scholarly journals Clostridioides difficile infection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism and other neurologic disorders?

2021 ◽  
Author(s):  
Akhil A. Vinithakumari ◽  
Piyush Padhi ◽  
Belen G. Hernandez ◽  
Susanne Je-Han Lin ◽  
Aaron Dunkerson-Kurzhumov ◽  
...  
Keyword(s):  
Brain Regions ◽  
Autism Spectrum ◽  
Dopamine Metabolism ◽  
Toxic Metabolite ◽  
Autistic Behavior ◽  
Clostridioides Difficile ◽  
Neurologic Disorders ◽  
Clostridioides Difficile Infection ◽  
Potential Link ◽  
The Brain

Gastrointestinal illnesses are one of the most common comorbidities reported in patients with neurodevelopmental diseases, including autism spectrum disorders (ASD). Gut dysbiosis, overgrowth of C. difficile in the gut, and gut microbiota-associated alterations in central neurotransmission have been implicated in ASD, where the dopaminergic axis plays an important role in the disease pathogenesis. Human C. difficile strains produce a significant amount of the toxic metabolite p-cresol, an inhibitor of dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine (DA) to norepinephrine (NE). p-cresol is known to precipitate and exacerbate autistic behavior in rodents by increasing DA levels and altering DA receptor sensitivity in brain regions relevant to ASD. Therefore, we hypothesized that C. difficile infection dysregulates dopaminergic metabolism in the brain by increasing p-cresol levels in the gut and circulation and by inhibiting DBH, ultimately leading to elevated DA in the brain. For testing this hypothesis, we induced antibiotic-associated C. difficile in mice and determined the gut and serum p-cresol levels, serum DBH activity, and dopamine and its metabolite levels in different brain regions relevant to ASD. The results showed that C. difficile infection causes significant alterations in the dopaminergic axis in mice (p < 0.05). In addition, significantly increased circulating p-cresol levels and reduced DBH activity was observed in C. difficile infected animals (p < 0.05). Therefore, the results from this study suggest a potential link between C. difficile infection and alterations in the dopaminergic axis implicated in the precipitation and aggravation of ASD.

scholarly journals Mimicry is associated with procedural learning, not social bonding, neural systems in autism

2020 ◽  
Author(s):  
Bahar Tunçgenç ◽  
Carolyn Koch ◽  
Amira Herstic ◽  
Inge-Marie Eigsti ◽  
Stewart Mostofsky
Keyword(s):  
Social Bonding ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Skill Learning ◽  
Autism Spectrum Conditions ◽  
Neural Systems ◽  
Procedural Skill ◽  
Communication Difficulties ◽  
Learning Functions ◽  
The Brain

AbstractMimicry facilitates social bonding throughout the lifespan. Mimicry impairments in autism spectrum conditions (ASC) are widely reported, including differentiation of the brain networks associated with its social bonding and learning functions. This study examined associations between volumes of brain regions associated with social bonding versus procedural skill learning, and mimicry of gestures during a naturalistic interaction in ASC and neurotypical (NT) children. Consistent with predictions, results revealed reduced mimicry in ASC relative to the NT children. Mimicry frequency was negatively associated with autism symptom severity. Mimicry was predicted predominantly by the volume of procedural skill learning regions in ASC, and by bonding regions in NT. Further, bonding regions contributed significantly less to mimicry in ASC than in NT, while the contribution of learning regions was not different across groups. These findings suggest that associating mimicry with skill learning, rather than social bonding, may partially explain observed communication difficulties in ASC.

scholarly journals Graph Ricci Curvatures Reveal Disease-related Changes in Autism Spectrum Disorder

2021 ◽  
Author(s):  
Pavithra Elumalai ◽  
Yasharth Yadav ◽  
Nitin Williams ◽  
Emil Saucan ◽  
Jürgen Jost ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Resting State ◽  
Neurodevelopmental Disorders ◽  
Data Exchange ◽  
Meta Analysis ◽  
Resting State Fmri ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
The Brain

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders that pose a significant global health burden. Measures from graph theory have been used to characterise ASD-related changes in resting-state fMRI functional connectivity networks (FCNs), but recently developed geometry-inspired measures have not been applied so far. In this study, we applied geometry-inspired graph Ricci curvatures to investigate ASD-related changes in resting-state fMRI FCNs. To do this, we applied Forman-Ricci and Ollivier-Ricci curvatures to compare networks of ASD and healthy controls (N = 1112) from the Autism Brain Imaging Data Exchange I (ABIDE-I) dataset. We performed these comparisons at the brain-wide level as well as at the level of individual brain regions, and further, determined the behavioral relevance of region-specific differences with Neurosynth meta-analysis decoding. We found brain-wide ASD-related differences for both Forman-Ricci and Ollivier-Ricci curvatures. For Forman-Ricci curvature, these differences were distributed across 83 of the 200 brain regions studied, and concentrated within the Default Mode, Somatomotor and Ventral Attention Network. Meta-analysis decoding identified the brain regions showing curvature differences as involved in social cognition, memory, language and movement. Notably, comparison with results from previous non-invasive stimulation (TMS/tDCS) experiments revealed that the set of brain regions showing curvature differences overlapped with the set of brain regions whose stimulation resulted in positive cognitive or behavioural outcomes in ASD patients. These results underscore the utility of geometry-inspired graph Ricci curvatures in characterising disease-related changes in ASD, and possibly, other neurodevelopmental disorders.

Executive Functions in Adolescents with Autism Spectrum Disorder

2017 ◽  
pp. 67-90
Author(s):  
Yael Dai ◽  
Inge-Marie Eigsti
Keyword(s):  
Autism Spectrum Disorder ◽  
Working Memory ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Clinical Implications ◽  
Future Directions ◽  
Adolescents With Autism ◽  
Memory Flexibility ◽  
The Brain

This chapter reviews strengths and weaknesses in executive function (EF) domains, including inhibition, working memory, flexibility, fluency, and planning, in adolescents (age 13–19) with autism spectrum disorder (ASD). Given the dramatic developmental changes in the brain regions that support EF during the period of adolescence, it is critical to evaluate which EF abilities show a distinct profile during this period. As this chapter will demonstrate, youth with ASD show deficits across all domains of EF, particularly in complex tasks that include arbitrary instructions. We describe the fundamental measures for assessing skills in each domain and discuss limitations and future directions for research, as well as clinical implications of these findings for working with youth with ASD.

scholarly journals Gastrointestinal dysfunction in autism displayed by altered motility and achalasia in Foxp1+/− mice

2019 ◽  
Vol 116 (44) ◽  
pp. 22237-22245 ◽  
Author(s):  
Henning Fröhlich ◽  
Marie Luise Kollmeyer ◽  
Valerie Catherine Linz ◽  
Manuel Stuhlinger ◽  
Dieter Groneberg ◽  
...  
Keyword(s):  
Language Impairment ◽  
Muscular Atrophy ◽  
Gastrointestinal Transit ◽  
Autism Spectrum ◽  
Autistic Behavior ◽  
Feeding Difficulties ◽  
Gastrointestinal Problems ◽  
Food And Water Intake ◽  
The Brain

Gastrointestinal dysfunctions in individuals with autism spectrum disorder are poorly understood, although they are common among this group of patients. FOXP1 haploinsufficiency is characterized by autistic behavior, language impairment, and intellectual disability, but feeding difficulties and gastrointestinal problems have also been reported. Whether these are primary impairments, the result of altered eating behavior, or side effects of psychotropic medication remains unclear. To address this question, we investigated Foxp1+/− mice reflecting FOXP1 haploinsufficiency. These animals show decreased body weight and altered feeding behavior with reduced food and water intake. A pronounced muscular atrophy was detected in the esophagus and colon, caused by reduced muscle cell proliferation. Nitric oxide-induced relaxation of the lower esophageal sphincter was impaired and achalasia was confirmed in vivo by manometry. Foxp1 targets (Nexn, Rbms3, and Wls) identified in the brain were dysregulated in the adult Foxp1+/− esophagus. Total gastrointestinal transit was significantly prolonged due to impaired colonic contractility. Our results have uncovered a previously unknown dysfunction (achalasia and impaired gut motility) that explains the gastrointestinal disturbances in patients with FOXP1 syndrome, with potential wider relevance for autism.

scholarly journals Cerebellar modulation of the reward circuitry and social behavior

Science ◽  
2019 ◽  
Vol 363 (6424) ◽  
pp. eaav0581 ◽  
Author(s):  
Ilaria Carta ◽  
Christopher H. Chen ◽  
Amanda L. Schott ◽  
Schnaude Dorizan ◽  
Kamran Khodakhah
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mental Disorders ◽  
Ventral Tegmental Area ◽  
Social Preference ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Reward Circuitry ◽  
The Social ◽  
The Brain

The cerebellum has been implicated in a number of nonmotor mental disorders such as autism spectrum disorder, schizophrenia, and addiction. However, its contribution to these disorders is not well understood. In mice, we found that the cerebellum sends direct excitatory projections to the ventral tegmental area (VTA), one of the brain regions that processes and encodes reward. Optogenetic activation of the cerebello-VTA projections was rewarding and, in a three-chamber social task, these projections were more active when the animal explored the social chamber. Intriguingly, activity in the cerebello-VTA pathway was required for the mice to show social preference in this task. Our data delineate a major, previously unappreciated role for the cerebellum in controlling the reward circuitry and social behavior.

scholarly journals Reduced Brain Volume and White Matter Alterations in Shank3-Deficient Rats

2020 ◽  
Author(s):  
Carla Esther Meyer Golden ◽  
Victoria X Wang ◽  
Hala Harony-Nicolas ◽  
Patrick R. Hof ◽  
Joseph Buxbaum
Keyword(s):  
White Matter ◽  
Brain Structure ◽  
Brain Volume ◽  
Diffusion Tensor ◽  
Brain Size ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Wild Type ◽  
Microstructural Alterations ◽  
The Brain

Abstract Background: Mutations and deletions in the SHANK3 synaptic gene cause the major neurodevelopmental features of Phelan-McDermid syndrome (PMS). The SHANK3 gene encodes a key structural component of excitatory synapses that is important for synaptogenesis. PMS is characterized by intellectual disability, autism spectrum disorder, cognitive deficits, physical dysmorphic features, sensory hyporeactivity, and alterations in the size of multiple brain regions. Clinical assessments and limited imaging studies have revealed a reduction in volume of multiple brain regions. They have also found white matter thinning and microstructural alterations to be persistent in patients with PMS. While many of these impairments have been replicated in mouse models of PMS, the brain structure of a rat model has not yet been studied. Methods: We assessed the brain structure of haploinsufficient and homozygous Shank3-deficient rats that model the behavioral deficits of PMS with magnetic resonance and diffusion tensor imaging, and compared their brain structure to wild type littermates.Results: Both gray and white matter structures were smaller in Shank3-deficient rats, leading to an overall reduction in brain size compared to wild type littermates. The largest region to be diminished in size was the neocortex. Some regions involved in sensory processing and white matter regions were also reduced in size. Lastly, the microstructure of two white matter tracts, the external capsule and fornix, was abnormal.Conclusions: Shank3-deficient rats replicate the reduced brain volume and altered white matter phenotypes present in individuals with PMS. Therefore, the brain regions that were altered represent potential cross-species structural biomarkers that warrant further study.

scholarly journals Brain Structural Covariance Network in Asperger’s Syndrome Differs From Other Types of Autism and Healthy Controls

2021 ◽  
Author(s):  
Farnaz Faridi ◽  
◽  
Afrooz Seyedebrahimi ◽  
Reza Khosrowabadi ◽  
◽  
...  
Keyword(s):  
Asperger's Syndrome ◽  
Asperger’S Syndrome ◽  
Neurodevelopmental Disorder ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Healthy Controls ◽  
Structural Differentiation ◽  
Structural Covariance ◽  
Behavioral Impairments ◽  
The Brain

Autism is a heterogeneous neurodevelopmental disorder associated with social, cognitive and behavioral impairments. These impairments are often reported along with alteration of the brain structure such as abnormal changes in the grey matter (GM) density. However, it is not yet clear whether these changes could be used to differentiate various subtypes of autism spectrum disorder (ASD). In this study, we compared the regional changes of GM density in ASD, Asperger's Syndrome (AS) individuals and a group of healthy controls (HC). In addition to regional changes itself, the amount of GM density changes in one region as compared to other brain regions was also calculated. We hypothesized that this structural covariance network could differentiate the AS individuals from the ASD and HC groups. Therefore, statistical analysis was performed on the MRI data of 70 male subjects including 26 ASD (age= 14-50, IQ= 92-132), 16 AS (age=7-58, IQ=93-133) and 28 HC (age=9-39, IQ=95-144). Results of one-way ANOVA on the GM density of 116 anatomically separated regions showed significant differences among the groups. The pattern of structural covariance network indicated that covariation of GM density between the brain regions is decreased in ASD. This attenuated structural differentiation could be considered as a reason for less efficient segregation and integration of information in the brain that could lead to cognitive dysfunctions in autism. We hope these findings could improve our understanding about the pathobiology of autism and may pave the way towards a more effective intervention paradigm.

scholarly journals Dysregulated Spliceosome Gene Expression May Be a Common Process in Brains of Neurological and Psychiatric Disorders

2021 ◽  
Author(s):  
Cuihua Xia ◽  
Rujia Dai ◽  
Jing Yu ◽  
Chunling Zhang ◽  
Ma-li Wong ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Mrna Splicing ◽  
Splicing Factors ◽  
Brain Disorders ◽  
Major Depressive ◽  
Transcriptome Database ◽  
Common Process ◽  
The Brain

Abstract Alternative splicing (AS) contributes to the increased cellular and functional tissue complexity that is substantial in the brain. AS is tightly regulated because it is critical to many biological processes. Defective splicing is observed in several neurological and psychiatric disorders. While exonic mutations usually affect the splicing of an individual RNA, mutations in the splicing factors (components of spliceosome) frequently produce widespread disruption in the processing of many precursor-mRNAs. Thus, we tested the hypotheses that expression changes of spliceosome genes may be a common process and shared splicing pathways may be involved in complex polygenic brain disorders. We searched for expression changes of spliceosome-related genes (SGs) using a transcriptome database of several brain regions in 6 neurological and psychiatric disorders, namely Alzheimer’s disease, and autism spectrum, bipolar and major depressive disorder, Parkinson’s disease, and schizophrenia. Out of 255 SGs detected in brain, 138 showed excessive, significant changes in one or more of these disorders. Dysregulation of 10 SGs was shared in 4 disorders, and they were mostly downregulated. Six associated pathways were over-represented in all 6 disorders, including the major and the minor mRNA splicing pathways and RNA metabolism. Therefore, we found that aberrations in the mRNA splicing process may be a common trajectory to many complex brain disorders involving the spliceosome complex.

scholarly journals The Development of a Practical Artificial Intelligence Tool for Diagnosing and Evaluating Autism Spectrum Disorder: Multicenter Study (Preprint)

2019 ◽  
Author(s):  
Tao Chen ◽  
Ye Chen ◽  
Mengxue Yuan ◽  
Mark Gerstein ◽  
Tingyu Li ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Autism Spectrum Disorder ◽  
Psychiatric Disorders ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Unknown Etiology ◽  
Healthy Controls ◽  
Anatomical Changes ◽  
The Brain

BACKGROUND Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with an unknown etiology. Early diagnosis and intervention are key to improving outcomes for patients with ASD. Structural magnetic resonance imaging (sMRI) has been widely used in clinics to facilitate the diagnosis of brain diseases such as brain tumors. However, sMRI is less frequently used to investigate neurological and psychiatric disorders, such as ASD, owing to the subtle, if any, anatomical changes of the brain. OBJECTIVE This study aimed to investigate the possibility of identifying structural patterns in the brain of patients with ASD as potential biomarkers in the diagnosis and evaluation of ASD in clinics. METHODS We developed a novel 2-level histogram-based morphometry (HBM) classification framework in which an algorithm based on a 3D version of the histogram of oriented gradients (HOG) was used to extract features from sMRI data. We applied this framework to distinguish patients with ASD from healthy controls using 4 datasets from the second edition of the Autism Brain Imaging Data Exchange, including the ETH Zürich (ETH), NYU Langone Medical Center: Sample 1, Oregon Health and Science University, and Stanford University (SU) sites. We used a stratified 10-fold cross-validation method to evaluate the model performance, and we applied the Naive Bayes approach to identify the predictive ASD-related brain regions based on classification contributions of each HOG feature. RESULTS On the basis of the 3D HOG feature extraction method, our proposed HBM framework achieved an area under the curve (AUC) of &gt;0.75 in each dataset, with the highest AUC of 0.849 in the ETH site. We compared the 3D HOG algorithm with the original 2D HOG algorithm, which showed an accuracy improvement of &gt;4% in each dataset, with the highest improvement of 14% (6/42) in the SU site. A comparison of the 3D HOG algorithm with the scale-invariant feature transform algorithm showed an AUC improvement of &gt;18% in each dataset. Furthermore, we identified ASD-related brain regions based on the sMRI images. Some of these regions (eg, frontal gyrus, temporal gyrus, cingulate gyrus, postcentral gyrus, precuneus, caudate, and hippocampus) are known to be implicated in ASD in prior neuroimaging literature. We also identified less well-known regions that may play unrecognized roles in ASD and be worth further investigation. CONCLUSIONS Our research suggested that it is possible to identify neuroimaging biomarkers that can distinguish patients with ASD from healthy controls based on the more cost-effective sMRI images of the brain. We also demonstrated the potential of applying data-driven artificial intelligence technology in the clinical setting of neurological and psychiatric disorders, which usually harbor subtle anatomical changes in the brain that are often invisible to the human eye.

scholarly journals Dance on the Brain: Enhancing Intra- and Inter-Brain Synchrony

2021 ◽  
Vol 14 ◽  
Author(s):  
Julia C. Basso ◽  
Medha K. Satyal ◽  
Rachel Rugh
Keyword(s):  
Brain Regions ◽  
Autism Spectrum ◽  
Oscillatory Activity ◽  
Interpersonal Coordination ◽  
Social Emotional ◽  
Future Directions ◽  
Dance Pedagogy ◽  
Definition Of ◽  
Fundamental Movement Patterns ◽  
The Brain

Dance has traditionally been viewed from a Eurocentric perspective as a mode of self-expression that involves the human body moving through space, performed for the purposes of art, and viewed by an audience. In this Hypothesis and Theory article, we synthesize findings from anthropology, sociology, psychology, dance pedagogy, and neuroscience to propose The Synchronicity Hypothesis of Dance, which states that humans dance to enhance both intra- and inter-brain synchrony. We outline a neurocentric definition of dance, which suggests that dance involves neurobehavioral processes in seven distinct areas including sensory, motor, cognitive, social, emotional, rhythmic, and creative. We explore The Synchronicity Hypothesis of Dance through several avenues. First, we examine evolutionary theories of dance, which suggest that dance drives interpersonal coordination. Second, we examine fundamental movement patterns, which emerge throughout development and are omnipresent across cultures of the world. Third, we examine how each of the seven neurobehaviors increases intra- and inter-brain synchrony. Fourth, we examine the neuroimaging literature on dance to identify the brain regions most involved in and affected by dance. The findings presented here support our hypothesis that we engage in dance for the purpose of intrinsic reward, which as a result of dance-induced increases in neural synchrony, leads to enhanced interpersonal coordination. This hypothesis suggests that dance may be helpful to repattern oscillatory activity, leading to clinical improvements in autism spectrum disorder and other disorders with oscillatory activity impairments. Finally, we offer suggestions for future directions and discuss the idea that our consciousness can be redefined not just as an individual process but as a shared experience that we can positively influence by dancing together.

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