adult individuals with ASD from both an implicit and explicit perspective. Specifically, at an implicit level, we investigated whether and how receiving an affective touch influenced participants' skin conductance tonic and phasic components. At the explicit level, we delved into the affective and unpleasant features of affective touch. Overall, we observed lower skin conductance level in ASD compared to TD subjects. Interestingly, the typically developing (TD) group showed an increased autonomic response for affective touch compared to a control touch, while ASD subjects' autonomic response did not differ between the two conditions. Furthermore, ASD participants provided higher ratings for both the affective and unpleasant components of the touch, compared to TD subjects. Our results reveal a noteworthy discrepancy in ASD population between the subjective experience, characterized by amplified hedonic but also unpleasant responses, and the physiological response, marked by a lack of autonomic activation related to affective touch. This insightful dissociation seems crucial for a deeper understanding of the distinctive challenges characterizing people with ASD and may have implications for diagnosis and therapeutic approaches.

Relationship between abnormal intrinsic functional connectivity of subcortices and autism symptoms in high-functioning adults with autism spectrum disorder

PurposeThis study explores subcortices and their intrinsic functional connectivity (iFC) in autism spectrum disorder (ASD) adults and investigates their relationship with clinical severity. MethodsResting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 74 ASD patients, and 63 gender and age-matched typically developing (TD) adults. Independent component analysis (ICA) was conducted to evaluate subcortical patterns of basal ganglia (BG) and thalamus. These two brain areas were treated as regions of interest to further calculate whole-brain FC. In addition, we employed multivariate machine learning to identify subcortices-based FC brain patterns and clinical scores to classify ASD adults from those TD subjects. ResultsIn ASD individuals, autism diagnostic observation schedule (ADOS) was negatively correlated with the BG network. Similarly, social responsiveness scale (SRS) was negatively correlated with the thalamus network. The BG-based iFC analysis revealed adults with ASD versus TD had lower FC, and its FC with the right medial temporal lobe (MTL), was positively correlated with SRS and ADOS separately. ASD could be predicted with a balanced accuracy of around 60.0 % using brain patterns and 84.7 % using clinical variables. ConclusionOur results revealed the abnormal subcortical iFC may be related to autism symptoms.

Expression of miRNAs in Pre-Schoolers with Autism Spectrum Disorders Compared with Typically Developing Peers and Its Effects after Probiotic Supplementation.

Alteration of the microbiota-gut-brain axis has been recently recognized as a possible contributor to the physiopathology of autism spectrum disorder (ASD). In this context, microRNA (miRNAs) dysfunction, implicated both in several neuropathological conditions including ASD and in different gastrointestinal disorders (GIDs), could represent an important modulating factor. In this contextual framework, we studied the transcriptional profile of specific circulating miRNAs associated with both ASD (miR-197-5p, miR-424-5p, miR-500a-5p, miR-664a-5p) and GID (miR-21-5p, miR-320a-5p, miR-31-5p, miR-223-5p) in a group of pre-schoolers with ASD and in typically developing (TD) peers. In the ASD group, we also assessed the same miRNAs after a 6-month supplementation with probiotics and their correlation with plasma levels of zonulin and lactoferrin. At baseline, the expression of miRNAs involved in ASD were significantly reduced in ASD pre-schoolers vs. TD controls. Regarding the miRNAs involved in GID, the expression levels of miR-320-5p, miR-31-5p, and miR-223-5p were significantly higher in ASD than in TD subjects, whereas miR-21-5p showed significantly reduced expression in the ASD group vs. TD group. Supplementation with probiotics did not significantly change the expression of miRNAs in the ASD population. We found a significative negative correlation between zonulin and miR-197-5p and miR-21-5p at baseline, as well as between lactoferrin and miR-223-5p after 6 months of probiotic supplementation. Our study confirms the presence of an altered profile of the miRNAs investigated in ASD versus TD peers that was not modified by supplementation with probiotics.

Relationship between gray matter structure and age in children and adolescents with high-functioning autism spectrum disorder.

The present study used magnetic resonance imaging to investigate the difference in the relationship between gray matter structure and age in children and adolescents with autism spectrum disorder (ASD) and typically developing (TD) subjects. After screening T1 structural images from the Autism Brain Imaging Data Exchange (ABIDE) database, 111 children and adolescents (7-18 years old) with high-functioning ASD and 151 TD subjects matched for age, sex and full IQ were included in the current study. By using the voxel-based morphological analysis method, gray matter volume/density (GMV/GMD) maps were obtained for each participant. Then, a multiple regression analysis was performed for ASD and TD groups, respectively to estimate the relationship between GMV/GMD and age with gender, education, site, and IQ scores as covariates. Furthermore, a z-test was used to compare such relationship difference between the groups. Results showed that compared with TD, the GMD of ASD showed stronger positive correlations with age in the prefrontal cortex, and a stronger negative correlation in the left inferior parietal lobule, and a weaker positive correlation in the right inferior parietal lobule. The GMV of ASD displayed stronger positive correlations with age in the prefrontal cortex and cerebellum. These findings may provide evidence to support that the brain structure abnormalities underlying ASD during childhood and adolescence may differ from each other.

Automated Diagnosis of Autism Spectrum Disorder Condition Using Shape Based Features Extracted from Brainstem.

Alterations to the brainstem can hamper cognitive functioning, including audiovisual and behavioral disintegration, leading to individuals with Autism Spectrum Disorder (ASD) face challenges in social interaction. In this study, a process pipeline for the diagnosis of ASD has been proposed, based on geometrical and Zernike moments features, extracted from the brainstem of ASD subjects. The subjects considered for this study are obtained from publicly available data base ABIDE (300 ASD and 300 typically developing (TD)). Distance regularized level set (DRLSE) method has been used to segment the brainstem region from the midsagittal view of MRI data. Similarity measures were used to validate the segmented images against the ground truth images. Geometrical and Zernike moments features were extracted from the segmented images. The significant features were used to train Support vector machine (SVM) classifier to perform classification between ASD and TD subjects. The similarity results show high matching between DRLSE segmented brainstem and ground truth with high similarity index scores of Pearson Heron-II (PH II) = 0.9740 and Sokal and Sneath-II (SS II) = 0.9727. The SVM classifier achieved 70.53% accuracy to classify ASD and TD subjects. Thus, the process pipeline proposed in this study is able to achieve good accuracy in the classification of ASD subjects.

Sleep Power Topography in Children with Attention Deficit Hyperactivity Disorder (ADHD).

Objective: Recent years saw an increasing interest towards sleep microstructure abnormalities in attention-deficit/hyperactivity disorder (ADHD). However, the existing literature on sleep electroencephalographic (EEG) power in ADHD is still controversial, often based on single electrode recordings, and mainly focused on slow wave activity (SWA) during NREM sleep. This study aimed to systematically investigate sleep power topography in all traditional frequency bands, in all sleep stages and across sleep cycles using high-density EEG (HD-EEG). Method: Thirty drug-naïve children with ADHD (10.5 ± 2.1 years, 21 male) and 23 typically developing (TD) control participants (mean age: 10.2 ± 1.6 years, 13 male) were included in the current analysis. Signal power topography was computed in classical frequency bands during sleep, contrasted between groups and sleep cycles, and correlated with measures of ADHD severity, cognitive functioning and estimated total sleep time. Results: Compared to TD subjects, patients with ADHD consistently displayed a widespread increase in low-frequency activity (between 3 and 10 Hz) during NREM sleep, but not during REM sleep and wake before sleep onset. Such a difference involved a wide centro-posterior cluster of channels in the upper SWA range, in Theta, and low-Alpha. Between-group difference was maximal in sleep stage N3 in the first sleep cycle, and positively correlated with average total sleep time. Conclusions: These results support the concept that children with ADHD, compared to TD peers, have a higher sleep pressure and altered sleep homeostasis, which possibly interfere with (and delay) cortical maturation.

Autonomic Modulation in Duchenne Muscular Dystrophy During a Computer Task: A Prospective Transversal Controlled Trial Assessment by Non-linear Techniques.

Introduction: Due to functional and autonomic difficulties faced by individuals with Duchenne Muscular Dystrophy (DMD), the use of assistive technology is critical to provide or facilitate functional abilities. The key objective was to investigate acute cardiac autonomic responses, by application of Heart Rate Variability (HRV), during computer tasks in subjects with DMD via techniques based on non-linear dynamics.Method: HRV was attained via a Polar RS800CX. Then, was evaluated by Chaotic Global Techniques (CGT). Forty-five male subjects were included in the DMD group and age-matched with 45 in the healthy Typical Development (TD) control group. They were assessed for 20 min at rest sitting, and then 5 min whilst performing the maze task on a computer.Results: Both TD and DMD subjects exhibited a significantly reduced HRV measured by chaotic global combinations when undertaking the computer maze paradigm tests. DMD subjects presented decreased HRV during rest and computer task than TD subjects.Conclusion: While there is an impaired HRV in subjects with DMD, there remains an adaptation of the ANS during the computer tasks. The identification of autonomic impairment is critical, considering that the computer tasks in the DMD community may elevate their level of social inclusion, participation and independence.

Children ASD Evaluation Through Joint Analysis of EEG and Eye-Tracking Recordings With Graph Convolution Network.

Recent advances in neuroscience indicate that analysis of bio-signals such as rest state electroencephalogram (EEG) and eye-tracking data can provide more reliable evaluation of children autism spectrum disorder (ASD) than traditional methods of behavior measurement relying on scales do. However, the effectiveness of the new approaches still lags behind the increasing requirement in clinical or educational practices as the “bio-marker” information carried by the bio-signal of a single-modality is likely insufficient or distorted. This study proposes an approach to joint analysis of EEG and eye-tracking for children ASD evaluation. The approach focuses on deep fusion of the features in two modalities as no explicit correlations between the original bio-signals are available, which also limits the performance of existing methods along this direction. First, the synchronization measures, information entropy, and time-frequency features of the multi-channel EEG are derived. Then a random forest applies to the eye-tracking recordings of the same subjects to single out the most significant features. A graph convolutional network (GCN) model then naturally fuses the two group of features to differentiate the children with ASD from the typically developed (TD) subjects. Experiments have been carried out on the two types of the bio-signals collected from 42 children (21 ASD and 21 TD subjects, 3–6 years old). The results indicate that (1) the proposed approach can achieve an accuracy of 95% in ASD detection, and (2) strong correlations exist between the two bio-signals collected even asynchronously, in particular the EEG synchronization against the face related/joint attentions in terms of covariance.

Near-point Findings in Children with Autism Spectrum Disorder and in Typical Peers.

SIGNIFICANCEClinicians can better diagnose and manage vision problems of autism spectrum disorder (ASD) children by establishing a standard of care for this population. Results also reinforce the importance of a comprehensive binocular vision evaluation in all patients with ASD.PURPOSEThe purposes of this study were to compare near-point and ocular motility test findings in ASD children and typically developing (TD) peers and to compare findings among ASD children by level of verbal communication.METHODSSixty-one children and adolescents (ASD, 34; TD, 27) aged 9 to 17 years completed an eye examination protocol including tests of distance and near phoria, near point of convergence, near fusional convergence and divergence, accommodative response, and Northeastern State University College of Optometry oculomotor testing. Testing was completed through refractive correction. Parents of ASD children provided information regarding subjects' verbal communication level (nonverbal, uses short words, verbal).RESULTSDistance phoria did not differ significantly between groups. Near phoria of ASD subjects was more exophoric (difference, 2.8 prism diopters). Mean near point of convergence break and recovery were 7.0 and 8.02 cm, respectively, in ASD subjects and 2.19 and 3.99 cm in TD subjects. Near fusional divergence and convergence showed no significant difference. Autism spectrum disorder subjects had significantly poorer stereoacuity (P < .0001) and, on Northeastern State University College of Optometry Oculomotor Testing, reduced fixation, poorer accuracy and stamina/ability, and increased head and body movement. Monocular estimation method retinoscopy results did not differ significantly between ASD and TD subjects. No significant differences in phoria, near point of convergence, and near fusional divergence or convergence were observed between ASD subgroups (nonverbal, uses short words, verbal).CONCLUSIONSAutism spectrum disorder children are more likely to show receded near point of convergence, poor fixation, inaccurate saccades, erratic pursuits, and exophoric posture. These differences occur, regardless of reported verbal communication level.

Development of Lower Extremity Strength in Ambulatory Children With Bilateral Spastic Cerebral Palsy in Comparison With Typically Developing Controls Using Absolute and Normalized to Body Weight Force Values

This cross-sectional study aimed to examine the development of lower limb voluntary strength in 160 ambulatory patients with bilateral spastic cerebral palsy (CP) (106 diplegics/54 quadriplegics) and 86 typically developing (TD) controls, aged 7–16 years. Handheld dynamometry was used to measure isometric strength of seven muscle groups (hip adductors and abductors, hip extensors and flexors, knee extensors and flexors, and ankle dorsiflexors); absolute force (AF) values in pounds were collected, which were then normalized to body weight (NF). AF values increased with increasing age (p < 0.001 for all muscle groups), whereas NF values decreased through adolescence (p < 0.001 for all muscle groups except for hip abduction where p = 0.022), indicating that increases in weight through adolescence led to decreases in relative force. Both AF and NF values were significantly greater in TD subjects when compared with children with CP in all muscle and all age groups (p < 0.001). Diplegics and quadriplegics demonstrated consistently lower force values than TD subjects for all muscle groups, except for the hip extensors where TD children had similar values with diplegics (p = 0.726) but higher than quadriplegics (p = 0.001). Diplegic patients also exhibited higher values than quadriplegics in all muscles, except for the knee extensors where their difference was only indicative (p = 0.056). The conversion of CP subjects' force values as a percentage of the TD subjects' mean value revealed a pattern of significant muscle strength imbalance between the CP antagonist muscles, documented from the following deficit differences for the CP muscle couples: (hip extensors 13%) / (hip flexors 32%), (adductors 27%) / (abductors 52%), and (knee extensors 37%) / (knee flexors 53%). This pattern was evident in all age groups. Similarly, significant force deficiencies were identified in GMFCS III/IV patients when compared with TD children and GMFCS I/II patients. In this study, we demonstrated that children and adolescents with bilateral CP exhibited lower strength values in lower limb muscles when compared with their TD counterparts. This difference was more prevalent in quadriplegic patients and those with a more severe impairment. An important pattern of muscle strength imbalance between the antagonist muscles of the CP subjects was revealed.

Performance in a gaze-cueing task is associated with autistic traits.

Individuals with autism spectrum disorder (ASD) show impairments in processing social cues such as facial expressions and gaze direction. Several researchers have proposed that autistic traits form a continuum that may be distributed within the general, typically developed, population. Accordingly, several studies have indicated that typically developed individuals with high levels of self-reported autistic traits have autistic-like performance in a variety of paradigms. Here, we designed a gaze-cueing task to examine whether gaze-triggered orienting is related to the extent of typically developed (TD) individuals' autistic traits (determined by their AQ test scores) and whether it is modulated by previous eye contact and different facial expressions. At each trial, TD subjects observed faces with or without eye contact. This facial stimulus then gazed toward the left or right side. Finally, a target appeared on the left or right side of the display and reaction time (RT) to the target was measured. RTs were modulated by congruency between gazing directions and target locations, and by prior eye contact in the congruent trials. In addition, individuals with higher AQ scores were slower at detecting the target when the cue was a happy face. Furthermore, faster RTs in congruent trials were associated with one specific autistic trait (attention switching deficits). Together, these results indicate that autistic traits may influence performance in a gaze cueing task.

An Association Between Serotonin 1A Receptor, Gray Matter Volume, and Sociability in Healthy Subjects and in Autism Spectrum Disorder.

Central serotonin is an important molecular pathway, involved in the regulation of social behavior and gray matter volume (GMV). In men with autism spectrum disorders (ASD), the serotonergic system and the GMV have been found disrupted. Here, we investigated the relation between serotonin, GMV, and social personality in men with typical development (TD) and in men with ASD. We combined anatomical magnetic resonance imaging, Positron emission tomography scan with 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine radioligand and revised NEO personality inventory personality questionnaire to examine the association between serotonin 1A receptor (5-HT1A R) binding potential, GMV and social personality in 24 adult male TD subjects and 18 male men with ASD. In both groups, we found a positive correlation between 5-HT1A R binding potential and GMV in a region dependent manner. In the TD group, we observed a negative correlation between 5-HT1A R and GMV in the left and right posterior putamen. 5HT1A R binding and GMV in the putamen further correlated with social personality scores in the TD group. None of these associations were found in men with ASD, although no differences were observed for 5-HT1A R concentration among the two groups. Our findings point to a deregulation of 5-HT1A R density in the striatum of men with ASD, a failure that might contribute to their social disturbances. Serotonin is suspected to be involved in the pathophysiology of autism. We provide evidence for a role of serotonin 1A receptor in social behavior through a specific regulation of GMV in the putamen region in neurotypical subjects but not in men with autism. This suggests a potential impairment of the serotonergic system in men with autism which may contribute to patients' social disturbances. Our findings suggest further investigation on the role of serotonin 1A receptor and its activity in the striatum to regulate social behavior. Autism Res 2020, 13: 1843-1855. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: Serotonin is suspected to be involved in the pathophysiology of autism. We provide evidence for a role of serotonin 1A receptor in social behavior through a specific regulation of gray matter volume in the putamen region in neurotypical subjects but not in men with autism. This suggests a potential impairment of the serotonergic system in men with autism which may contribute to patients' social disturbances. Our findings suggest further investigation on the role of serotonin 1A receptor and its activity in the striatum to regulate social behavior.

In vivo imaging of dopamine D1 receptor and activated microglia in attention-deficit/hyperactivity disorder: a positron emission tomography study.

Alterations in the cortical dopamine system and microglial activation have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), one of neurodevelopmental disorders that can be conventionally treated with a dopamine enhancer (methylphenidate) albeit unsatisfactorily. Here, we investigated the contributions of the dopamine D1 receptor (D1R) and activated microglia and their interactions to the clinical severities in ADHD individuals using positron emission tomography (PET). Twenty-four psychotropic-naïve ADHD individuals and 24 age- and sex-matched typically developing (TD) subjects underwent PET measurements with [11C]SCH23390 for the D1R and [11C](R)PK11195 for activated microglia as well as assessments of clinical symptoms and cognitive functions. The ADHD individuals showed decreased D1R in the anterior cingulate cortex (ACC) and increased activated microglia in the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) compared with the TD subjects. The decreased D1R in the ACC was associated with severe hyperactivity in the participants with ADHD. Microglial activation in the DLPFC were associated with deficits in processing speed and attentional ability, and that in the OFC was correlated with lower processing speed in the ADHD individuals. Furthermore, positive correlations between the D1R and activated microglia in both the DLPFC and the OFC were found to be significantly specific to the ADHD group and not to the TD group. The current findings suggest that microglial activation and the D1R reduction as well as their aberrant interactions underpin the neurophysiological mechanism of ADHD and indicate these biomolecular changes as a novel therapeutic target.

Neural responses in autism during movie watching: Inter-individual response variability co-varies with symptomatology

Naturalistic movie paradigms are exquisitely dynamic by nature, yet dedicated analytical methods typically remain static. Here, we deployed a dynamic inter-subject functional correlation (ISFC) analysis to study movie-driven functional brain changes in a population of male young adults diagnosed with autism spectrum disorder (ASD). We took inspiration from the resting-state research field in generating a set of whole-brain ISFC states expressed by the analysed ASD and typically developing (TD) subjects along time.Change points of state expression often involved transitions between different scenes of the movie, resulting in the reorganisation of whole-brain ISFC patterns to recruit different functional networks. Both subject populations showed idiosyncratic state expression at dedicated time points, but only TD subjects were also characterised by episodes of homogeneous recruitment. The temporal fluctuations in both quantities, as well as in cross-population dissimilarity, were tied to contextual movie cues.The prominent idiosyncrasy seen in ASD subjects was linked to individual symptomatology by partial least squares analysis, as different temporal sequences of ISFC states were expressed by subjects suffering from social and verbal communication impairments, as opposed to nonverbal communication deficits and stereotypic behaviours. Furthermore, the temporal expression of several of these states was correlated with the movie context, the presence of faces on screen, or overall luminosity.Overall, our results support the use of dynamic analytical frameworks to fully exploit the information obtained by naturalistic stimulation paradigms. They also show that autism should be understood as a multi-faceted disorder, in which the functional brain alterations seen in a given subject will vary as a function of the extent and balance of expressed symptoms.

Inter-hemispheric Asymmetry Patterns in the ADHD Brain: A Neuroimaging Replication Study.

Attention-deficit/ hyperactivity disorder (ADHD) is the most common neurodevelopment disorder in children, and many genetic markers have been linked to the behavioral phenotypes of this highly heritable disease. The neuroimaging correlates are similarly complex, with multiple combinations of structural and functional alterations associated with the disease presentations of hyperactivity and inattentiveness. Thus far, neuroimaging studies have provided mixed results in ADHD patients, particularly with respect to the laterality of findings. It is possible that hemispheric asymmetry differences may help reconcile the variability of these findings. We recently reported that inter-hemispheric asymmetry differences were more sensitive descriptors for identifying differences between ADHD and typically developing (TD) brains (n=849) across volumetric, morphometric, and white matter neuroimaging metrics. Here, we examined the replicability of these findings across a new data set (n=202) of TD and ADHD subjects at the time of diagnosis (medication naive) and after a six week course of either stimulant drugs, non-stimulant medications, or combination therapy. Our findings replicated our earlier work across a number of volumetric and white matter measures confirming that asymmetry is more robust at detecting differences between TD and ADHD brains. However, the effects of medication failed to produce significant alterations across either lateralized or symmetry measures. We suggest that the delay in brain volume maturation observed in ADHD youths may be hemisphere dependent. Future work may investigate the extent to which these inter-hemispheric asymmetry differences are causal or compensatory in nature.

Self-Regulation of the Fusiform Face Area in Autism Spectrum: A Feasibility Study With Real-Time fMRI Neurofeedback.

One of the most important and early impairments in autism spectrum disorder (ASD) is the abnormal visual processing of human faces. This deficit has been associated with hypoactivation of the fusiform face area (FFA), one of the main hubs of the face-processing network. Neurofeedback based on real-time fMRI (rtfMRI-NF) is a technique that allows the self-regulation of circumscribed brain regions, leading to specific neural modulation and behavioral changes. The aim of the present study was to train participants with ASD to achieve up-regulation of the FFA using rtfMRI-NF, to investigate the neural effects of FFA up-regulation in ASD. For this purpose, three groups of volunteers with normal I.Q. and fluent language were recruited to participate in a rtfMRI-NF protocol of eight training runs in 2 days. Five subjects with ASD participated as part of the experimental group and received contingent feedback to up-regulate bilateral FFA. Two control groups, each one with three participants with typical development (TD), underwent the same protocol: one group with contingent feedback and the other with sham feedback. Whole-brain and functional connectivity analysis using each fusiform gyrus as independent seeds were carried out. The results show that individuals with TD and ASD can achieve FFA up-regulation with contingent feedback. RtfMRI-NF in ASD produced more numerous and stronger short-range connections among brain areas of the ventral visual stream and an absence of the long-range connections to insula and inferior frontal gyrus, as observed in TD subjects. Recruitment of inferior frontal gyrus was observed in both groups during FAA up-regulation. However, insula and caudate nucleus were only recruited in subjects with TD. These results could be explained from a neurodevelopment perspective as a lack of the normal specialization of visual processing areas, and a compensatory mechanism to process visual information of faces. RtfMRI-NF emerges as a potential tool to study visual processing network in ASD, and to explore its clinical potential.

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children.MethodsGenome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis.ResultsWhile cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR q < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions.LimitationsASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder.ConclusionsThis is the first study to identify gene expression differences in cord blood specific to ASD through a meta-analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.

Integrated Analysis of microRNA and mRNA Expression Profiles: An Attempt to Disentangle the Complex Interaction Network in Attention Deficit Hyperactivity Disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood-onset neurodevelopmental disorder, whose etiology and pathogenesis are still largely unknown. In order to uncover novel regulatory networks and molecular pathways possibly related to ADHD, we performed an integrated miRNA and mRNA expression profiling analysis in peripheral blood samples of children with ADHD and age-matched typically developing (TD) children. The expression levels of 13 miRNAs were evaluated with microfluidic qPCR, and differentially expressed (DE) mRNAs were detected on an Illumina HiSeq 2500 genome analyzer. The miRNA targetome was identified using an integrated approach of validated and predicted interaction data extracted from seven different bioinformatic tools. Gene Ontology (GO) and pathway enrichment analyses were carried out. Results showed that six miRNAs (miR-652-3p, miR-942-5p, let-7b-5p, miR-181a-5p, miR-320a, and miR-148b-3p) and 560 genes were significantly DE in children with ADHD compared to TD subjects. After correction for multiple testing, only three miRNAs (miR-652-3p, miR-148b-3p, and miR-942-5p) remained significant. Genes known to be associated with ADHD (e.g., B4GALT2, SLC6A9 TLE1, ANK3, TRIO, TAF1, and SYNE1) were confirmed to be significantly DE in our study. Integrated miRNA and mRNA expression data identified critical key hubs involved in ADHD. Finally, the GO and pathway enrichment analyses of all DE genes showed their deep involvement in immune functions, reinforcing the hypothesis that an immune imbalance might contribute to the ADHD etiology. Despite the relatively small sample size, in this study we were able to build a complex miRNA-target interaction network in children with ADHD that might help in deciphering the disease pathogenesis. Validation in larger samples should be performed in order to possibly suggest novel therapeutic strategies for treating this complex disease.

Paternal age contribution to brain white matter aberrations in autism spectrum disorder.

Although advanced parental age holds an increased risk for autism spectrum disorder (ASD), its role as a potential risk factor for an atypical white matter development underlying the pathophysiology of ASD has not yet been investigated. The current study was aimed to detect white matter disparities in ASD, and further investigate the relationship of paternal and maternal age at birth with such disparities. Thirty-nine adult males with high-functioning ASD and 37 typically developing (TD) males were analyzed in the study. The FMRIB Software Library and tract-based spatial statistics were utilized to process and analyze the diffusion tensor imaging data. Subjects with ASD exhibited significantly higher mean diffusivity (MD) and radial diffusivity (RD) in white matter fibers, including the association (inferior fronto-occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculi, uncinate fasciculus, and cingulum), commissural (forceps minor), and projection tracts (anterior thalamic radiation and right corticospinal tract) compared to TD subjects (Padjusted < 0.05). No differences were seen in either fractional anisotropy or axial diffusivity. Linear regression analyses assessing the relationship between parental ages and the white matter aberrations revealed a positive correlation between paternal age (PA), but not maternal age, and both MD and RD in the affected fibers (Padjusted < 0.05). Multiple regression showed that only PA was a predictor of both MD and RD. Our findings suggest that PA contributes to the white matter disparities seen in individuals with ASD compared to TD subjects.

NCREANN: Nonlinear Causal Relationship Estimation by Artificial Neural Network; Applied for Autism Connectivity Study.

Quantifying causal (effective) interactions between different brain regions are very important in neuroscience research. Many conventional methods estimate effective connectivity based on linear models. However, using linear connectivity models may oversimplify the functions and dynamics of the brain. In this paper, we propose a causal relationship estimator called nonlinear Causal Relationship Estimation by Artificial Neural Network (nCREANN) that identifies both linear and nonlinear components of effective connectivity in the brain. Furthermore, it can distinguish between these two types of connectivity components by calculating the linear and nonlinear parts of the network input-output mapping. The nCREANN performance has been verified using synthesized data and then it has been applied on EEG data collected during rest in children with autism spectrum disorder (ASD) and typically developing (TD) children. The results show that overall linear connectivity in TD subjects is higher, while the nonlinear connectivity component is more dominant in ASDs. We suggest that our findings may represent different underlying neural activation dynamics in ASD and TD subjects. The results of nCREANN may provide new insight into the connectivity between the interactive brain regions.