Volume-based and Surface-Based Methods in Autism Compared with Healthy Controls Are Free surfer and CAT12 in Agreement?

Autism spectrum disorder (ASD) is a neuropsychiatric childhood disorder that affects social skill and language development, and is characterized by persistent stereotypic behaviors, restricted social interests, and impaired language/social skills. ASD subjects have dysregulated immune responses due to impairment in inflammatory and antioxidant signaling in immune cells, such as T cells. Thioredoxin reductase-1 (TrxR1) and thioredoxin-1 (Trx1) play a crucial role in the maintenance of redox equilibrium in several immune cells, including T cells. T-cell apoptosis plays a crucial role in the pathogenesis of several inflammatory diseases. However, it remains to be explored how the TrxR1/Trx1 redox couple affects T-cells apoptosis in ASD and typically developing control (TDC) groups. Therefore, this single-center cross-sectional study explored the expression/activity of TrxR1/Trx1, and Bcl2, 7-AAD/annexin V immunostaining in T cells of ASD (n = 25) and TDC (n = 22) groups. Further, effects of the LPS were determined on apoptosis in TDC and ASD T cells. Our data show that T cells have increased TrxR1 expression, while having decreased Trx1 expression in the ASD group. Further, TrxR enzymatic activity was also elevated in T cells of the ASD group. Furthermore, T cells of the ASD group had a decreased Bcl2 expression and an increased % of annexin V immunostaining. Treatment of T cells with LPS caused greater apoptosis in the ASD group than the TDC group, with same treatment. These data reveal that the redox couple TrxR1/Trx1 is dysregulated in T cells of ASD subjects, which is associated with decreased Bcl2 expression and increased apoptosis. This may lead to decreased survival of T cells in ASD subjects during chronic inflammation. Future studies should investigate environmental factors, such as gut dysbiosis and pollutants, that may cause abnormal immune responses in the T cells of ASD subjects due to chronic inflammation.

Attention orienting is a cognitive process that facilitates the movement of attention focus from one location to another: this may be impaired in autism spectrum disorder (ASD). Dorsal and ventral attention networks (DAN and VAN) sub-serve the process of attention orienting. This study investigated the functional connectivity of attention orienting in these networks in ASD using the Posner Cueing Task. Twenty-one adolescents with ASD and 21 age and IQ matched controls underwent functional magnetic resonance imaging. A psychophysical interaction (PPI) analysis was implemented to investigate task-dependent functional connectivity, measuring synchronicity of brain regions during the task. Regions of interest (ROI) were selected to explore functional connectivity in the DAN during cue-only conditions and in the VAN during invalid and valid trials. Behaviourally, the ASD and control groups performed the task in a similar manner. Functional MRI results indicated that the ASD and control groups activated similar brain regions. During invalid trials (VAN), the ASD group showed significant positive functional connectivity to multiple brain regions, whilst the control group demonstrated negative connectivity. During valid trials (VAN), the two groups also showed contrasting patterns of connectivity. In the cue-only conditions (DAN), the ASD group showed weaker functional connectivity. The DAN analysis suggests that the ASD group has weaker coherence between brain areas involved in goal-driven, endogenous attention control. The strong positive functional connectivity exhibited by the ASD group in the VAN during the invalid trials suggests that individuals with ASD may generate compensatory mechanisms to achieve neurotypical behaviour. These results support the theory of abnormal cortical connectivity in autism.

Individuals with autism spectrum disorders (ASD) often exhibit difficulties in sensory processing, including visual hypersensitivity such as photophobia. This study investigates the neural mechanisms underlying photophobia in participants with ASD by analyzing pupillary responses. To achieve this, we examined the amplitude and velocity gradient (latency) of these responses. Pupillary responses were recorded using an eye-tracking system in participants with ASD (n = 17) and typically developing (TD) (n = 23). Stimuli alternated between bright (89.03 cd/m2) and dark (0.07 cd/m2) conditions following a dim state (2.75 cd/m2) with intervals of five seconds in Experiment 1 and 30 seconds in Experiment 2. The sensory profile test (AASP-J) showed that hypersensitivity was significantly defined in the ASD group than in the TD group. The pupillary response in the ASD group often featured missing values due to blinking during rapid alternation between bright and dark conditions, resulting in a decrease in the total number of participants. Specifically, only eight of the 17 participants in the ASD group and 20 of the 23 participants in the TD group remained for analysis in Experiment 1, and in Experiment 2, 15 of the 17 participants in the ASD group and 20 of the 23 participants in the TD group remained for analysis. In the dim state, pupillary diameter was large in the ASD and TD group in both experiments, while the pupil diameter decreased in the TD group in Experiment 2. In both experiments, maximum amplitude and its latency showed no significant differences between the two groups. However, the velocity gradient for the early mydriatic process in the dark condition was significantly faster in the ASD group. ASD individuals with hypersensitivity tend to have large pupil diameters under the dim state, as well as rapid dilation in the dark condition. These results may suggest a problem in the sympathetic nervous system, which controls pupil constriction.

Neurological, structural, and behavioral abnormalities are widely reported in individuals with autism spectrum disorder (ASD); yet there are no objective markers to date. We postulated that by using dominant and nondominant ear data, underlying differences in auditory evoked potentials (AEPs) between ASD and control groups can be recognized. The primary purpose was to identify if significant differences exist in AEPs recorded from dominant and nondominant ear stimulation in (1) children with ASD and their matched controls, (2) adults with ASD and their matched controls, and (3) a combined child and adult ASD group and control group. The secondary purpose was to explore the association between the significant findings of this study with those obtained in our previous study that evaluated the effects of auditory training on AEPs in individuals with ASD. Factorial analysis of variance with interaction was performed. Forty subjects with normal hearing between the ages of 9 and 25 years were included. Eleven children and 9 adults with ASD were age- and gender-matched with neurotypical peers. Auditory brainstem responses (ABRs) and auditory late responses (ALRs) were recorded. Adult and child ASD subjects were compared with non-ASD adult and child control subjects, respectively. The combined child and adult ASD group was compared with the combined child and adult control group. No significant differences in ABR latency or amplitude were observed between ASD and control groups. ALR N1 amplitude in the dominant ear was significantly smaller for the ASD adult group compared with their control group. Combined child and adult data showed significantly smaller amplitude for ALR N1 and longer ALR P2 latency in the dominant ear for the ASD group compared with the control group. In our earlier study, the top predictor of behavioral improvement following auditory training was ALR N1 amplitude in the dominant ear. Correspondingly, the ALR N1 amplitude in the dominant ear yielded group differences in the current study. ALR peak N1 amplitude is proposed as the most feasible AEP marker in the evaluation of ASD.

Studies suggest that trace element and vitamin deficiencies are common in children with autism spectrum disorder (ASD). Data describing the rates of vitamin and trace element deficiencies in the ASD population of the northwest of Ireland is lacking. We wished to determine the prevalence of zinc and vitamin A deficiency in the ASD population compared with controls within this geographical area. Parents of children aged 2-18years with ASD were invited to participate in the study. The control group consisted of well children attending the paediatric department for routine blood sampling. Children on vitamin supplements were excluded from both ASD and control groups. Informed written consent was obtained prior to recruitment. Samples were analysed for zinc and vitamin A levels according to standardized laboratory procedures. Seventy-four of the 150 children with ASD who were invited and 72 controls underwent blood sampling. Mean zinc and vitamin A levels were normal in both groups. There were significantly more males in the ASD group (88% versus 56%, p value<0.001). The mean (SD) zinc level was not different between the groups (ASD 11.7 [1.7] versus control 11.6 [2.1] μmol/L, p value=0.86). The mean (standard deviation) vitamin A level was higher in the ASD group (ASD 350.6 [82.6] versus 319.2 [82.8] μg/L, p value=0.03), but this was likely confounded by age. Children with ASD in the northwest of Ireland have mean zinc and vitamin A levels within the normal range. It is important that these findings are relayed to health professionals and to parents of children with ASD so that informed decisions on vitamin supplementation can be made.

Background/Objectives: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impairments in social interaction and communication, as well as by repetitive behaviors, with a rising global prevalence. Concurrently, the use of Assisted Reproductive Technologies (ART) has increased among couples experiencing infertility. This study aimed to compare the frequency of ART-conceived children between those diagnosed with ASD and those with other neurodevelopmental disorders (nASD), and to examine differences in prenatal, perinatal and medical histories of ART- and spontaneously (non-ART)-conceived children within an ASD group. Methods: We retrospectively analyzed data from 507 children with a neurodevelopmental disorders (NDDs) diagnosis, classified into ASD (n = 234) and nASD (n = 273) groups. Subsequent analyses focused on the ASD group, further divided into an ART and non-ART group according to the conception mode. Results: ART-conceived children were more frequent in the ASD group than in the nASD group. Moreover, within ASD, ART was significantly associated with potential risk factors such as twin pregnancy, cesarean delivery, low birth weight and parental age. Logistic Binary Regression confirmed these results, suggesting that ART co-occurs with a cluster of perinatal and familial risk factors. Conclusions: Our results indicate that ART is not an independent causal exposure; however, given the retrospective design and the absence of a general population control group, causal inference cannot be drawn. The observed association with ASD appears to be mediated by perinatal and parental variables. These findings underscore the importance of improving obstetric management and care, and ensuring early developmental monitoring for ART-conceived children.

We investigated manifestations of jealousy in preschoolers (n=32) with autism spectrum disorder (ASD) and in a group of typically developing children (n=18) matched on mental age, verbal mental age, nonverbal mental age, and mother's education. Main results revealed explicit indices of jealousy in two thirds of the children with ASD compared with 94.5% in the typical group. In addition, different manifestations of this emotion emerged in the ASD group compared with the matched control group. Regarding mental and affective correlates of jealousy, expressions of jealousy correlated with IQ only for the children in the ASD group, and the ASD group revealed deficient emotional responsiveness (ER) capabilities. Significant correlations emerged between jealousy and ER in both the ASD and control groups. Discussion focuses on implications of these findings for understanding the core emotional deficit in autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, which has increased markedly during the last decades. Essential trace elements play an important role in neurological function and their imbalances are common in children with ASD. The objective of the present study was to investigate whole blood levels of trace elements including zinc (Zn), copper (Cu), iron (Fe), and magnesium (Mg) in Chinese children with ASD. In total, 113 children diagnosed with ASD and 141 age-matched and gender-matched neurotypical children, divided into two gender and age groups of preschool age (2-5years old) and school (6-10years old) age, were examined. The quantitative analyses of whole blood trace element contents were performed by using flame atomic absorption spectroscopy. In the present study, the children with ASD generally had lower whole blood levels of Zn than the neurotypical controls. No significant differences in the whole blood Cu, Zn/Cu ratio, Fe, or Mg was detected between the ASD group and the control group. It is notable that whole blood Fe level in boys with ASD was significantly higher than in girls with ASD, and was nearly significant when compared with the control level of boys. After stratification for age, a significant 6% decrease in whole blood Zn levels was detected in preschool-aged children with ASD as compared to the control values. However, this significant ASD-related change was not detected in school-aged children. The whole blood Zn level and Zn/Cu ratio were significantly increased in school-aged children than in preschool-aged children in both ASD and control group. In addition, school-aged children with ASD had a significantly higher level of whole blood Fe than preschool-aged children with ASD. The results of the present study suggest an association between whole blood levels of Zn in Chinese children with ASD.

BackgroundAccumulating evidence for the co-occurrence Autism spectrum disorder (ASD) and schizotypal personality disorder (SPD) at both the diagnostic and symptom/trait levels raises important questions about the nature of their association and the effect of their co-occurrence on the individual’s phenotype and functional outcome. It has been recommend that informing etiological and phenotypic overlaps between ASD and schizophrenia spectrum disorders (SSD) would require the utilization of a dual-diagnosis cohort compared with two control groups, each singly diagnosed with ASD or SSD, and that the development of a multidimensional model for understanding the relationship between these two spectra would require cohorts to be described not solely by diagnosis, but also by using dimensional measures that cut across diagnostic boundaries. Research comparing adults with ASD and SPD, as well as the impact of their co-occurrence on outcomes is extremely limited. To fill in this gap, we investigated executive functioning in terms of response inhibition and sustained attention, candidate endophenotypes of both conditions, in adults with ASD, SPD, comorbid ASD and SPD, and neurotypical adults using both categorical and dimensional approaches.MethodsA total of 88 adults (Mean Age ± SD = 37.54 ± 10.17): ASD (n = 26; m/f = 20/6); SPD (n = 20; m/f = 14/6); comorbid ASD and SPD (n=9; m/f =6/3) and neurotypicals (n=33; m/f =23/10) completed the Sustained Attention to Response Task (SART) in both its fixed and random forms.Individuals with ASD had a DSM-IV diagnosis of either autism or Asperger Syndrome and met ASD cut-offs on the Autism Diagnostic Observational Schedule-Generic (ADOS-G). All individuals with SPD met DSM-IV criteria for SPD using the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II). Individuals in the comorbid group met criteria for both ASD (determined by DSM-IV and the ADOS) and SPD (determined by the SCID-II). In addition, in both the clinical and healthy participants, positive and autistic symptom severity were assessed with the positive subscale of the Positive and Negative Syndrome Scale (PANSSpos) and the PANSS Autism Severity Score (PAUSS), respectively.ResultsControlling for full scale IQ, working memory and medication dosage, group analyses revealed that the comorbid group committed fewer omission errors than the ASD group on the fixed SART, and fewer omission errors than the ASD and SPD groups on the random SART. The individual difference analyses revealed that the PANSSpos and PAUSS interactively reduced omission errors in both the fixed and random SARTs, as well as increased d’ scores, indicative of improved overall performance.DiscussionConcurrent elevated levels of autistic and positive psychotic symptoms seem to be associated with improved sustained attention abilities. We propose that sustaining and switching attention may represent two poles of irregularities across the autism and schizotypal spectra, which appear to converge in a compensatory manner in the comorbid group. Our findings highlight the importance of investigating the concurrent effect of ASD and SPD at both the symptom and diagnostic levels, and the potential benefit of this research approach to understanding the underlying mechanisms of seemingly overlapping phenotypes.

Autism spectrum disorder (ASD) is a neurodevelopmental disability with global implication. Altered brain connectivity in the language network has frequently been reported in ASD patients using task-based functional magnetic resonance imaging (fMRI) compared to typically developing (TD) participants. Most of these studies have focused on a specific age group or mixed age groups with ASD. In the current study, we investigated age-related changes in functional connectivity related measure, degree centrality (DC), in the language network across three age groups with ASD (113 children, 113 adolescents and 103 adults) using resting-state fMRI data collected from the autism brain imaging data exchange repository. We identified regions with significant group-wise differences between ASD and TD groups for three age cohorts using DC based on graph theory. We found that both children and adolescents with ASD showed decreased DC in Broca’s area compared to age-matched TD groups. Adults with ASD showed decreased DC in Wernicke’s area compared to TD adults. We also observed increased DC in the left inferior parietal lobule (IPL) and left middle temporal gyrus (MTG) for children with ASD compared to TD children and for adults with ASD compared to TD adults, respectively. Overall, functional differences occurred in key language processing regions such as the left inferior frontal gyrus (IFG) and superior temporal gyrus (STG) related to language production and comprehension across three age cohorts. We explored correlations between DC values of our findings with autism diagnostic observation schedule (ADOS) scores related to severity of ASD symptoms in the ASD group. We found that DC values of the left IFG demonstrated negative correlations with ADOS scores in children and adolescents with ASD. The left STG showed significant negative correlations with ADOS scores in adults with ASD. These results might shed light on the language network regions that should be further explored for prognosis, diagnosis, and monitoring of ASD in three age groups.

Background:Brain-derived neurotrophic factor (BDNF) is a key factor in neurodevelopment of autism spectrum disorder (ASD), yet the variability of peripheral BDNF levels in ASD remains debated. We sought to investigate the relationship between circulating oxidative stress and peripheral BDNF in children with ASD.Methods:We analyzed plasma BDNF levels and redox status in both plasma and peripheral blood mononuclear cells (PBMCs) among children with ASD and typically developing (TD) children aged 2–5 years. We generated an autism-like mouse model via prenatal exposure to medroxyprogesterone acetate (MPA). To modulate circulating redox balance, we employed tyrosine kinase–driven lentiviral expression of superoxide dismutase 2 (Sod2) and hematopoietic stem cell (HSC) transplantation with Sod2 overexpression. We then assessed circulating redox balance, gene expression, epigenetic changes, peripheral BDNF levels, and autism-like behaviours in offspring.Results:We included 78 children in the ASD group and 63 children in the TD group. Children with ASD exhibited elevated plasma BDNF levels and an altered redox balance compared with TD controls. In the mouse model, MPA-exposed autism-like offspring demonstrated increased peripheral BDNF levels and heightened oxidative stress in hematopoietic stem cells, endothelial cells, and PBMCs. Tyrosine kinase–Sod2 lentiviral expression in the endothelium fully normalized peripheral BDNF levels, while HSC transplantation with Sod2 overexpression not only reduced plasma BDNF levels, but also alleviated autism-like behaviours.Limitations:This study’s cross-sectional data limit causal inference between oxidative stress and BDNF levels among children with ASD. The mouse model, while informative, may not fully recapitulate human ASD heterogeneity.Conclusion:In ASD, elevated peripheral BDNF levels are associated with circulating oxidative stress. Prenatal progestin exposure induces both increased peripheral BDNF and oxidative stress, effects that can be completely reversed through SOD2 modulation in circulation among mouse offspring.

Assisted reproductive technology and risk for autism spectrum disorder

Gut microbiota and their metabolic products might play important roles in regulating the pathogenesis of autism spectrum disorder (ASD). The purpose of this study was to characterize gut microbiota and serum amino acid metabolome profiles in children with ASD. A non-randomized controlled study was carried out to analyze the alterations in the intestinal microbiota and their metabolites in patients with ASD (n = 30) compared with neurotypical controls (NC) (n = 30) by metagenomic sequencing to define the gut microbiota community and liquid chromatography/mass spectrometry (LC/MS) analysis to characterize the metabolite profiles. Compared with children in the NC group, those in the ASD group showed lower richness, higher evenness, and an altered microbial community structure. At the class level, Deinococci and Holophagae were significantly lower in children with ASD compared with TD. At the phylum level, Deinococcus-Thermus was significantly lower in children with ASD compared with TD. In addition, the functional properties (such as galactose metabolism) displayed significant differences between the ASD and NC groups. Five dominant altered species were identified and analyzed (LDA score > 2.0, P < 0.05), including Subdoligranulum, Faecalibacterium_praushitzii, Faecalibacterium, Veillonellaceae, and Rumminococcaceae. The peptides/nickel transport system was the main metabolic pathway involved in the differential species in the ASD group. Decreased ornithine levels and elevated valine levels may increase the risk of ASD through a metabolic pathway known as the nickel transport system. The microbial metabolism in diverse environments was negatively correlated with phascolarctobacterium succinatutens. Our study provides novel insights into compositional and functional alterations in the gut microbiome and metabolite profiles in ASD and the underlying mechanisms between metabolite and ASD.

Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other-DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other-DD including intellectual disability and language disorder) according to DSM-IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (DNUM ) and the tract-averaged fractional anisotropy (DFA ) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other-DD groups. The network differences resulted in an over-connectivity pattern (i.e., higher DNUM and DFA values) in the ASD group with a significance of P < 0.05. No contra-comparison results were found. The over-connectivity pattern in ASD occurred in networks primarily involving the fronto-temporal nodes, known to be crucial for social-skill development and basal ganglia, related to restricted and repetitive behaviours in ASD. To our knowledge, this is the first network-based diffusion study comparing toddlers with ASD and those with other-DD. Results indicate the detection of different connectivity patterns in ASD and other-DD at an age when clinical differential diagnosis is often challenging. Hum Brain Mapp 38:2333-2344, 2017. © 2017 Wiley Periodicals, Inc.

Objective:Many studies supported that children with autism spectrum disorder (ASD) have worse executive functions (EFs) when compared to typically developmental (TD) children in many domains, such as planning, flexibility, inhibition, and self-monitoring. The current study aims to use an adapted version of the computerized tower test to investigate the EFs of children with ASD. Furthermore, the researcher also assessed children's EFs-related behaviors in their schools using a teacher-filled behavior rating inventory of executive function, 2nd edition (BRIEF-2).Participants and Methods:61 Children aged 7 to 12 years old (M = 9.23) were included in the current study. 29 of them were in the ASD group, and 31 of them were in the TD group. All participants conducted an adapted computerized tower test. All participants' teachers completed BRIEF-2 to investigate their EFs-related behaviors in their schools.Results:The results indicated that there were no significant differences in the tower test between the ASD group and TD group in all indexes. Therefore, it implied that the current indexes might not be sensitive enough to distinguish whether a child has ASD or not. In addition, we further investigate the correlations between the tower test and the teacher-filled BRIEF-2. We found the different patterns in the two groups. In the ASD group, we found that the task-monitor index was positively correlated with total-number-of-rule-violations, total-complete-time, and total-rule-violations-per-item-ratio. The task-monitor index was negatively correlated with total-achievement-score, implying that poorer ability to monitor tasks leads to a longer completion time, more rule violations, and a lower total achievement score. Moreover, we also found a high correlation between the organization-of-materials in BRIEF-2 and total-complete-time in the tower test, suggesting the long problem-solving time in ASD groups is highly related to the disability of keeping working space ordered. In addition, we found that the shift index is positively correlated with total-complete-time and total-rule-violations-per-item-ratio. Hence, it indicates that those with poor flexibility in solving problems tend to need more time to complete tasks and violate more rules in ASD groups. In the TD group, we only found the correlation effects were significant between inhibition and self-monitor in the BRIEF-2 and the total-rule-violations-per-item-ratio in the tower test. It suggested that individuals with behavioral regulation problems, such as impulse control and monitoring problems are more likely to make rule violations. The result indicated that behavioral regulations play a more significant role in the TD group. In contrast, cognitive and emotional regulations are more critical in ASD children.Conclusions:Our findings found no significant difference in the computerized tower test between children with and without ASD, suggesting that the current indexed might not be sensitive enough to differentiate children with or without ASD. However, the results of the correlation between the tower test and teacher-filled BRIEF-2 showed that different patterns might be the cause of the EF performances between the two groups, indicating that there might be a different domain of EFs the children used in the tower test between two groups.Therefore, further research could focus on developing new indexes in the Tower test and finding the EF mechanism of ASD children with different approaches.