Classification of autism spectrum disorder using electroencephalography in Chinese children: a cross-sectional retrospective study.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by diverse clinical features. EEG biomarkers such as spectral power and functional connectivity have emerged as potential tools for enhancing early diagnosis and understanding of the neural processes underlying ASD. However, existing studies yield conflicting results, necessitating a comprehensive, data-driven analysis. We conducted a retrospective cross-sectional study involving 246 children with ASD and 42 control children. EEG was collected, and diverse EEG features, including spectral power and spectral coherence were extracted. Statistical inference methods, coupled with machine learning models, were employed to identify differences in EEG features between ASD and control groups and develop classification models for diagnostic purposes. Our analysis revealed statistically significant differences in spectral coherence, particularly in gamma and beta frequency bands, indicating elevated long range functional connectivity between frontal and parietal regions in the ASD group. Machine learning models achieved modest classification performance of ROC-AUC at 0.65. While machine learning approaches offer some discriminative power classifying individuals with ASD from controls, they also indicate the need for further refinement.

Identification of diagnostic markers for ASD: a restrictive interest analysis based on EEG combined with eye tracking.

Electroencephalography (EEG) functional connectivity (EFC) and eye tracking (ET) have been explored as objective screening methods for autism spectrum disorder (ASD), but no study has yet evaluated restricted and repetitive behavior (RRBs) simultaneously to infer early ASD diagnosis. Typically developing (TD) children (n = 27) and ASD (n = 32), age- and sex-matched, were evaluated with EFC and ET simultaneously, using the restricted interest stimulus paradigm. Network-based machine learning prediction (NBS-predict) was used to identify ASD. Correlations between EFC, ET, and Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) were performed. The Area Under the Curve (AUC) of receiver-operating characteristics (ROC) was measured to evaluate the predictive performance. Under high restrictive interest stimuli (HRIS), ASD children have significantly higher α band connectivity and significantly more total fixation time (TFT)/pupil enlargement of ET relative to TD children (p = 0.04299). These biomarkers were not only significantly positively correlated with each other (R = 0.716, p = 8.26e-4), but also with ADOS total scores (R = 0.749, p = 34e-4) and RRBs sub-score (R = 0.770, p = 1.87e-4) for EFC (R = 0.641, p = 0.0148) for TFT. The accuracy of NBS-predict in identifying ASD was 63.4%. ROC curve demonstrated TFT with 91 and 90% sensitivity, and 78.7% and 77.4% specificity for ADOS total and RRB sub-scores, respectively. Simultaneous EFC and ET evaluation in ASD is highly correlated with RRB symptoms measured by ADOS-2. NBS-predict of EFC offered a direct prediction of ASD. The use of both EFC and ET improve early ASD diagnosis.

Probiotic and intra-nasal oxytocin combination therapy on autonomic function and gut-brain axis signaling in young children and teens with autism spectrum disorder.

Autonomic dysfunction has been widely studied in individuals with autism spectral disorder (ASD); however, the autonomic response to probiotic and oxytocin (OT) combination intervention has not yet been explored. We conducted the present study that includes 35 individuals with ASD aged 3-20 years to explore autonomic responses to daily Lactobacillus plantarum probiotic supplementation and OT nasal spray treatment both alone and in combination. We identified significant improvements in autonomic indices from subjects receiving combination treatment relative to those receiving placebo. Parameters that were observed to improve following combination treatment are time domain metrics of heart rate variability (HRV), including the root mean square of successive differences between normal heartbeats (RMSSD), standard deviation of normal-to-normal R-R intervals (SDNN), and proportion of the number of pairs of adjacent NN intervals that differ by more than 50ms (pNN50, p < 0.05). Furthermore, individuals that received either probiotics or OT alone demonstrated fewer changes in RMSSD, pNN50, and SDNN. Several parameters that demonstrated significant improvements in combination therapy were found to be correlated with baseline levels of OT (LF power: r = -0.86, p = 0.024; mean HR: r = 0.89, p = 0.012). Additionally, Social Responsiveness Scale (SRS) raw total scores (mean HR, r = 0.86, p = 0.024) and Aberrant Behavior Checklist (ABC) raw total scores (mean HR r = 0.94, p = 0.017) were correlated with mean heart rate (HR) and HRV-derived parameters. These results provide further evidence of synergy of probiotic and OT combination and help us gain a better understanding of the role of the gut-brain axis in ASD phenotypes and pathogenesis.

Correction: Huang et al. A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder. Cells 2022, 11, 10.

In the original publication [...].

Carbon monoxide (CO) correlates with symptom severity, autoimmunity, and responses to probiotics treatment in a cohort of children with autism spectrum disorder (ASD): a post-hoc analysis of a randomized controlled trial.

BACKGROUND: Inflammation, autoimmunity, and gut-brain axis have been implicated in the pathogenesis of autism spectrum disorder (ASD). Carboxyhemoglobin (SpCO) as a non-invasive measurement of inflammation has not been studied in individuals with ASD. We conducted this post-hoc study based on our published clinical trial to explore SpCO and its association with ASD severity, autoimmunity, and response to daily Lactobacillus plantarum probiotic supplementation. METHODS: In this study, we included 35 individuals with ASD aged 3-20 years from a previously published clinical trial of the probiotic Lactobacillus plantarum. Subjects were randomly assigned to receive daily Lactobacillus plantarum probiotic (6 × 1010 CFUs) or a placebo for 16 weeks. The outcomes in this analysis include Social Responsiveness Scale (SRS), Aberrant Behavior Checklist second edition (ABC-2), Clinical Global Impression (CGI) scale, SpCO measured by CO-oximetry, fecal microbiome by 16 s rRNA sequencing, blood serum inflammatory markers, autoantibodies, and oxytocin (OT) by ELISA. We performed Kendall's correlation to examine their interrelationships and used Wilcoxon rank-sum test to compare the means of all outcomes between the two groups at baseline and 16 weeks. RESULTS: Elevated levels of serum anti-tubulin, CaM kinase II, anti-dopamine receptor D1 (anti-D1), and SpCO were found in the majority of ASD subjects. ASD severity is correlated with SpCO (baseline, R = 0.38, p = 0.029), anti-lysoganglioside GM1 (R = 0.83, p = 0.022), anti-tubulin (R = 0.69, p = 0.042), and anti-D1 (R = 0.71, p = 0.045) in treatment group. CONCLUSIONS: The findings of the present study suggests that the easily administered and non-invasive SpCO test offers a potentially promising autoimmunity and inflammatory biomarker to screen/subgroup ASD and monitor the treatment response to probiotics. Furthermore, we propose that the associations between autoantibodies, gut microbiome profile, serum OT level, GI symptom severity, and ASD core symptom severity scores are specific to the usage of probiotic treatment in our subject cohort. Taken together, these results warrant further studies to improve ASD early diagnosis and treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03337035 , registered November 8, 2017.

Different Eye Tracking Patterns in Autism Spectrum Disorder in Toddler and Preschool Children.

Background: Children with autism spectrum disorder (ASD) have been observed to be associated with fixation abnormality as measured eye tracking, but the dynamics behind fixation patterns across age remain unclear. Materials and Methods: In this study, we investigated gaze patterns between toddlers and preschoolers with and without ASD while they viewed video clips and still images (i.e., mouth-moving face, biological motion, mouthing face vs. moving object, still face picture vs. objects, and moving toys). Results: We found that the fixation time percentage of children with ASD showed significant decrease compared with that of TD children in almost all areas of interest (AOI) except for moving toy (helicopter). We also observed a diagnostic group (ASD vs. TD) and chronological age (Toddlers vs. preschooler) interaction for the eye AOI during the mouth-moving video clip. Support vector machine analysis showed that the classifier could discriminate ASD from TD in toddlers with an accuracy of 80% and could discriminate ASD from TD in preschoolers with an accuracy of 71%. Conclusion: Our results suggest that toddlers and preschoolers may be associated with both common and distinct fixation patterns. A combination of eye tracking and machine learning methods has the potential to shed light on the development of new early screening/diagnosis methods for ASD.

Altered Salivary Microbiota Following Bifidobacterium animalis Subsp. Lactis BL-11 Supplementation Are Associated with Anthropometric Growth and Social Behavior Severity in Individuals with Prader-Willi Syndrome.

To evaluate the influence of oral probiotic Bifidobacterium animalis subsp. lactis (BL-11) supplementation on salivary microbiota composition and the association with growth parameters, and behavioral symptoms in individuals with Prader-Willi syndrome (PWS). In this post hoc analysis, we included a subset of 36 PWS patients with available saliva samples from our original randomized, double-blinded, placebo-controlled trial (Chinese Clinical Trial Registry, ChiCTR1900022646, April 20, 2019). Among the 36 subjects, 17 subjects were allocated to the probiotic group for daily use of the BL-11 probiotic and 19 subjects were allocated to the placebo group. Groupwise and longitudinal differences in salivary microbiota abundances, biodiversity metrics, and height were analyzed. Linear correlations were found between identified differentially abundant salivary microbiota and clinical parameters. Salivary microbiome α-diversity was found to be higher in the probiotic-treated group at week 12 relative to placebo controls (P < 0.05). Leptotrichia, Paracoccus, and Faecalibacterium were found to be more abundant in the probiotic-treated group (P < 0.05). Salivary microbiota abundance and predicted functional profiling abundance correlations were found to be associated with anti-inflammation, anti-obesity, toxin degradation, and anti-oxidative injury effects (Q < 0.1). Several oral taxa also displayed correlations with social behavior severity scores in the probiotic-treated group (Q < 0.1). The findings suggest novel salivary microbiota compositional changes in response to the oral supplementation of BL-11 probiotic in individuals with PWS. The observed differentially abundant taxa between groups post-treatment were highly correlated with interventional effects on growth and social behaviors, although further investigation is warranted. Clinical Trial Registration The original clinical trial was registered under the Chinese Clinical Trial Registry with registration number ChiCTR1900022646 (April 20, 2019).

Microbiome-Specific Statistical Modeling Identifies Interplay Between Gastrointestinal Microbiome and Neurobehavioral Outcomes in Patients With Autism: A Case Control Study.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear mechanisms of pathogenesis. Gastrointestinal microbiome alterations were found to correlate with ASD core symptoms, but its specific role in ASD pathogenesis has not been determined. In this study, we used a case-control strategy that simultaneously compared the ASD gastrointestinal microbiome with that from age-sex matched controls and first-degree relative controls, using a statistical framework accounting for confounders such as age. Enterobacteriaceae (including Escherichia/Shigella) and Phyllobacterium were significantly enriched in the ASD group, with their relative abundances all following a pattern of ASD > first degree relative control > healthy control, consistent with our hypothesis of living environment and shared microbial and immunological exposures as key drivers of ASD gastrointestinal microbiome dysbiosis. Using multivariable omnibus testing, we identified clinical factors including ADOS scores, dietary habits, and gastrointestinal symptoms that covary with overall microbiome structure within the ASD cohort. A microbiome-specific multivariate modeling approach (MaAsLin2) demonstrated microbial taxa, such as Lachnoclostridium and Tyzzerella, are significantly associated with ASD core symptoms measured by ADOS. Finally, we identified alterations in predicted biological functions, including tryptophan and tyrosine biosynthesis/metabolism potentially relevant to the pathophysiology of the gut-brain-axis. Overall, our results identified gastrointestinal microbiome signature changes in patients with ASD, highlighted associations between gastrointestinal microbiome and clinical characteristics related to the gut-brain axis and identified contributors to the heterogeneity of gastrointestinal microbiome within the ASD population.

Case Report: Off-Label Use of Omalizumab in a 6-Year-Old Boy With ASD Ameliorated Severe Allergic Rhinitis and Subsequently Improved Behavioral Symptoms.

Children with ASD have elevated risk for developing allergic symptoms. The severity of allergic symptoms can exacerbate behavioral problems in children with ASD. Omalizumab, an anti-IgE antibody, has previously shown efficacy in treating allergic rhinitis and behavioral problems in a 12-year-old child with ASD. The present case report provides robust characterization of behavioral improvement in a 6-year-old child with ASD, allergic rhinitis, and autoimmune disorder. A 6-year-old boy with ASD and Hashimoto's disease presented to the clinic with severe allergic rhinitis, irritability, and language delay. After other treatments failed to improve symptoms, our patient was treated with omalizumab at 300 mg/month via subcutaneous injection for a total of 6 months. Marked improvement in allergic symptoms were observed at 2 months into treatment and were maintained through the treatment period. At the conclusion of the treatment period, results from multiple behavioral questionnaires, including the SRS-2, ABC, RBS-R, and PSQI, demonstrated substantial improvement in ASD-related behavioral symptoms. In this case, omalizumab markedly improved ASD-related and sleep behavior in a 6-year-old with ASD, allergic rhinitis, and autoimmune disorder. Future studies with larger patient populations are warranted to investigate the efficacy of omalizumab in patients with ASD and allergy symptoms.

Serum Oxytocin Level Correlates With Gut Microbiome Dysbiosis in Children With Autism Spectrum Disorder.

To investigate the levels of serum oxytocin (OT) in children with autism spectrum disorder (ASD) and explore the association between OT levels and gut microbiota relative abundances, we recruited 39 children with ASD children-mother dyads and 44 healthy controls. Serum OT levels were determined via enzyme-linked immunosorbent assay and gut microbiota abundances were determined by 16S rRNA sequencing. We found that the OT level of ASD was lower than the healthy control group overall (P < 0.05). Furthermore, we present preliminary evidence of gut microbiome dysbiosis observed among children with ASD to lower levels of OT based on correlational analysis between serum OT and specific gut microbiota abundances (P < 0.05). We also found sex-related differences in serum OT levels and GIS index (P < 0.05). However, the generalizability of findings relevant to females with ASD require further validation in future studies involving larger sample sizes and balanced sex distributions due to the small number of females involved in this study. Nonetheless, these new findings further our understanding of the effects of low serum OT levels among individuals with ASD, which provides preliminary evidence in hopes of guiding future study design or mechanistic studies. The findings of the present study may be suggestive of potential ASD subtypes based on ASD severity and gut microbiome composition that may facilitate the prediction of the therapeutic responses of OT among those with ASD.

Validation of Rapid Interactive Screening Test for Autism in Toddlers Using Autism Diagnostic Observation Schedule™ Second Edition in Children at High-Risk for Autism Spectrum Disorder.

The Rapid Interactive screening Test for Autism in Toddlers (RITA-T) is a fast and inexpensive early screening measure for autism spectrum disorder (ASD) that was tested previously in children 18-36 months-old; the current validation study compared the RITA-T with the Autism Diagnostic Observation Schedule™ Second Edition (ADOS-2). The hypothesis is to validate the RITA-T with comparison to the ADOS-2. Thirty-five individuals (18-84 months-old) identified as at risk for ASD received the RITA-T and the ADOS-2 during a single visit. Participants were split into two age groups and both whole-group and sub-group data analysis were conducted. With all participants, RITA-T scores correlated significantly with ADOS-2 total scores (P < 0.001), social affect (SA) sub-scores (P < 0.001), and restrictive and repetitive behavior (RRB) sub-scores (P < 0.05). Similarly, ADOS-2 total and SA scores were significantly correlated in both age groups, while the RRB sub-score was only significant in females (P < 0.05). Lastly, correlations using subgroups based on ethnicity were only significant in the minority ("Other") group for ADOS-2 total scores and in the Asian group for SA sub-scores (P < 0.05). Our receiver operating characteristic analysis showed that the optimal cut-off score of the RITA-T was consistently at 14, with a sensitivity of 81% and a specificity of 89% in the combined age group with the ADOS-2 and with a sensitivity 74% and specificity 50% with the DSM-5; The area under the curve was 0.84 (95%CI: 0.69-0.99) for ASD classified by ADOS-2 and 0.89 (95%CI: 0.79-0.99) for ASD diagnosed by DSM-5. The RITA-T performed similarly to the ADOS-2 when both were administered in a single visit. Significant correlations between the measures help validate the potential usefulness of the RITA-T as a rapid early screening measure of ASD. This study helps to show that the RITA-T may be used in a larger age range than originally reported and in different ethnic groups. The study involves human participants and was reviewed and approved by the Institutional Review Board (IRB) of Massachusetts General Hospital (MGH, 2017P0000857).

Transcranial Direct Current Stimulation (tDCS) over the Left Dorsal Lateral Prefrontal Cortex in Children with Autism Spectrum Disorder (ASD).

Recently, transcranial direct current stimulation (tDCS) has been applied to relieve symptoms in individuals with autism spectrum disorder (ASD). In this prospective, parallel, single-blinded, randomized study, we investigate the modulation effect of three-week tDCS treatment at the left dorsal lateral prefrontal cortex (DLPFC) in children with ASD. 47 children with ASD were enrolled, and 40 (20 in each group) completed the study. The primary outcomes are Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), and the Repetitive Behavior Scale-Revised (RBS-R). We found that children with ASD can tolerate three-week tDCS treatment with no serious adverse events detected. A within-group comparison showed that real tDCS, but not sham tDCS, can significantly reduce the scores of CARS, Children's Sleep Habits Questionnaire (CSHQ), and general impressions in CARS (15th item). Real tDCS produced significant score reduction in the CSHQ and in CARS general impressions when compared to the effects of sham tDCS. The pilot study suggests that three-week left DLPFC tDCS is well-tolerated and may hold potential in relieving some symptoms in children with ASD.

Interaction between genetic predisposition, smoking, and dementia risk: a population-based cohort study.

We evaluated whether the association between cigarette smoking and dementia risk is modified by genetic predisposition including apolipoprotein E (APOE) genotype and polygenic risk (excluding the APOE region). We included 193,198 UK Biobank participants aged 60-73 years without dementia at baseline. Of non-APOE-ε4 carriers, 0.89% (95% CI 0.73-1.08%) current smokers developed dementia compared with 0.49% (95% CI 0.44-0.55%) of never smokers (adjusted HR 1.78; 95% CI 1.39-2.29). In contrast, of one APOE-ε4 allele carriers, 1.69% (95% CI 1.31-2.12%) current smokers developed dementia compared with 1.40% (95% CI 1.25-1.55%) of never smokers (adjusted HR 1.06; 95% CI 0.77-1.45); of two APOE-ε4 alleles carriers, 4.90% (95% CI 2.92-7.61%) current smokers developed dementia compared with 3.87% (95% CI 3.11-4.74%) of never smokers (adjusted HR 0.94; 95% CI 0.49-1.79). Of participants with high polygenic risk, 1.77% (95% CI 1.35-2.27%) current smokers developed dementia compared with 1.05% (95% CI 0.91-1.21%) of never smokers (adjusted HR 1.63; 95% CI 1.16-2.28). A significant interaction was found between APOE genotype and smoking status (P = 0.002) while no significant interaction was identified between polygenic risk and smoking status (P = 0.25). APOE genotype but not polygenic risk modified the effect of smoking on dementia risk.

The Effects of Limosilactobacillus reuteri LR-99 Supplementation on Body Mass Index, Social Communication, Fine Motor Function, and Gut Microbiome Composition in Individuals with Prader-Willi Syndrome: a Randomized Double-Blinded Placebo-Controlled Trial.

Prader-Willi syndrome (PWS) is a rare genetic disorder associated with developmental delay, obesity, and neuropsychiatric comorbidities. Limosilactobacillus reuteri (Lactobacillus reuteri, Lact. reuteri) has demonstrated anti-obesity and anti-inflammatory effects in previous studies. In the present study, we aim to evaluate the effects of Lact. reuteri supplementation on body mass index (BMI), social behaviors, and gut microbiota in individuals with PWS. We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 71 individuals with PWS aged 6 to 264 months (64.4 ± 51.0 months). Participants were randomly assigned to either receive daily Lact. reuteri LR-99 probiotic (6 × 1010 colony forming units) or a placebo sachet. Groupwise differences were assessed for BMI, ASQ-3, and GARS-3 at baseline, 6 weeks, and 12 weeks into treatment. Gut microbiome data was analyzed with the QIIME2 software package, and predictive functional profiling was conducted with PICRUSt-2. We found a significant reduction in BMI for the probiotic group at both 6 weeks and 12 weeks relative to the baseline (P < 0.05). Furthermore, we observed a significant improvement in social communication and interaction, fine motor function, and total ASQ-3 score in the probiotics group compared to the placebo group (P < 0.05). Altered gut microbiota was observed in the probiotic group to favor weight loss and improve gut health. The findings suggest a novel therapeutic potential for Lact. reuteri LR-99 probiotic to modulate BMI, social behaviors, and gut microbiota in Prader-Willi syndrome patients, although further investigation is warranted.Trial registration Chinese Clinical Trial Registry: ChiCTR1900022646.

Probiotic and Oxytocin Combination Therapy in Patients with Autism Spectrum Disorder: A Randomized, Double-Blinded, Placebo-Controlled Pilot Trial.

Autism spectrum disorder (ASD) is a rapidly growing neurodevelopmental disorder. Both probiotics and oxytocin were reported to have therapeutic potential; however, the combination therapy has not yet been studied. We conducted a randomized, double-blinded, placebo-controlled, 2-stage pilot trial in 35 individuals with ASD aged 3-20 years (median = 10.30 years). Subjects were randomly assigned to receive daily Lactobacillus plantarum PS128 probiotic (6 × 1010 CFUs) or a placebo for 28 weeks; starting on week 16, both groups received oxytocin. The primary outcomes measure socio-behavioral severity using the Social Responsiveness Scale (SRS) and Aberrant Behavior Checklist (ABC). The secondary outcomes include measures of the Clinical Global Impression (CGI) scale, fecal microbiome, blood serum inflammatory markers, and oxytocin. All outcomes were compared between the two groups at baseline, 16 weeks, and 28 weeks into treatment. We observed improvements in ABC and SRS scores and significant improvements in CGI-improvement between those receiving probiotics and oxytocin combination therapy compared to those receiving placebo (p < 0.05). A significant number of favorable gut microbiome network hubs were also identified after combination therapy (p < 0.05). The favorable social cognition response of the combination regimen is highly correlated with the abundance of the Eubacterium hallii group. Our findings suggest synergic effects between probiotics PS128 and oxytocin in ASD patients, although further investigation is warranted.

Dysfunction of the Auditory Brainstem as a Neurophysiology Subtype of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is very heterogeneous, particularly in language. Studies have suggested that language impairment is linked to auditory-brainstem dysfunction in ASD. However, not all ASD children have these deficits, which suggests potential subtypes of ASD. We classified ASD children into two subtypes according to their speech-evoked auditory brainstem response (speech-ABR) and explored the neural substrates for possible subtypes. Twenty-nine children with ASD and 25 typically developing (TD) peers were enrolled to undergo speech-ABR testing and structural magnetic resonance imaging (sMRI). There were significant differences between the ASD group and TD group in surface area, cortical volume and cortical thickness. According to speech-ABR results, ASD participants were divided into the ASD-typical (ASD-T) group and ASD-atypical (ASD-A) group. Compared with the ASD-T group, the ASD-A group had a lower score in language of the Gesell Developmental Diagnosis Scale (GDDS), increased left rostral middle frontal gyrus (lRMFG) area and decreased local gyrification index of the right superior temporal gyrus. GDDS-language and surface area of lRMFG were correlated to the wave-A amplitude in ASD. Surface area of lRMFG had an indirect effect on language performance via alteration of the wave-V amplitude. Thus, cortical deficits may impair language ability in children with ASD by causing subcortical dysfunction at preschool age. These evidences support dysfunction of the auditory brainstem as a potential subtype of ASD. Besides, this subtype-based method may be useful for various clinical applications.

Altered Extended Locus Coeruleus and Ventral Tegmental Area Networks in Boys with Autism Spectrum Disorders: A Resting-State Functional Connectivity Study.

INTRODUCTION: Previous studies have suggested that cerebral projections of the norepinephrine (NE) and dopamine (DA) systems have important etiology and treatment implications for autism spectrum disorder (ASD). METHODS: We used functional magnetic resonance imaging to evaluate spontaneous resting state functional connectivity in boys aged 7-15 years with ASD (n=86) and age-, intelligence quotient-matched typically developing boys (TD, n=118). Specifically, we investigated functional connectivity of the locus coeruleus (LC) and ventral tegmental area (VTA), the main source projection of neurotransmitters NE and DA, respectively. RESULTS: 1) Both the LC and VTA showed reduced connectivity with the postcentral gyrus (PoCG) in boys with ASD, reflecting the potential roles of NE and DA in modulating the function of the somatosensory cortex in boys with ASD. 2) The VTA had increased connectivity with bilateral thalamus in ASD; this alteration was correlated with repetitive and restrictive features. 3) Altered functional connectivity of both the LC and VTA with brain regions such as the angular gyrus (AG), middle temporal gyrus visual area (MT/V5), and occipital face area (OFA) in ASD group. DISCUSSION: Our findings implicate the role of LC-NE and VTA-DA systems from the perspective of functional neuroimaging and may shed light on pharmacological studies targeting NE and DA for the treatment of autism in the future.

Dysbiotic Gut Microbiota and Dysregulation of Cytokine Profile in Children and Teens With Autism Spectrum Disorder.

Inflammation and the gut-brain axis have been implicated in the pathogenesis of autism spectrum disorders (ASDs). To further understand the relationship between aberrant immune responses and dysbiotic features of the gut microbiome in ASD, we enrolled 45 ASD individuals and 41 healthy control subjects with ages ranging from 2 to 19 years. We found that ASD group subjects have significantly higher plasma levels of IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, TNF-ß, and IFN-γ when compared to healthy controls (FDR-adjusted p < 0.05). The plasma levels of pro-inflammatory cytokines IFN-γ and IL-6 are found to be further associated with several largely pathogenic gut microbiota uniquely detected in subjects with ASD. Furthermore, the ASD gut microbiome is characterized by reduced levels of several beneficial microbiota, including Bacteroides (FDR-adjusted p < 0.01) and Lachnospiraceae (FDR-adjusted p < 0.001). Analysis of Lachnospiraceae family and genus level taxa suggested that relative abundances of such taxa are negatively correlated with pro-inflammatory signaling cytokines IFN-γ and IL-6, particularly in subjects with severe ASD as defined by CARS (p < 0.05). Several largely pathogenic genera are determined to be associated with the pro-inflammatory cytokines IFN-γ and IL-6 (FDR-adjusted p < 0.1). Additionally, IL-4 is significantly negatively correlated with CARS total score (p < 0.05). Based on such results, we propose that the association between the disturbances of specific cytokines and alterations in gut microbiota abundance observed in children and adolescents with ASD provides additional evidence on the induction of aberrant pro-inflammatory mechanisms in ASD and its early diagnosis.

The Effects of Probiotic Supplementation on Anthropometric Growth and Gut Microbiota Composition in Patients With Prader-Willi Syndrome: A Randomized Double-Blinded Placebo-Controlled Trial.

Background: Prader-Willi Syndrome (PWS) is a rare genetic disorder associated with developmental delay, obesity, and neuropsychiatric comorbidities. Bifidobacterium animalis subsp. lactis has demonstrated anti-obesity and anti-inflammatory effects in previous studies. Aim: To evaluate the effects of Bifidobacterium animalis subsp. lactis probiotics supplementation on anthropometric growth, behavioral symptoms, and gut microbiome composition in patients with PWS. Methods: Ethical Approval was issued by the Internal Review Board (IRB) of the Second Affiliated Hospital of Kunming Medical University (Review-YJ-2016-06). We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 68 patients with Prader-Willi syndrome aged 11 months-16 years (mean = 4.2 years old) who were randomly assigned to receive daily B. lactis-11 probiotics (6 × 1010 CFUs) or a placebo sachet. Weight, height, ASQ-3, ABC, SRS-2, and CGI-I were compared between the two groups at baseline and at 6 and 12 weeks into treatment. Gut microbiome data were analyzed with the QIIME 2 software package, and functional gene analysis was conducted with PICRUSt-2. Results: We found a significant increase in height (mean difference = 2.68 cm, P < 0.05) and improvement in CGI-I (P < 0.05) in the probiotics group compared to the placebo group. No significant change in weight or psychological measures were observed. Probiotic treatment altered the microbiome composition to favor weight loss and gut health and increased the abundance of antioxidant production-related genes. Conclusions: The findings suggest a novel therapeutic potential for Bifidobacterium animalis subsp. lactis probiotics in Prader-Willi syndrome patients, although further investigation is warranted.

Altered Autonomic Functions and Gut Microbiome in Individuals with Autism Spectrum Disorder (ASD): Implications for Assisting ASD Screening and Diagnosis.

Autism spectrum disorder (ASD) is a complex neurological and developmental disorder, and a growing body of literature suggests the presence of autonomic nervous system (ANS) dysfunction in individuals with ASD. ANS is part of the "gut brain axis", which consists of an intricate interplay between the gut microbiome, mucosal immune system, enteric nervous system, ANS, and central processes receiving input from the vagus nerve. Measurements of the gut microbiome and the autonomic indices can serve as non-invasive markers of the status of the gut-brain axis in ASD. To our knowledge, no previous studies have explored the relationship between ANS and gut microbiome in individuals with ASD. Furthermore, while previous studies investigated the use of autonomic indices and gut microbiome independently as markers of ASD-related comorbidities, such as anxiety, cardiovascular issues, and gastrointestinal dysfunction, the use of combined autonomic indices and gut microbiome factors to classify ASD and control subjects has not been explored. In this study, we characterized autonomic function of a group of individuals with ASD in comparison to their paired, first-degree relative controls. Second, we explored the ASD gut-brain-axis through the relationship between gut microbiome markers and autonomic indices, as well as the correlation between the gut-brain-axis and clinical presentation of ASD. Lastly, this study explores the predictive capability of gut-brain-axis biomarkers (including autonomic and microbiome indices) in subtyping ASD cases, serving as a starting point to investigate the possibility of assisting in ASD screening and diagnosis that still heavily relies on psychological testing, which may be based on highly subjective standards.