Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases.
Neurochem Int. 2018 Aug 13;:
Authors: Spielman LJ, Gibson DL, Klegeris A
The number of bacterial cells living within the human body is approximately equal to, or greater than, the total number of human cells. This dynamic population of microorganisms, termed the human microbiota, resides mainly within the gastrointestinal tract. It is widely accepted that highly diverse and stable microbiota promote overall human health. Colonization of the gut with maladaptive and pathogenic microbiota, a state also known as dysbiosis, is associated with a variety of peripheral diseases ranging from type 2 diabetes mellitus to cardiovascular and inflammatory bowel disease. More recently, microbial dysbiosis has been associated with a number of brain pathologies, including autism spectrum disorder, Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), suggesting a direct or indirect communication between intestinal bacteria and the central nervous system (CNS). In this review, we illustrate two pathways implicated in the crosstalk between gut microbiota and CNS involving 1) the vagus nerve and 2) transmission of signaling molecules through the circulatory system and across the blood-brain barrier (BBB). We summarize the available evidence of the specific changes in the intestinal microbiota, as well as microorganism-induced modifications to intestinal and BBB permeability, which have been linked to several neurodegenerative disorders including ALS, AD, and PD. Even though each of these diseases arises from unique pathogenetic mechanisms, all are characterized, at least in part, by chronic neuroinflammation. We provide an interpretation for the substantial evidence that healthy intestinal microbiota have the ability to positively regulate the neuroimmune responses in the CNS. Even though the evidence is mainly associative, it has been suggested that bacterial dysbiosis could contribute to an adverse neuroinflammatory state leading to increased risk of neurodegenerative diseases. Thus, developing strategies for regulating and maintaining healthy intestinal microbiota could be a valid approach for lowering individual risk and prevalence of neurodegenerative diseases.
PMID: 30114473 [PubMed – as supplied by publisher]
Alterations in hub organization in the white matter structural network in toddlers with autism spectrum disorder: A 2-year follow-up study.
Autism Res. 2018 Aug 16;:
Authors: Qian L, Wang Y, Chu K, Li Y, Xiao C, Xiao T, Xiao X, Qiu T, Xiao Y, Fang H, Ke X
Little is currently known about the longitudinal developmental patterns of hubs in the whole-brain white matter (WM) structural networks among toddlers with autism spectrum disorder (ASD). This study utilized diffusion tensor imaging (DTI) and deterministic tractography to map the WM structural networks in 37 ASD toddlers and 27 age-, gender- and developmental quotient-matched controls with developmental delay (DD) toddlers aged 2-3 years old at baseline (Time 1) and at 2-year follow-up (Time 2). Furthermore, graph-theoretical methods were applied to investigate alterations in the network hubs in these patients at the two time points. The results showed that after 2 years, 17 hubs were identified in the ASD subjects compared to the controls, including 13 hubs that had not changed from baseline and 4 hubs that were newly identified. In addition, alterations in the properties of the hubs of the right middle frontal gyrus, right insula, left median cingulate gyri, and bilateral precuneus were significantly correlated with alterations in the behavioral data for ASD patients. These results indicated that at the stage of 2-5 years of age, ASD children showed distributions of network hubs that were relatively stable, with minor differences. Abnormal developmental patterns in the five areas mentioned above in ASD may contribute to abnormalities in the social and nonsocial characteristics of this disorder.
LAY SUMMARY: This work studied the longitudinal developmental patterns of hubs in the whole-brain white matter (WM) structural network among toddlers with autism spectrum disorder (ASD). The findings of this study could have implications for understanding how the abnormalities in hub organization in ASD account for behavioral deficits in patients and may provide potential biomarkers for disease diagnosis and the subsequent monitoring of progression and treatment effects for patients with ASD.
PMID: 30114344 [PubMed – as supplied by publisher]
Heart rate mean and variability as a biomarker for phenotypic variation in preschoolers with autism spectrum disorder.
Autism Res. 2018 Aug 16;:
Authors: Bazelmans T, Jones EJH, Ghods S, Corrigan S, Toth K, Charman T, Webb SJ
Interest in autonomic arousal in autism spectrum disorder (ASD) is increasing; however, reliability of these measures in ASD is unknown, and previously reported associations with social and cognitive abilities are inconsistent. This study assesses heart rate (HR) and HR variability (HRV) in preschoolers with ASD or typical development (TD) while they passively watched naturalistic videos. Measurement reliability, group differences, and the relationship with social and cognitive abilities were evaluated. Seventy one ASD and 66 TD children (2-4 years) provided cardiac data from two sessions. Test-retest intraclass correlations of HR and HRV over a 3-week period were moderate to good in both groups. Groups did not differ in mean level of HR or HRV. Intra-individual variability of HR between video segments within a session was higher in the ASD group, but intraclass correlations of this metric were low. Higher HR related to better language skills in TD children, but not after accounting for age and nonverbal ability. Higher HRV related to better expressive and receptive language in ASD children after controlling for age and nonverbal ability. HR/HRV were not related to social or executive functioning skills and did not explain any additional variance in abilities at a 12-month follow-up visit. In summary, variation in language abilities is associated with HR in the TD group and HRV in the ASD group. While preliminary, these results are promising for consideration of autonomic control as a biomarker for individual differences in ASD and may help us understand the mechanisms that contribute to communication skills.
LAY SUMMARY: Cardiac activity, such as heart rate and heart rate variability, is linked to a wide range of psychological functions. This study shows that there is an association between heart rate and heart rate variability and language skills in young children with autism spectrum disorder (ASD). These results may help us understand what underlies individual differences in developmental abilities in young children with ASD.
PMID: 30114343 [PubMed – as supplied by publisher]
Brain morphometry of preschool age children affected by autism spectrum disorder: correlation with clinical findings.
Clin Anat. 2018 Aug 16;:
Authors: Lucibello S, Verdolotti T, Giordano FM, Lapenta L, Infante A, Piludu F, Tartaglione T, Chieffo D, Colosimo C, Mercuri E, Battini R
INTRODUCTION: The aim of our study was to use a combined imaging and clinical approach to identify possible patterns of clinical and imaging findings in a cohort of preschool age Autism Spectrum Disorder (ASD) patients.
MATERIAL AND METHODS: In order to identify imaging patterns that could be related to specific clinical features, a selected group of ASD patients (age range 3-6 years) without dysmorphic features, epilepsy or other major neurological signs, malformations or other lesions at MRI was subjected to brain volumetric analysis using semiautomatic brain segmentation. An age-matched group of typically developing children was subjected to the same analysis.
RESULTS: Our results were consistent with previous literature: Total Gray Matter Volume, Total Cortical Gray Matter Volume and amygdalar volumes were significantly greater in the ASD group than the control group. When we divided the study group into subgroups on the basis of clinical findings such as high- or low-functioning, or verbal and non-verbal, the only significant difference between verbal and non-verbal subjects was in cerebellar hemispheric size.
CONCLUSIONS: Our results confirm that newer brain MRI techniques using semiautomatic brain segmentation can provide information useful for defining the differences between ASD patients and controls, particularly if they form part of an integrated approach between MRI and cognitive-behavioral and genetic data. This article is protected by copyright. All rights reserved.
PMID: 30113100 [PubMed – as supplied by publisher]
Racial-ethnic and neighborhood inequities in age of treatment receipt among a national sample of children with autism spectrum disorder.
Autism. 2018 Aug 16;:1362361318791816
Authors: Yingling ME, Bell BA
The aim of this study is to examine the impact of child race-ethnicity and neighborhood characteristics on age of treatment receipt among children with autism spectrum disorder. Here, we included 1309 children diagnosed with autism spectrum disorder in the National Survey of Children’s Health, 2011-2012. Controlling for key covariates, we used a weighted generalized logit model to analyze differences in age of treatment receipt (<2 years, 2 years, 3 years, and ⩾4 years). Compared to non-Hispanic White children, the relative probability (odds) of entering treatment at 3 years and ⩾4 years rather than <2 years was 326% and 367% higher, respectively, for non-Hispanic Black children. Compared to children whose parents perceived their neighborhood to be cohesive, the relative probability of entering treatment at 2 years and 3 years rather than <2 years was 59% and 61% lower, respectively, for children whose parents did not. Significant racial-ethnic and neighborhood inequities exist in age of treatment receipt, suggesting a need for research that explores the underlying causal mechanisms of inequities.
PMID: 30112915 [PubMed – as supplied by publisher]
Measuring the service system impact of a novel telediagnostic service program for young children with autism spectrum disorder.
Autism. 2018 Aug 16;:1362361318787797
Authors: Stainbrook JA, Weitlauf AS, Juárez AP, Taylor JL, Hine J, Broderick N, Nicholson A, Warren Z
As prevalence of autism spectrum disorder continues to increase, so too does the need for timely, accessible diagnostic consultation. The present work extends from a previous study which provided preliminary evidence for the feasibility of expert clinicians to utilize telemedicine to triage autism spectrum disorder risk in young children. However, it did not examine whether a telediagnostic model had a demonstrable impact on tertiary care center referrals and usage. We therefore examined whether the introduction of telemedicine-based diagnostic consultation for families served by a rural medical facility affected referrals overall as well as to a metropolitan tertiary care diagnostic center. Results suggest that telemedicine diagnostic consultation in partnership with a referring early intervention system may positively impact referrals for diagnostic evaluation as well as the ability of families to schedule and attend appointments.
PMID: 30112912 [PubMed – as supplied by publisher]
The Use of Multi-parametric Biomarker Profiles May Increase the Accuracy of ASD Prediction.
J Mol Neurosci. 2018 Aug 15;:
Authors: Hassan WM, Al-Ayadhi L, Bjørklund G, Alabdali A, Chirumbolo S, El-Ansary A
Effective biomarkers are urgently needed to facilitate early diagnosis of autism spectrum disorder (ASD), permitting early intervention, and consequently improving prognosis. In this study, we evaluate the usefulness of nine biomarkers and their association (combination) in predicting ASD onset and development. Data were analyzed using multiple independent mathematical and statistical approaches to verify the suitability of obtained results as predictive parameters. All biomarkers tested appeared useful in predicting ASD, particularly vitamin E, glutathione-S-transferase, and dopamine. Combining biomarkers into profiles improved the accuracy of ASD prediction but still failed to distinguish between participants with severe versus mild or moderate ASD. Library-based identification was effective in predicting the occurrence of disease. Due to the small sample size and wide participant age variation in this study, we conclude that the use of multi-parametric biomarker profiles directly related to autism phenotype may help predict the disease occurrence more accurately, but studies using larger, more age-homogeneous populations are needed to corroborate our findings.
PMID: 30112624 [PubMed – as supplied by publisher]
A Novel Deep Learning Approach for Recognizing Stereotypical Motor Movements within and across Subjects on the Autism Spectrum Disorder.
Comput Intell Neurosci. 2018;2018:7186762
Authors: Sadouk L, Gadi T, Essoufi EH
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent difficulties including repetitive patterns of behavior known as stereotypical motor movements (SMM). So far, several techniques have been implemented to track and identify SMMs. In this context, we propose a deep learning approach for SMM recognition, namely, convolutional neural networks (CNN) in time and frequency-domains. To solve the intrasubject SMM variability, we propose a robust CNN model for SMM detection within subjects, whose parameters are set according to a proper analysis of SMM signals, thereby outperforming state-of-the-art SMM classification works. And, to solve the intersubject variability, we propose a global, fast, and light-weight framework for SMM detection across subjects which combines a knowledge transfer technique with an SVM classifier, therefore resolving the “real-life” medical issue associated with the lack of supervised SMMs per testing subject in particular. We further show that applying transfer learning across domains instead of transfer learning within the same domain also generalizes to the SMM target domain, thus alleviating the problem of the lack of supervised SMMs in general.
PMID: 30111994 [PubMed – in process]
Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing.
Nature. 2018 Aug 15;:
Authors: Parras A, Anta H, Santos-Galindo M, Swarup V, Elorza A, Nieto-González JL, Picó S, Hernández IH, Díaz-Hernández JI, Belloc E, Rodolosse A, Parikshak NN, Peñagarikano O, Fernández-Chacón R, Irimia M, Navarro P, Geschwind DH, Méndez R, Lucas JJ
Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.
PMID: 30111840 [PubMed – as supplied by publisher]
Alterations in the MicroRNA of the Blood of Autism Spectrum Disorder Patients: Effects on Epigenetic Regulation and Potential Biomarkers.
Behav Sci (Basel). 2018 Aug 15;8(8):
Authors: Vaccaro TDS, Sorrentino JM, Salvador S, Veit T, Souza DO, de Almeida RF
Aims: Autism spectrum disorder (ASD) refers to a group of heterogeneous brain-based neurodevelopmental disorders with different levels of symptom severity. Given the challenges, the clinical diagnosis of ASD is based on information gained from interviews with patients’ parents. The heterogeneous pathogenesis of this disorder appears to be driven by genetic and environmental interactions, which also plays a vital role in predisposing individuals to ASD with different commitment levels. In recent years, it has been proposed that epigenetic modifications directly contribute to the pathogenesis of several neurodevelopmental disorders, such as ASD. The microRNAs (miRNAs) comprises a species of short noncoding RNA that regulate gene expression post-transcriptionally and have an essential functional role in the brain, particularly in neuronal plasticity and neuronal development, and could be involved in ASD pathophysiology. The aim of this study is to evaluate the expression of blood miRNA in correlation with clinical findings in patients with ASD, and to find possible biomarkers for the disorder. Results: From a total of 26 miRNA studied, seven were significantly altered in ASD patients, when compared to the control group: miR34c-5p, miR92a-2-5p, miR-145-5p and miR199a-5p were up-regulated and miR27a-3p, miR19-b-1-5p and miR193a-5p were down-regulated in ASD patients. Discussion: The main targets of these miRNAs are involved in immunological developmental, immune response and protein synthesis at transcriptional and translational levels. The up-regulation of both miR-199a-5p and miR92a-2a and down-regulation of miR-193a and miR-27a was observed in AD patients, and may in turn affect the SIRT1, HDAC2, and PI3K/Akt-TSC:mTOR signaling pathways. Furthermore, MeCP2 is a target of miR-199a-5p, and is involved in Rett Syndrome (RTT), which possibly explains the autistic phenotype in male patients with this syndrome.
PMID: 30111726 [PubMed]
Paranoia, autism and the architecture of genomic conflicts: a reply to Abu-Akel 2018.
Biol Lett. 2018 Aug;14(8):
Authors: Crespi BJ
PMID: 30111660 [PubMed – in process]
Genetic variations in the SNP rs850807 reflect a trade-off between autism and paranoia symptom expressions: a comment on Crespi et al. 2018.
Biol Lett. 2018 Aug;14(8):
Authors: Abu-Akel A
PMID: 30111658 [PubMed – in process]
Discoveries on the Genetics of ADHD in the 21st Century: New Findings and Their Implications.
Am J Psychiatry. 2018 Aug 16;:appiajp201818040383
Authors: Thapar A
The 21st century has witnessed the discovery of multiple rare and common gene variants associated with attention deficit hyperactivity disorder (ADHD), and these discoveries have already provided a starting point for the investigation of the biology of the disorder and novel treatments. The purpose of this selective review is to examine genetic findings from the past 5 years and consider their implications for the conceptualization of ADHD and future clinical practice. Recent discoveries reveal the strong genetic overlaps between ADHD and autism spectrum disorder (ASD) as well as intellectual disability. Thus, the removal of the previous diagnostic exclusion criteria for ADHD in the presence of ASD is a welcome change in DSM-5. However, ADHD also shows substantial genetic correlations with a much broader group of neuropsychiatric disorders as well as with nonpsychiatric conditions (e.g., lung cancer). Investigating potential explanations for these links is an important next step. ADHD, while usefully conceptualized as a disorder in clinical practice, can be viewed as a trait. Recent genome-wide association study findings, consistent with twin studies, highlight that ADHD lies at the extreme end of a continuously distributed dimension, akin to hypertension along the continuum of blood pressure. Although ADHD levels typically decline with age, twin and molecular genetic studies suggest that a persistent trajectory is associated with higher genetic loading. Routine testing for rare mutations in ADHD is not yet recommended, although guidelines in many countries recommend testing individuals with mild intellectual disability or ASD, so practice could change. Common gene variants for ADHD are only weakly predictive and therefore have limited clinical value at present, as does pharmacogenomics. [AJP at 175: Remembering Our Past As We Envision Our Future November 1938: Electroencephalographic Analyses of Behavior Problem Children The electroencephalogram was the first biological technique to be applied to childhood behavioral disorders. Jasper, Solomon, and Bradley reported that “the electroencephalogram has succeeded in revealing a definite abnormality of brain function in over one half of a group of childhood behavior disorders which had been previously considered as largely psychogenic.” (Am J Psychiatry 1938; 95:641-658 )].
PMID: 30111187 [PubMed – as supplied by publisher]
Association of Maternal Insecticide Levels With Autism in Offspring From a National Birth Cohort.
Am J Psychiatry. 2018 Aug 16;:appiajp201817101129
Authors: Brown AS, Cheslack-Postava K, Rantakokko P, Kiviranta H, Hinkka-Yli-Salomäki S, McKeague IW, Surcel HM, Sourander A
OBJECTIVE: Autism is a complex neurodevelopmental disorder with a largely unknown etiology. To date, few studies have investigated prenatal exposure to toxins and risk of autism by using maternal biomarkers of exposure. Persistent organic pollutants are lipophilic halogenated organic compounds and include the insecticide dichlorodiphenyltrichloroethane (DDT), as well as its metabolite p,p’-dichlorodiphenyl dichloroethylene (p,p’-DDE), and polychlorinated biphenyls (PCBs). The objective of this study was to test whether elevated maternal levels of persistent organic pollutants are associated with autism among offspring.
METHOD: The investigation was derived from the Finnish Prenatal Study of Autism, a national birth cohort study based on a nested case-control design. Cases of autism among children born between 1987 and 2005 were ascertained by national registry linkages. In cases of childhood autism and matched control subjects (778 matched case-control pairs), maternal serum specimens from early pregnancy were assayed for levels of p,p’-DDE and total levels of PCBs.
RESULTS: The odds of autism among offspring were significantly increased with maternal p,p’-DDE levels that were in the highest 75th percentile, with adjustment for maternal age, parity, and history of psychiatric disorders (odds ratio=1.32, 95% CI=1.02, 1.71). The odds of autism with intellectual disability were increased by greater than twofold with maternal p,p’-DDE levels above this threshold (odds ratio=2.21, 95% CI=1.32, 3.69). There was no association between total levels of maternal PCBs and autism.
CONCLUSIONS: These findings provide the first biomarker-based evidence that maternal exposure to insecticides is associated with autism among offspring. Although further research is necessary to replicate this finding, this study has implications for the prevention of autism and may provide a better understanding of its pathogenesis.
PMID: 30111184 [PubMed – as supplied by publisher]
Evaluating Efficacy and Preference for Prompt Type During Discrete-Trial Teaching.
Behav Modif. 2018 Aug 16;:145445518792245
Authors: Markham V, Giles A, May R
The components of discrete-trial teaching (DTT) may be individualized to each learner during instruction (e.g., the type of prompts used). However, there is limited research on the relative efficiency and effectiveness of these different prompt types. In addition, the learner’s preference for how they are taught is not always considered. The present study compared relative effectiveness of three prompt types (i.e., a gesture, modeling, physical guidance) to a no-prompt control condition during a receptive identification task with three boys with autism. One participant met the mastery criterion first in the model prompt condition, and two participants in the physical prompt condition. All participants selected the physical prompt during a concurrent-chains preference assessment. In addition, all participants completed a chained task using the most effective prompt type.
PMID: 30111164 [PubMed – as supplied by publisher]
Dietary supplements in child and adolescent psychiatry.
Actas Esp Psiquiatr. 2017 Sep;45(Supplement):48-64
Authors: Espín-Jaime JC, Cerezo-Navarro MV
Complementary and alternative treatments, including dietary supplements, are very popular and increasingly used in developed countries. Some features such as accessibility, ease of use, the possibility of self-administration and the belief they are safe without side effects, have led to an increase in their consumption. However, there is limited evidence of the effectiveness and safety of these treatments because of methodological issues. The level of scientific evidence is particularly low and weak in the field of child and adolescent Psychiatry. The purpose of this article is to give an updated overview of dietary treatments in this area. We make a brief introduction about general questions, including legal aspects, and propose general practical recommendations for a proper management by the families that choose these treatments. We focus on reviewing the current state of research into dietary treatments in some childhood and juvenile psychiatric disorders, highlighting current evidence of specific treatments. The final purpose of this article is to describe the level of current evidence on dietary treatments and to provide professionals involved in the care of children and adolescents with a useful tool to help, guide and educate families about their use in order to achieve the greatest benefit to patients.
PMID: 29171641 [PubMed – indexed for MEDLINE]
Regional Volumetric Abnormalities in Pediatric Autism Revealed by Structural Magnetic Resonance Imaging.
Int J Dev Neurosci. 2018 Aug 12;:
Authors: Levman J, Vasung L, MacDonald P, Rowley S, Stewart N, Lim A, Ewenson B, Galaburda A, Takahashi E
Autism is a group of complex neurodevelopmental disorders characterized by impaired social interaction, restricted and repetitive behavior. We performed a large-scale retrospective analysis of 1,996 structural magnetic resonance imaging (MRI) examinations of the brain from 1,769 autistic and neurologically typically developing patients (aged 0 to 32 years), and extracted regional volumetric measurements distributed across 463 brain regions of each patient. The youngest autistic patients (< 2.5 years) were diagnosed after imaging and identified retrospectively. Our study demonstrates increased corpus callosum volumes among autistic patients in early childhood (0 to 5 years old), followed by a shift towards known decreased volumes in later ages. Results confirm known increases in ventricular volumes among autistic populations and extends those findings to increased volumes of the choroid plexus. Our study also demonstrates distributed volumetric abnormalities among autistic patients that affect a variety of key regional white and grey matter areas of the brain potentially associated with known symptoms of autism.
PMID: 30110650 [PubMed – as supplied by publisher]
Common Genetic Variants Link the Abnormalities in the Gut-Brain Axis in Prematurity and Autism.
Cerebellum. 2018 Aug 14;:
Authors: Sajdel-Sulkowska EM, Makowska-Zubrycka M, Czarzasta K, Kasarello K, Aggarwal V, Bialy M, Szczepanska-Sadowska E, Cudnoch-Jedrzejewska A
This review considers a link between prematurity and autism by comparing symptoms, physiological abnormalities, and behavior. It focuses on the bidirectional signaling between the microbiota and the brain, here defined as the microbiota-gut-vagus-heart-brain (MGVHB) axis and its systemic disruption accompanying altered neurodevelopment. Data derived from clinical and animal studies document increased prevalence of gastrointestinal, cardiovascular, cognitive, and behavioral symptoms in both premature and autistic children and suggest an incomplete maturation of the gut-blood barrier resulting in a “leaky gut,” dysbiosis, abnormalities in vagal regulation of the heart, altered development of specific brain regions, and behavior. Furthermore, this review posits the hypothesis that common genetic variants link the abnormalities in the MGVHB axis in premature and autistic pathologies. This hypothesis is based on the recently identified common genetic variants: early B cell factor 1 (EBF1), selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC), and angiotensin II receptor type 2 (AGTR2), in the maternal and infant DNA samples, associated with risk of preterm birth and independently implicated in a risk of autism. We predict that the AGTR2 variants involved in the brain maturation and oxytocin-arginine-vasopressin (OXT-AVP) pathways, related to social behavior, will contribute to our understanding of the link between prematurity and autism paving a way to new therapies.
PMID: 30109601 [PubMed – as supplied by publisher]
A Randomized, Placebo-Controlled, Blinded, Crossover, Pilot Study of the Effects of Dextromethorphan/Quinidine for the Treatment of Neurobehavioral Symptoms in Adults with Autism.
J Autism Dev Disord. 2018 Aug 14;:
Authors: Chez M, Kile S, Lepage C, Parise C, Benabides B, Hankins A
Prior studies have demonstrated successful irritability treatment using dopaminergic antagonists in autistic patients. The purpose of this pilot study was to assess the effect of dextromethorphan/quinidine (DM/Q) in autistic adults (18-60 years of age). This was a randomized, blinded, crossover, study of 14 patients randomized to DM/Q or a placebo for 8 weeks, washed out for 4 weeks, then crossed over to the opposite treatment. There were no serious adverse events. Subjects were significantly lower on the Aberrant Behavioral Checklist for Irritability (ABC-IR) (F1,10 = 7.42; p = 0.021). Improvements in aggression and Clinical Global Impression were also seen. The findings suggest that DM/Q is well-tolerated and associated with improvements in irritability and aggression in adults with autism.
PMID: 30109474 [PubMed – as supplied by publisher]
Recent advances in understanding the mechanisms of cerebellar granule cell development and function and their contribution to behavior.
Authors: Lackey EP, Heck DH, Sillitoe RV
The cerebellum is the focus of an emergent series of debates because its circuitry is now thought to encode an unexpected level of functional diversity. The flexibility that is built into the cerebellar circuit allows it to participate not only in motor behaviors involving coordination, learning, and balance but also in non-motor behaviors such as cognition, emotion, and spatial navigation. In accordance with the cerebellum’s diverse functional roles, when these circuits are altered because of disease or injury, the behavioral outcomes range from neurological conditions such as ataxia, dystonia, and tremor to neuropsychiatric conditions, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. Two major questions arise: what types of cells mediate these normal and abnormal processes, and how might they accomplish these seemingly disparate functions? The tiny but numerous cerebellar granule cells may hold answers to these questions. Here, we discuss recent advances in understanding how the granule cell lineage arises in the embryo and how a stem cell niche that replenishes granule cells influences wiring when the postnatal cerebellum is injured. We discuss how precisely coordinated developmental programs, gene expression patterns, and epigenetic mechanisms determine the formation of synapses that integrate multi-modal inputs onto single granule cells. These data lead us to consider how granule cell synaptic heterogeneity promotes sensorimotor and non-sensorimotor signals in behaving animals. We discuss evidence that granule cells use ultrafast neurotransmission that can operate at kilohertz frequencies. Together, these data inspire an emerging view for how granule cells contribute to the shaping of complex animal behaviors.
PMID: 30109024 [PubMed – in process]
Relationship Between Theory of Mind, Emotion Recognition, and Social Synchrony in Adolescents With and Without Autism.
Front Psychol. 2018;9:1337
Authors: Fitzpatrick P, Frazier JA, Cochran D, Mitchell T, Coleman C, Schmidt RC
Difficulty in social communication and interaction is a primary diagnostic feature of ASD. Research has found that adolescents with ASD display various impairments in social behavior such as theory of mind (ToM), emotion recognition, and social synchrony. However, not much is known about the relationships among these dimensions of social behavior. Adolescents with and without ASD participated in the study. ToM ability was measured by viewing social animations of geometric shapes, recognition of facial emotions was measured by viewing pictures of faces, and synchrony ability was measured with a spontaneously arising interpersonal movement task completed with a caregiver and an intentional interpersonal task. Attention and social responsiveness were measured using parent reports. We then examined the relationship between ToM, emotion recognition, clinical measures of attention and social responsiveness, and social synchronization that arises either spontaneously or intentionally. Results indicate that spontaneous synchrony was related to ToM and intentional synchrony was related to clinical measures of attention and social responsiveness. Facial emotion recognition was not related to either ToM or social synchrony. Our findings highlight the importance of biological motion perception and production and attention for more fully understanding the social behavior characteristic of ASD. The findings suggest that the processes underlying difficulties in spontaneous synchrony in ASD are different than the processes underlying difficulties in intentional synchronization.
PMID: 30108541 [PubMed]
Diet Can Impact Microbiota Composition in Children With Autism Spectrum Disorder.
Front Neurosci. 2018;12:515
Authors: Berding K, Donovan SM
Diet is one of the most influential environmental factors in determining the composition of the gastrointestinal microbiota. Microbial dysbiosis in children with Autism Spectrum Disorder (ASD) and the impact of some bacterial taxa on symptoms of ASD has been recognized. Children with ASD are often described as picky eaters with low intake of fiber-rich foods, including fruits and vegetables. However, the impact of diet on the microbiota composition in children with ASD is largely unknown. Herein, fecal samples, 3 day food diaries and the Youth and Adolescence Food Frequency questionnaire (YAQ) were collected from children with ASD (ASD; n = 26) and unaffected controls (CONT; n = 32). Children’s ASD symptoms were determined using the Pervasive Developmental Disorder Behavior Inventory Screening Version (PDDBI-SV). Differences in the microbiota composition at the phyla, order, family, and genus level between ASD and CONT were observed. Microbiota composition of children with ASD was investigated in relation to feeding behavior, nutrient and food group intake as well as dietary patterns derived from the YAQ. In children with ASD, two distinct dietary patterns (DP) were associated with unique microbial profiles. DP1, characterized by higher intakes of vegetables, legumes, nuts and seeds, fruit, refined carbohydrates, and starchy vegetables, but lower intakes of sweets, was associated with lower abundance of Enterobacteriaceae, Lactococcus, Roseburia, Leuconostoc, and Ruminococcus. DP2, characterized by low intakes of vegetables, legumes, nuts and seeds and starchy vegetables, was associated with higher Barnesiellaceae and Alistipes and lower Streptophyta, as well as higher levels of propionate, isobutyrate, valerate, and isovalerate. Peptostreptococcaceae and Faecalibacterium predicted social deficit scores in children with ASD as measured by the PDDBI-SV. Diet-associated microbial profiles were related to GI symptoms, but no significant interaction between nutrition and microbiota in predicting social deficit scores were observed. In conclusion, dietary patterns associated with fecal microbiota composition and VFA concentrations in children with ASD were identified. Future studies using a larger sample size and measuring other behaviors associated with ASD are needed to investigate whether dietary intake may be a modifiable moderator of ASD symptoms.
PMID: 30108477 [PubMed]
Oxytocin Enhancement of Emotional Empathy: Generalization Across Cultures and Effects on Amygdala Activity.
Front Neurosci. 2018;12:512
Authors: Geng Y, Zhao W, Zhou F, Ma X, Yao S, Hurlemann R, Becker B, Kendrick KM
Accumulating evidence suggests that the neuropeptide oxytocin (OXT) can enhance empathy although it is unclear which specific behavioral and neural aspects are influenced, and whether the effects are modulated by culture, sex, and trait autism. Based on previous findings in Caucasian men, we hypothesized that a single intranasal dose of OXT would specifically enhance emotional empathy (EE) via modulatory effects on the amygdala in an Asian (Chinese) population and explored the modulatory role of sex and trait autism on the effects. We first conducted a double-blind, randomized between-subject design experiment using a modified version of the multifaceted empathy task to determine whether OXT’s facilitation of EE can be replicated in Chinese men (n = 60). To further explore neural mechanisms behind and potential sex differences, functional MRI and skin conductance measures were acquired in an independent experiment incorporating men and women (n = 72). OXT enhanced EE across experiments and sex, an effect that was accompanied by reduced amygdala activity and increased skin conductance responses. On the network level OXT enhanced functional coupling of the right amygdala with the insula and posterior cingulate cortex for positive valence stimuli but attenuated coupling for negative valence stimuli. The effect of OXT on amygdala functional connectivity with the insula was modulated by trait autism. Overall, our findings provide further support for the role of OXT in facilitating EE and demonstrate that effects are independent of culture and sex and involve modulatory effects on the amygdala and its interactions with other key empathy regions.
PMID: 30108475 [PubMed]
Association study and mutation sequencing of genes on chromosome 15q11-q13 identified GABRG3 as a susceptibility gene for autism in Chinese Han population.
Transl Psychiatry. 2018 Aug 14;8(1):152
Authors: Wang L, Li J, Shuang M, Lu T, Wang Z, Zhang T, Yue W, Jia M, Ruan Y, Liu J, Wu Z, Zhang D, Wang L
Cytogenetic studies suggested that chromosome 15q11-q13 might be a candidate region that increases the risk of autism. Previous association studies in Caucasian populations identified the risk variants of genes in this region. However, the association of these genes with autism in Chinese Han population remains unclear. Herein, 512 autism trios were utilized for a family-based association study of 41 tag single nucleotide polymorphisms (SNPs) in this region to explore the association between protein-coding genes on chromosome 15q11-q13 and autism in Chinese Han population. Furthermore, we sequenced these autism-related genes to detect rare variants in 512 autism trios and 575 healthy controls. Our results showed that the C allele of rs7180500 in GABRG3 was a risk variant for autism (p = 0.00057). The expression quantitative trait loci (eQTL) analysis revealed that the C allele of rs7180500 might be associated with the expression of GABRG3 in the cerebellum (Braineac: p = 0.0048; GTEx: p = 0.0010). Moreover, the sequencing identified two rare variants rs201602655 (p.Val233Met) and rs201427468 (p.Pro365Ser) in GABRG3 and six rare variants in GABRB3 in autistic patients. Among these variants, rs201602655 (p.Val233Met) in GABRG3 were observed in 9 of 512 autistic children and 2 of 575 healthy controls (Pearson χ2-test, χ2 = 5.375, p = 0.020). The functional prediction indicated that rs201602655 (p.Val233Met) might be deleterious. Thus, these findings demonstrated that GABRG3 might contribute to the pathogenesis of autism in Chinese Han population.
PMID: 30108208 [PubMed – in process]
Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8.
Proc Natl Acad Sci U S A. 2018 Aug 14;:
Authors: Marie C, Clavairoly A, Frah M, Hmidan H, Yan J, Zhao C, Van Steenwinckel J, Daveau R, Zalc B, Hassan B, Thomas JL, Gressens P, Ravassard P, Moszer I, Martin DM, Lu QR, Parras C
Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.
PMID: 30108144 [PubMed – as supplied by publisher]
Family-Driven Goals To Improve Care for Children With Autism Spectrum Disorder.
Pediatrics. 2018 Aug 14;:
Authors: Bellesheim KR, Cole L, Coury DL, Yin L, Levy SE, Guinnee MA, Klatka K, Malow BA, Katz T, Taylor J, Sohl K
OBJECTIVES: Constipation and insomnia are not consistently identified and treated in children with autism spectrum disorder (ASD) despite their high prevalence and deleterious impact in this population. To standardize care, a constipation practice pathway and an insomnia practice pathway were previously developed by Autism Treatment Network clinicians. Our objective was to implement and refine these practice pathways in clinical settings.
METHODS: Eleven Autism Treatment Network sites participated in a Learning Collaborative (ie, multidisciplinary quality improvement team) and chose to implement either the constipation or insomnia practice pathway in the clinical setting. Families set intervention goals (eg, increase stool frequency, decrease nighttime awakenings) before treatment. Each site began implementation with 1 patient and then increased implementation by factors of 5. Before each increase, the Learning Collaborative evaluated progress and refined the practice pathways. Process improvement was measured primarily by duration until goal attainment and by percentage of families who meet their goals.
RESULTS: Across sites, 82 children with ASD and constipation and 101 children with ASD and insomnia were managed. Difficulties with intervention adherence and communication between providers and families were reported and were subsequently improved with parallel refinements to both practice pathways. The most notable modification was incorporating a goal-setting session in which families generated their own intervention goals (ie, family-driven goals). In this quality improvement initiative, 75% of families met at least 1 constipation or insomnia goal, with the median time to improvement being 6 weeks.
CONCLUSIONS: By integrating a family-centered approach into the standardization of care, constipation and insomnia practice pathways may improve engagement, adherence, and management of medical conditions in children with ASD.
PMID: 30108141 [PubMed – as supplied by publisher]
The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13).
Autism Res. 2018 Aug 14;:
Authors: Wegiel J, Brown WT, La Fauci G, Adayev T, Kascsak R, Kascsak R, Flory M, Kaczmarski W, Kuchna I, Nowicki K, Martinez-Cerdeno V, Wisniewski T, Wegiel J
Fragile X syndrome (FXS), caused by lack of fragile X mental retardation protein (FMRP), is associated with a high prevalence of autism. The deficit of FMRP reported in idiopathic autism suggests a mechanistic overlap between FXS and autism. The overall goal of this study is to detect neuropathological commonalities of FMRP deficits in the brains of people with idiopathic autism and with syndromic autism caused by dup15q11.2-q13 (dup15). This study tests the hypothesis based on our preliminary data that both idiopathic and syndromic autism are associated with brain region-specific deficits of neuronal FMRP and structural changes of the affected neurons. This immunocytochemical study revealed neuronal FMRP deficits and shrinkage of deficient neurons in the cerebral cortex, subcortical structures, and cerebellum in subjects with idiopathic and dup(15)/autism. Neuronal FMRP deficit coexists with surprising infiltration of the brains of autistic children and adults with FMRP-positive astrocytes known to be typical only for the fetal and short postnatal periods. In the examined autistic subjects, these astrocytes selectively infiltrate the border between white and gray matter in the cerebral and cerebellar cortex, the molecular layer of the cortex, part of the amygdala and thalamus, central cerebellar white matter, and dentate nucleus. Astrocyte pathology results in an additional local loss of FMRP in neurons and their shrinkage. Neuronal deficit of FMRP and shrinkage of affected neurons in structures free of FMRP-positive astrocytes and regions infiltrated with FMRP-expressing astrocytes appear to reflect mechanistic, neuropathological, and functional commonalities of FMRP abnormalities in FXS and autism spectrum disorder.
LAY SUMMARY: Immunocytochemistry reveals a deficit of fragile X mental retardation protein (FMRP) in neurons of cortical and subcortical brain structures but increased FMRP expression in astrocytes infiltrating gray and white matter. The detected shrinkage of FMRP-deficient neurons may provide a mechanistic explanation of reported neuronal structural and functional changes in autism. This study contributes to growing evidence of mechanistic commonalities between fragile X syndrome and autism spectrum disorder.
PMID: 30107092 [PubMed – as supplied by publisher]
The autism spectrum phenotype in ADNP syndrome.
Autism Res. 2018 Aug 14;:
Authors: Arnett AB, Rhoads CL, Hoekzema K, Turner TN, Gerdts J, Wallace AS, Bedrosian-Sermone S, Eichler EE, Bernier RA
Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits.
LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment.
PMID: 30107084 [PubMed – as supplied by publisher]
Oral microbiome activity in children with autism spectrum disorder.
Autism Res. 2018 Aug 14;:
Authors: Hicks SD, Uhlig R, Afshari P, Williams J, Chroneos M, Tierney-Aves C, Wagner K, Middleton FA
Autism spectrum disorder (ASD) is associated with several oropharyngeal abnormalities, including buccal sensory sensitivity, taste and texture aversions, speech apraxia, and salivary transcriptome alterations. Furthermore, the oropharynx represents the sole entry point to the gastrointestinal (GI) tract. GI disturbances and alterations in the GI microbiome are established features of ASD, and may impact behavior through the “microbial-gut-brain axis.” Most studies of the ASD microbiome have used fecal samples. Here, we identified changes in the salivary microbiome of children aged 2-6 years across three developmental profiles: ASD (n = 180), nonautistic developmental delay (DD; n = 60), and typically developing (TD; n = 106) children. After RNA extraction and shotgun sequencing, actively transcribing taxa were quantified and tested for differences between groups and within ASD endophenotypes. A total of 12 taxa were altered between the developmental groups and 28 taxa were identified that distinguished ASD patients with and without GI disturbance, providing further evidence for the role of the gut-brain axis in ASD. Group classification accuracy was visualized with receiver operating characteristic curves and validated using a 50/50 hold-out procedure. Five microbial ratios distinguished ASD from TD participants (79.5% accuracy), three distinguished ASD from DD (76.5%), and three distinguished ASD children with/without GI disturbance (85.7%). Taxonomic pathways were assessed using the Kyoto Encyclopedia of Genes and Genomes microbial database and compared with one-way analysis of variance, revealing significant differences within energy metabolism and lysine degradation. Together, these results indicate that GI microbiome disruption in ASD extends to the oropharynx, and suggests oral microbiome profiling as a potential tool to evaluate ASD status.
LAY SUMMARY: Previous research suggests that the bacteria living in the human gut may influence autistic behavior. This study examined genetic activity of microbes living in the mouth of over 300 children. The microbes with differences in children with autism were involved in energy processing and showed potential for identifying autism status.
PMID: 30107083 [PubMed – as supplied by publisher]
Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
J Clin Invest. 2018 Aug 14;:
Authors: Hacohen-Kleiman G, Sragovich S, Karmon G, Gao AYL, Grigg I, Pasmanik-Chor M, Le A, Korenková V, McKinney RA, Gozes I
Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/-) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet, drug candidate NAP (NAPVSIPQ also known as CP201), which binds to microtubule end binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane tagged green fluorescent protein expressing Adnp+/- mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/- mice further exhibited global developmental delays, vocalization impediments, gait/motor dysfunctions and social/object memory impairments, all partially reversed by daily NAP administration (systemic/nasal). In conclusion, we now connected ADNP-related synaptic pathology to developmental/behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave the path toward clinical development of NAP (CP201) in the ADNP syndrome.
PMID: 30106381 [PubMed – as supplied by publisher]