This paper offers an in-depth exploration of the complex relationship between seasonality and Autism Spectrum Disorder (ASD). It reviews existing research, providing a comprehensive summary of findings and highlighting the multifaceted dimensions of seasonality as an environmental factor that influences the etiology of ASD. The discussion encompasses various factors, including birth months, maternal health, dietary choices, and vitamin D deficiency, and delves into the intricate interplay of seasonality with environmental influences such as viral infections and solar radiation. The present study raises essential questions regarding the timing of environmental influences and the factors contributing to the rising prevalence of ASD. Ultimately, it underscores the need for future epidemiological research to incorporate more extensive investigations of environmental risk factors and employ advanced statistical analyses. This comprehensive overview contributes to a deeper understanding of how seasonality factors may be linked to the occurrence of ASD and its increasing prevalence, recognizing the multifaceted and diverse nature of these interactions.

Social communication skills, especially eye contact and joint attention, are highly impaired in autism spectrum disorder (ASD) and predict functional outcomes. Applied Behavior Analysis is one of the best evidence-based treatments for ASD, but it is not accessible to most families in low- and middle-income countries (LMICs) as it is a costly and intensive and needs to be delivered by highly specialized professionals. Parental training has emerged as an effective alternative. The aim of this study was to test the efficacy of a parental intervention group via video modeling to acquire eye contact and joint attention. Four graded measures of eye contact and joint attention (full physical prompt, partial physical prompt, gestural prompt, and independent) were assessed in 34 children with ASD and intellectual disability (ID). There was a progressive reduction in the level of prompt required over time to acquire eye contact and joint attention, and a positive correlation between the time of exposure to the intervention and acquisition of the abilities. This parent training using video modelling to teach eye contact and joint attention skills to children with ASD and ID is a low-cost intervention that can be applied in low- resource settings.

Abstract: Autism spectrum disorders (ASDs) are complex, lifelong, neurodevelopmental conditions of largely unknown cause. The global prevalence of autism has increased twentyfold to thirtyfold since the earliest epidemiologic studies were conducted in the late 1960s and early 1970s. Recent reports agree on the association of ASD with the alteration of the microbiome (dysbiosis), which raises the possible role of external factors. Our study aimed at identifying antibiotic classes that might be associated with the development of ASD-related dysbiosis either promoting or inhibiting the process. Statistical comparison was made between the average yearly consumption of different antibiotic classes (1997-2020) and the number of individuals living with ASD estimated for 2023/100000 population in 30 European countries and the results were statistically analyzed. Tetracycline (J01A) showed significant positive (promoting) association with the prevalence of ASD (Pearson r: 0.373, p: 0.043. OR: 1.312, CI95%: 0.995-1.791, p: 0.065) and narrow-spectrum, beta-lactamase resistant penicillin (J01CF) (Pearson r: 0.524, p: 0.003, OR: 3.240, CI95%: 1.710-8.853, p: 0.004, Kruskal-Wallis p: 0.032). Mild, negative (inhibitory) association was observed with broad-spectrum, beta-lactamase sensitive penicillin (J01CA) (Pearson r: -0.278, p: 0.157, OR: 0.808, CI95%: 0649-0957, p: 0.028) and narrow-spectrum, beta-lactamase-sensitive penicillin (J01CE) (Pearson p: -0.032, r: 0.865, OR: 0.725, CI95%: 0.543-0.885, p: 0,009). Our findings strongly support the animal experiments when penicillin-exposed newborn mice developed "autism-like" behavior.

Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with gastrointestinal symptoms, indicating alterations in both intestinal microbiota composition and metabolic activities. The intestinal microbiota influences the function and development of the nervous system. In individuals with ASD, there is an increase in bacterial genera such as Clostridium, as well as species involved in the synthesis of branched-chain amino acids (BCAA) like Prevotella copri. Conversely, decreased amounts of Akkermansia muciniphila, and Bifidobacterium spp. are observed. Epigallocatechin gallate (EGCG) is one of the polyphenols with the greatest beneficial activity on microbial growth and its consumption is associated with reduced psychological distress. Therefore, the objective of this review is to analyze how EGCG and its metabolites can improve the microbial dysbiosis present in ASD and its impact on the pathology. The analysis reveals that EGCG inhibits the growth of pathogenic bacteria like Clostridium perfringens and Clostridium difficile. Moreover, it increases the abundance of Bifidobacterium spp. and Akkermansia spp. As a result, EGCG demonstrates efficacy in increasing the production of metabolites involved in maintaining epithelial integrity and improving brain function. This identifies EGCG as highly promising for complementary treatment in ASD.

The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair-bonding, however, when dysregulated, it is associated with adverse psychiatric traits, like various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor MEF2A as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare-respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction.

Maternal infectious disease may pose considerable challenges to the fetal health due to the distribution of important elements of the sanguine and lymphatic system from the mother via the umbilical cord. The mother and the fetus have a degree of interdependence that is similar to the one between the eukaryotic cell and the mitochondrion, particularly during the first half term of the pregnancy, which explains the increased appetite of the expecting mother during the first stages of the fetal development. There is a solid bridge between the adaptive immune system and the encephalon that was only discovered a few decades ago. As a result, scientists may still be in the introductory stages of research, and there might be a significant and profound degree of association between the immune system and a healthy neurological development. There is a significant link between the onset of significant maternal infectious disease and the onset of neurodevelopmental disease in the fetus, and virtually all immune cells play major roles in the promotion and inhibition of neurogenesis alike. Likewise, there is a probability that maternal infectious diseases during pregnancy represent a risk factor of fetal neurodevelopmental disease, as a pressurised development of the adaptive immune memory could result in a pressurised or inhibited neurological development, which both can result in a delayed development of certain sub-regions of the brain. For example, the fetus may display poorer social abilities and sharp analytical skills later in life, which is an important sign of neurodevelopmental disease. A pressurised development of the adaptive immune memory could not require the development of a significant form of disease, but rather just a sharp rate of immune preparation against several important pathogenic agents during the introductory stages of life, when the encephalon experiences the sharpest increase rate in development. The problem per se is not the process of immunisation, but a much sharper process of immunisation over the first stages of life in case of an exposure to one dangerous pathogen or more numerous kinds of pathogens and antigens that normally cause moderate disease morbidity. The more dangerous the microbe is, the sharper the development of the adaptive immune memory will be, and the same happens in the case of an increased number of infectious microbes and antigens that infected the cells of the mothers and the fetuses in cause, and this may, in the majority of the situations, still be the case even if the pathogens are already significantly weakened or lifeless, given that the gain of adaptive immune memory alone constitutes an important factor of neurogenesis and an increased rate of neurological development, and that the infant will become almost or fully protected against the pathogens in cause, despite not having had experienced the disease beforehand. In this case, neurodevelopmental delays are possibly not caused by an impaired neurogenesis, but by an excessive one, whilst maternal infection-associated neurodevelopmental delays may be caused by an impaired neurogenesis. Nevertheless, the aetiology of immunity-related neurodevelopmental delays may be more complex in nature and implicate a chronological and spatial sequence of induced excedentary and deficitary rates of neurogenesis, hence reflecting the incredibly complex nature and various forms of neurodevelopmental disease. It is important to mention that a single dose of infant immunisation brings significantly lower risks of adverse neurological events than the onset of a significant maternal infectious disease during pregnancy. The objective of paediatric neuro-immunological studies may be to improve the understanding of the association between a healthy immune developmental rate and a balanced ratio of the developmental rates of important brain regions and sub-regions.

Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein, Neuroligin-3, was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3R451C mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3R451C mice bred on a mixed genetic background. Here we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3R451C mice show faster gastrointestinal transit in vivo and have longer small intestines compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3R451C mice, we observed a decrease in resting jejunal diameter and neurally-regulated dysmotility as well as shorter durations of contractile complexes in the ileum. In Nlgn3R451C mouse colons, short contractions were inhibited to a greater extent by the GABAA antagonist, gabazine, compared to wild-type mice. Inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum, but not the ileum, in both wild-type and Nlgn3R451C mice. These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein.

Purpose: School-age children with autism spectrum conditions (ASC) often experience difficulties in speech-in-noise (SiN) perception, leading to increased listening effort that impacts their well-being and academic performance. This study aimed to investigate the SiN processing challenges faced by Mandarin-speaking children with ASC and its impact on their listening effort. Methods: Participants completed sentence recognition tests in both quiet and noisy conditions, with a steady-state noise masker presented at 0 dB signal-to-noise ratio in the noisy condition. We compared recognition accuracy and task-evoked pupil responses from 23 Mandarin-speaking children with ASC to 19 age-matched neurotypical (NT) counterparts to gauge their behavioral performance and listening effort during these auditory tasks. Results: The ASC group demonstrated notably decreased accuracy in noise compared to their NT peers, suggesting poorer SiN perception. Pupillometric data further revealed significantly larger peak dilations in the ASC group than in the NT group under comparable conditions. Importantly, the ASC group's peak dilation in quiet mirrored the NT group's in noise. However, the ASC group exhibited shorter peak latencies and reduced mean dilations than the NT group in similar conditions. Such patterns indicate the ASC group might initially experience a heightened cognitive load but utilize fewer cognitive resources as the task continued, indicating an atypical allocation of cognitive resources and a potential tendency towards relatively superficial and automated auditory processing. Conclusion: Our findings highlight the unique SiN processing challenges children with ASC face, underscoring the importance of a nuanced, individual-centric approach for interventions and support.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition, characterized by persistent deficits in communication/social interaction and restricted and repetitive patterns of behavior, interests or activities. It is usually identified in childhood, despite late diagnoses in cases of greater functionality. Havighurst proposes a set of fundamental tasks throughout the life cycle, whose achievement is probably compromised in the ASD, even though it lacks scientific evidence. This study innovates, as it is based on Havighurst's theoretical model for understanding the development process of three adults and one young person, diagnosed with ASD level I, at different life stages. Through the methodology of life histories, interviews were subject to content analysis. Results pointed out the early detection and interventions importance, minimizing adversities, above all by those who had late diagnoses. Self-perceived success, not expected, was found in some development tasks (e.g. conscience and morality development). Also were noticed expected limitations related to ASD (e.g. difficulties in relationships with peers and in the labor market inclusion). Probably, in cases of greater severity and less functionality/autonomy, there would be greater failure in development tasks. It is crucial to improve research on this developmental model and on the factors that delay the diagnosis, including cases of different levels of severity.

Equine Assisted Activities (EAA) are considered a suitable innovative rehabilitative practice for children with neurodevelopmental disorders, including Autism Spectrum Disorder (ASD). While standardized scales have been previously used as a tool to evaluate the effects of EAA on different domains of functioning in ASD children, few studies have considered an ethological approach as a means to describe human-horse interactions in the context of ASD. In this study, we aimed to evaluate the behaviour of 19 children with ASD - in comparison with 19 typically developing children (TD) - during EAA sessions. We developed an ethogram from the video-recordings, to assess spatial relationships, social interactions and communicative behaviours displayed by the child towards the horse, as well as the occurrence of problem behaviours. Results indicate that children’s behaviours during EAA sessions are modulated by sex and age, while previous children’s experience with EAA appeared to improve interpersonal distance and horse handling. Results from this study highlight the importance of exploring children's behavioural response during animal-assisted activities through direct measurements. This may allow linking the quality/strength of the child-horse relationship to the benefits obtained by the child, particularly in the social/communicative domain, a core symptom of ASD.

Molecular autism research is evolving towards a biopsychosocial framework that is more informed by autistic experiences. In this context, research aims are moving away from correcting external autistic behaviors and towards alleviating internal distress. Autism Spectrum Conditions (ASCs) are associated with high rates of depression, suicidality and other comorbid psychopathologies, but this relationship is poorly understood. Here, we integrate emerging characterizations of internal autistic experiences within a molecular framework to yield insight into the prevalence of psychopathology in ASC. We demonstrate that descriptions of social camouflaging and autistic burnout resonate closely with the accepted definitions for early life stress (ELS) and chronic adolescent stress (CAS). We propose that social camouflaging could be considered a distinct form of CAS that contributes to allostatic overload, culminating in a pathophysiological state that is experienced as autistic burnout. Autistic burnout is thought to contribute to psychopathology via psychological and physiological mechanisms, but these remain largely unexplored by molecular researchers. Building on converging fields in molecular neuroscience, we discuss the substantial evidence implicating mitochondrial dysfunction in ASC to propose a novel role for mitochondrial allostatic load in the relationship between autism and psychopathology. An interplay between mitochondrial, neuroimmune and neuroendocrine signaling is increasingly implicated in stress-related psychopathologies, and these molecular players are also associated with neurodevelopmental, neurophysiological and neurochemical aspects of ASC etiology. Together, this suggests an increased exposure and underlying molecular susceptibility to ELS that increases the risk of psychopathology in ASC. This article describes an integrative framework shaped by autistic experiences that highlights novel avenues for molecular research into mechanisms that directly affect the quality of life and well-being of autistic individuals. Moreover, this framework emphasizes the need for increased access to diagnoses, accommodations, and resources to improve mental health outcomes in autism.

What does the way autistics bypass, learn, and eventually master language tell us about humans’ genetically encoded linguistic ability? In this theoretical review, we argue that autistic non-social acquisition of language, as well as autistic savant abilities, provide a strong argument for an innate, human-specific orientation toward (and mastery of) complex embedded structures. Autistic non-social language learning may represent a widening of the material processed during development beyond oral language. Structure detection and manipulation and generative production of non-linguistic embedded and chained material (savant abilities in calendar calculation, musical composition and interpretation, three-dimensional drawing) may thus represent an application of such innate mechanisms to non-standard materials. Typical language learning through exposure to the child’s mother tongue may represent but one of many possible achievements of the same capacity. The deviation from typical language development in autism may ultimately allow access to oral language, sometimes in its most elaborate forms, but also explains the possibility of the absence of its development when applied exclusively to non-linguistic structured material. Such an extension of human capacities beyond, or in parallel to, their usual limits call into question what we consider to be specific or expected in humans and, therefore, does not necessarily represent a genetic “error”. Regardless of the adaptive success or failure of non-social language learning, it is up to science and ethical principles to strive to maintain autism as a human potentiality to further foster our vision of a plural society.

What does the way autistics bypass, learn, and eventually master language tell us about human linguistic ability? Here, we argue that non-social acquisition of language, in addition to representing a strong argument for nativist models of human language, may be encompassed within the human-specific orientation and mastery of complex embedded structures, of which language represents one realization. Non-social language learning could thus represent the extension of available linguistic, and non-linguistic material processed by human genetic constraints, allowing language acquisition. This deviation from typical developmental language acquisition may ultimately allow access to language, sometimes in its most elaborate forms, and also explains the possibility of the absence of its development when applied to primarily non-linguistic structured material. However, such enlargement of material-specificity does not cast doubts about its human nature. Regardless of the adaptive success or failure of non-social language learning, it is up to science, legal policies, and ethical principles to strive to maintain autism as a human potentiality to further foster our vision of a plural society.

Autism Spectrum Disorder (ASD) is a neuro-developmental disorder that limits social interactions, cognitive skills, and abilities. Since ASD can last during an affected person's entire life cycle, the diagnosis at the early onset can yield a significant positive impact. The current medical diagnostic systems (e.g., DSM-5/ICD-10) are somewhat subjective; rely purely on the behavioral observation of symptoms, and hence, some individuals often go misdiagnosed or late-diagnosed. Therefore, researchers have focused on developing data-driven automated diagnosis systems with less screening time, low cost, and improved accuracy while significantly reducing professional intervention. Human Activity Analysis (HAA) is considered one of the most promising niches in computer vision research. This paper aims to analyze its potentialities in the automated detection of autism by tracking the exclusive characteristics of autistic individuals such as repetitive behavior, atypical walking style, and unusual visual saliency. This review provides a detailed inspection of HAA-based autism detection literature published in 2011 on-wards depicting core approaches, challenges, probable solutions, available resources, and scopes of future exploration in this arena. According to our study, deep learning outperforms machine learning in ASD detection with a classification accuracy of 76\% to 95\% on different datasets comprise of video, image, or skeleton data that recorded participants performing a large number of actions. However, machine learning provides satisfactory results on datasets with a small number of action classes and has a range of 60\% to 93\% accuracy among numerous studies. We hope this extensive review will provide a comprehensive guideline for researchers in this field.

The etiopathogenesis of autism spectrum disorder (ASD) remains largely unclear. Among other biological hypotheses, researchers have evidenced an imbalance in the endocannabinoid (eCB) system, which regulates some functions typically impaired in ASD, such as emotional responses and social interaction. Also, cannabidiol (CBD), the non-intoxicating component of Cannabis sativa, has been recently approved for treatment-resistant epilepsy. Seizures represent frequent medical comorbidities of ASD and could be responsible for the onset or worsening of behavioral problems. Thus, it has been hypothesized that cannabinoids could be useful in improving some ASD symptoms. Our systematic review was conducted according to the PRISMA guidelines and aimed to summarize the literature regarding the use of cannabinoids in ASD. After searching in Web of Knowledge^TM, PsycINFO, and Embase, we included ten studies (eight papers and two abstracts). Four ongoing trials were retrieved in ClinicalTrials.gov. Findings are promising, as cannabinoids appeared to improve problem behaviors, sleep, hyperactivity, and communication deficits, with limited cardiac and metabolic side effects. Interestingly, they generally allowed to reduce the number of prescribed medications and decreased the frequency of seizures in epileptic patients. Mechanisms of action could be linked to the excitatory/inhibitory imbalance found in people with ASD. However, further trials need to be implemented with better characterization and homogenization of samples, and well-defined outcomes.

The Reeler mutation was described in mouse more than fifty year ago. Later, its causative gene (reln) was discovered in mouse, and its human orthologue (RELN) was demonstrated to be causative of lissencephaly 2 (LIS2) and about 20% of the cases of autosomal-dominant lateral temporal epilepsy (ADLTE). In both human and mice the gene encodes for a glycoprotein referred to as Reelin (Reln) that plays a primary role in neuronal migration during development and synaptic stabilization in adulthood. Besides LIS2 and ADLTE, RELN and/or other genes coding for the proteins of the Reln intracellular cascade have been associated more or less substantially to other conditions such as spinocerebellar ataxia type 7 and 37, VLDLR-associated cerebellar hypoplasia, PAFAH1B1-associated lissencephaly, autism and schizophrenia. According to their modalities of inheritances and with substantial differences among each other, these neuropsychiatric disorders can be modeled in the homozygous (reln-/-) or heterozygous (reln+/-) mouse. The usefulness of these mice as translational models is discussed, with focus on their construct and face validity. The latter is mainly treated directing the attention to the histological, neurochemical and functional observations in the cerebral cortex, hippocampus and cerebellum of Reeler mice and their human counterparts.

The aim of this study was to examine the prevalence of self-reported and parent-reported bullying victimization, perpetration, and victimization-perpetration and the associations of autistic social impairment and attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) symptoms with bullying involvement in adolescents with high functioning autism spectrum disorder (ASD). A total of 219 adolescents with high functioning ASD participated in this study. The associations of sociodemographic characteristics, parent-reported autistic social impairment on the Chinese Social Responsiveness Scale, and parent-reported ADHD and ODD symptoms on the Short form of the Swanson, Nolan, and Pelham Version IV Scale (SNAP-IV)-Chinese version with self-reported and parent-reported bullying victimization, perpetration, and victimization-perpetration evaluated using the Chinese version of the School Bullying Experience Questionnaire were examined using logistic regression analysis. The agreement between self-reported and parent-reported bullying involvement was low. Compared with bullying involvement experiences reported by adolescents themselves, parents reported higher rates of pure bullying victimization (23.7% vs. 17.8%) and victimization-perpetration (28.8% vs. 9.1%) but a lower rate of pure bullying perpetration (5.9% vs. 9.1%). Deficit in socio-communication increases the risk of being pure victims and victim-perpetrators. Parent-reported victim-perpetrators had more severe ODD symptoms than did parent-reported pure victims. The agreement between self-reported and parent-reported bullying involvement of adolescents with high functioning ASD was low. Deficit in socio-communication and ODD symptoms were significantly associated with a high risk of bullying involvement in adolescents with high functioning ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by persistent deficits in social interaction and communication, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Brain neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid (VPA) or acetaminophen (APAP) or ingestion of propionic acid (PPA) can increase the risk of ASD. Recently, epigenetic influences on ASD have been brought to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here we specifically focus on the molecular influence of the above-mentioned drugs on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. It is concluded that a better understanding of these phenomena can lead to more effective interventions in ASD.

Dog Assisted Therapy is hypothesized to lower stress in children with Autism Spectrum Disorder (ASD) and children with Down Syndrome (DS), which may be visible on a physiological level. In this study, we measured Heart Rate Variability (HRV) and salivary cortisol of 20 children with DS or ASD at the beginning and end of 6 weekly sessions of Dog-Assisted Therapy. We found a decrease of cortisol levels during single sessions, but no overall effect after 6 sessions (6 weeks). The effect of Dog Assisted Therapy on the increase of HRV could not be confirmed. This study is one of the first to use physiological measurements to test the effects of DAT.

Background: Gut-Brain-Axis provides bidirectional communicational route; imbalance of which can have pathophysiological consequences. It is a frontier in autism research, affects 85% of autistic children (NIH report). Their microbiome has few overall microbes and smaller number of health promising microbes than their neurotypical peers. We hypothesize autism gut might play a role in manifestation of autism behaviours and on treatment, can revert back to normal behaviour considerably. The aim is to better understand to what degree gut microbiota of autism subjects differs from controls and identify bacterial species present exclusively in autism. Materials and Methods: 16s-rRNA-sequence of autism-subjects were retrieved from the American Gut Project Archive. Taxonomic assignment was inferred by similarity based methods using Quantitative Insights Into Microbial Ecology (QIIME). Species abundance was characterized and co-occurrence network was built to infer species interaction using measures of diversity. Statistical parameters were considered to validate the findings. Result: A total of 206 (1.8%) of American Gut Project datasets onstituted of autistic samples. Various bacteria such as Akkermansia sp., and Prevotella sp., were harboured in higher abundance in autistic children with statistical significance than in controls. Conclusion: These findings indicate connecting-link between gut-microbiome-brain-axis and autistic behaviour which can result in improved management

Neurodevelopmental disorders are characterized by an amalgam of genetic and epigenetic faults implicating neuronal protein-related loss-of-function and gain-of-function respectively, hence their inclusion into the category of complex diseases. Neurodevelopmental disorders are regarded as autism spectrum disorder due to this reason; that the risk factors and phenotype constitute a spectrum of faults and protein overactivity. One example of an epigenetic factor leading to the onset of neurodevelopmental delays constitutes a set of immune response-based dysregulations, as well as the excessive growth of the adaptive immune memory of the fetus or the baby following significant infectious disease during pregnancy, as well as in babies aged 0-2, given the existence of profound links between developmental immunity and developmental neurology. Given that genetic information very likely represents a form of energy, the intake of excessive pathogen-related information may transiently overload the adaptive immune memory similarly to the manner functional pathogens do whilst inducing significant illness, and if events as such occur during important stages of neuro-immunological development, then there could often be irreversible effects upon the rate of development in neurological networks that normally have a major importance in the modulation of the related cognitive and behavioral phenotype. The full extent of evidence may only be obtained via a thorough study of the applications of physical laws into biology and medicine, given the foundational role of the physical matter in the development and maintenance of life. A common misconception is that neurodevelopmental delays are characterized solely by an accumulation of protein loss-of-function incidences in the central nervous system area, rather than a disruption of neuronal region developmental rates. For example, an overexpression of neuronal proteins related to cognition factors that is accompanied by an underexpression of proteins related to social behavior is phenotypically manifested in people with sharper rational thinking and poorer communication skills, with an impact on the abilities of decision-making as well, and this tends to be regarded as a classical example of the clinical manifestation of neurodevelopmental delays. More severe forms of autism spectrum disorder tend to implicate a more generalistic impact upon the developmental rates of key human behaviors, including those related with the development and maintenance of social and intimate relationships. Likewise, more severe implications upon regular developmental rates tend to bring a major impact upon the healthy function of related functions. As a result, lower functioning forms of neurodevelopmental delays bring fresh concerns with regards to a possible uncanny increase of incidences of deviated sexuality during years of adulthood, and in the worst cases, such deviations may lead to the planning and development of criminal activity, particularly in individuals who are or become prone to breaking the moral code that established the civilized society. What holds the concerns valid is the exponential increase in the number of lower functioning autism cases throughout the world and the major signs that such an increase will continue with a full force. One major solution to this potential future problem would be a much higher investment into awareness of the exact genetic and environmental factors that directly or indirectly result in the onset of lower-functioning autism and of the current research efforts to develop the matching support for people found in situations as such. The most important aim of future research with regards to such a scenario would be a separation of disease and disability with choices made to step into more severe forms of disease and into areas that are outside of the established moral circle.

The prevalence of diagnosed cases of autism has increased rapidly, which raise interest in studying the variables related to the well-being of these families. The purpose of this paper is to review recent literature on other variables related to family well-being such a parenting styles. We conducted a systematic review using PRISMA check list and bias assessment ESTROBE with the aim of analyzing if the concepts of autism, well-being and parenting style are related. We screened 753 references, 16 full text articles and abstracts were read. It was identified that authoritative parenting style, those based on warmth, establishing relationships and emotional bonding, and low expressed emotion were positively related to family well-being. On the other hand, authoritarian, permissive and overprotective styles, as well as critical, punishing and training-based were negatively associated with well-being and quality of family life.

The rising prevalence of autism internationally has been accompanied with an increased appreciation of the poorer mental health experienced by people with this condition and also of their family care-givers. In particular higher incidences of anxiety and depression are reported in high income nations and these conditions are likely to be under-recognised and under-reported in lower resourced regions or countries. Mainstream mental health services seem to be ill-equipped to respond adequately to the needs of autistic persons and their care-givers. This scoping review of 30 recently published literature reviews covering over 1,000 journal articles, summarises the insights and strategies that have been shown to promote the mental health and emotional wellbeing of autistic persons. In particular, a focus on family-centred, community-based supports is needed that aim to enhance social communication, extend social connections and promote an individual’s self-esteem, self-determination and social motivation. These low-cost interventions are especially pertinent in low resourced settings but they can be used internationally to prevent mental illness and assist in the treatment of anxiety and depression in autistic persons and their family carers. The priority is to focus on primary care responses with cross-sectoral working rather than investing in high-cost psychiatric provision.

Bone marrow mononuclear cells (BMMNCs) have emerged as a potential therapeutic strategy for various incurable conditions including autism spectrum disorder (ASD). To study its safety and efficacy, we analyzed 1011 patients who underwent intrathecal administration of autologous BMMNCs along with neurorehabilitation. At mean follow-up of 19.3 months after intervention, 90.6% patients showed overall improvement. Improvements were observed in attention concentration, command following, eye contact, sitting tolerance, social interaction, hyperactivity, communication, speech, aggressiveness, stereotypical and self-injurious behavior. Statistically significant changes were observed in scores of Indian Scale of Autism Assessment and Childhood Autism Rating Scale (p<0.05). On subgroup analysis, improvements were recorded irrespective of age and disease severity and better outcome was observed in patients who took multiple doses of cell therapy compared to single dose. Comparative Brain PET-CT scan of 401 patients showed improved brain metabolism after the intervention. No major adverse events were reported. Only 9 out of 1011 patients experienced seizures which were managed using medications. 4 out of 9 had history of seizures while 5 had normal EEG with no history. However, improvements were still observed in these 9 patients. Thus, intrathecal transplantation of autologous BMMNCs along with neurorehabilitation is safe and efficacious in patients with ASD.

Equipped with an early social predisposition immediately post-birth, humans typically form associations with mothers and other family members through exposure learning, canalized by a spontaneous predisposition to biological motion, face configuration, and other cues of animacy. If impaired, reduced social preferences can lead to social interaction impairments such as autism spectrum disorder (ASD) via misguided canalization. Despite being taxonomically distant, domestic chicks also follow a homologous developmental trajectory toward adaptive socialization through imprinting, which is guided via predisposed preferences that are homologous to those of humans, thereby suggesting that chicks are valid animal models of ASD. In addition to the convergent similarities in predisposition with human newborns, accumulating evidence suggests the construct validity of the chick model. Considering the recent progress in the evolutionary neurobiology of vertebrates, we reviewed the advantages and limitations of the chick model of developmental mental diseases in humans.

Purpose: Hearing assistive technology (HAT) has been shown to be a viable solution to the speech-in-noise perception (SPIN) issue in children with autism spectrum disorder (ASD); however, little is known about its efficacy in tonal language speakers. This study compared sentence-level SPIN performance between Chinese children with ASD and neurotypical (NT) children and evaluated HAT use in improving SPIN performance and easing SPIN difficulty. Methods: Children with ASD (n=26) and NT children (n=19) aged 6-12 performed two adaptive tests in steady-state noise and three fixed-level tests in quiet and steady-state noise with and without using HAT. Speech recognition thresholds (SRT) and accuracy rates were assessed using adaptive and fixed-level tests, respectively. Parents or teachers of the ASD group completed a questionnaire regarding children’s listening difficulty under six circumstances before and after a ten-day trial period of HAT use. Results: Although the two groups of children had comparable SRTs, the ASD group showed a significantly lower SPIN accuracy rate than the NT group. Also, a significant impact of noise was found in the ASD group’s accuracy rate, but not in the NT group’s. There was a general improvement in the ASD group’s SPIN performance with HAT and a decrease in their listening difficulty ratings across all conditions after the device trial. Conclusion: The findings indicated inadequate SPIN in the ASD group using a relatively sensitive measure to gauge SPIN performance among children. The markedly increased accuracy rate in noise during HAT-on sessions for the ASD group confirmed the feasibility of HAT for improving SPIN performance in controlled laboratory settings, and the reduced post-use ratings of listening difficulty further confirmed the benefits of HAT use in daily scenarios.

Poor social skills in autism spectrum disorder (ASD) are associated with reduced independence in daily life. Current interventions for improving the social skills of individuals with ASD fail to represent the complexity of real-life social settings and situations. Virtual reality (VR) may facilitate social skills training in social environments and situations proximal to real life, however, more research is needed for elucidating aspects such as the acceptability, usability, and user experience of VR systems in ASD. Twenty-five participants with ASD attended a neuropsychological evaluation and three sessions of VR social skills training, incorporating 5 social scenarios with three difficulty levels for each. Participants reported high acceptability, system usability, and user experience. Significant correlations were observed between performance in social scenarios, self-reports, and executive functions. Working memory and planning ability were significant predictors of functionality level in ASD and the VR system’s perceived usability respectively. Yet, performance in social scenarios was the best predictor of usability, acceptability, and functionality level in ASD. Planning ability substantially predicted performance in social scenarios, postulating an implication in social skills. Immersive VR social skills training appears effective in individuals with ASD, yet an error-less approach, which is adaptive to the individual’s needs, should be preferred.

The art of observing and describing behaviors has driven diagnosis and informed basic science in Psychiatry. In recent times, studies of mental illness are focused on understanding the brain’s neurobiology but there is a paucity of information on the potential contributions from peripheral activity to mental health. In Precision Medicine, this common practice leaves a gap between bodily behaviors and genomics that we here propose to address with a new layer of inquiry that includes genes’ expression on tissues inclusive of brain, heart, muscle-skeletal and organs for vital bodily functions. We interrogate genes’ expression on human tissue as a function of disease-associated genes. By removing genes linked to disease from the typical human set, and recomputing the genes’ expressions on the tissues, we can compare the outcomes across mental illnesses, well-known neurological conditions, and non-neurological ones. We find that major neuropsychiatric conditions that are behaviorally defined today (e.g. Autism, Schizophrenia, Depression) through DSM-observation criteria, have strong convergence with well-known neurological ones (e.g. Ataxias, Parkinson), but less overlap with non-neurological ones. Surprisingly, tissues majorly involved in the central control, coordination, adaptation and learning of movements, emotion and memory are maximally affected in psychiatric diagnoses along with peripheral heart and muscle-skeletal tissues. Our results underscore the importance of considering both the brain-body connection and the contributions of the peripheral nervous systems to mental health.

This paper develops mathematical models examining possible roles of oxytocin and oxytocin receptors in the development of autism. This is done by demonstrating that mathematical operations on normalized data from the Stanford study (K.J. Parker, 2016), which establishes a correspondence between severity of autism in children and their oxytocin blood levels, generates a graph that is the same as the graph of mathematical operations on a normalized theoretical model for the severity of autism. This procedure establishes the validity of the theoretical model and the significance of oxytocin receptors in autism. A steady-state model follows, explaining the constant baseline concentrations of oxytocin observed in the cerebral spinal fluid and blood in terms of the neuromodulation by oxytocin of oxytocin receptors on the magnocellular neurons that produce oxytocin in nuclei in the hypothalamus. The implications of these models for possible roles of oxytocin and oxytocin receptors in autism is considered for several unrelated conditions that may be associated with autism. These are: oxytocin receptor desensitization and down-regulation as factors during labor in offspring autism development; reductions in the oxytocin receptor numbers in the fixed oxytocin receptor expression that occurs before birth; MAST Immune System disease; and the excess number of dendritic spines from lack of pruning observed in brains of autistic people. Research into the feasibility of generating magnocellular neurons and other neurons from adult stem cells is suggested as a way of doing invitro studies of oxytocin and oxytocin receptors to assess the validity of theories presented in this paper.

Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. Evidence based studies have reported the extensive therapeutic application of music on various part of the brain in a nonverbal child with autism through hearing or making music.Hence we hypothesized that MT intervention can improve the communication capacity in people with ASD, than customary neurorestoration therapy alone.

SHANK3 encodes scaffold protein involved in postsynaptic receptor density in glutamatergic synapses, including those in the parvalbumin (PV)+inhibitory neurons – the key players in generation of sensory gamma oscillations, such as 40-Hz auditory steady-state response(ASSR). Here we describe a clinical and neurophysiological phenotype of a 15-years old girl (SH01) with microduplication of 16389 bp in 22q13.33, affecting the SHANK3 gene in comparison to typically developing children (n=32). EEG were recorded during the binaurally presentation of 40-Hz clicks’ trains lasting for 500 ms with inter-trial intervals 500-800 ms. SH01 was diagnosed with mild mental retardation and learning disabilities(F70.88) and had problems with reading and writing, as well as smaller vocabulary than TD peers. Her clinical phenotype generally resembled the phenotype of previously described patients with 22q13.33 microduplication. SH01 had mild autistic symptoms but below the threshold for ASD diagnosis. No seizures or MRI abnormalities were reported. While SH01 had relatively preserved auditory event-related potential(ERP) with slightly attenuated P1, her 40-Hz ASSR was totally absent significantly deviating from TD’s ASSR. Absence of 40-Hz ASSR in patient with microduplication, affected SHANK3 gene, indicates deficient temporal resolution of the auditory system, that might underlie language problems, and represent neurophysiological biomarker of SHANK3 abnormalities.

The cytokine-producing nucleotide-binding domain leucine-rich repeat and pyrin-containing receptor 3 (NLRP3) inflammasome is generally recognized to play a central role in the immune response to vaccination and NLRP3 activity is known to be increased by both aluminum adjuvants and by oxidative stress. Thus, the presence of oxidative stress may place individuals at higher risk for exaggerated or prolonged inflammatory responses and related side effects from vaccination. We here examine the relationship between oxidative stress and NLRP3 inflammasome activity, particularly in the context of aluminum-adjuvanted vaccines, and its implications for subpopulations of individuals with restricted antioxidant capacity.

‘Inner mitochondrial membrane peptidase 2 like’ (IMMP2L) is a nuclear encoded mitochondrial peptidase that has been conserved through evolutionary history as has its target enzyme ‘mitochondrial glycerol phosphate dehydrogenase 2’ (GPD2). IMMP2L is known to cleave the mitochondrial transit peptide from GPD2 and another nuclear encoded mitochondrial respiratory related protein cytochrome C1 (CYC1). However, it is not known whether IMMP2L peptidase activates or alters the activity or respiratory related functions of GPD2 or CYC1. Previous investigations found compelling evidence of behavioural change in the Immp2lKD-/- KO mouse and in this study EchoMRI analysis found that many organs of the Immp2lKD-/- KO mouse were smaller and that the KO mouse had significantly less lean mass and overall body weight compared with wildtype littermates (p&lt;0.05). Moreover, all of the organs analysed from the Immp2lKD-/- KO had lower relative levels of mitochondrial reactive oxygen species (mitoROS). The kidneys of the Immp2lKD-/- KO mouse displayed the greatest decrease in mitoROS levels that were over 50% less compared with wildtype litter mates. Mitochondrial respiration was also lower in the kidney of the Immp2lKD-/- KO mouse compared with other tissues when using succinate as the respiratory substrate, whereas respiration was similar to wildtype when glutamate was used as substrate. When glycerol-3-phosphate (G3P) was used as the substrate for Gpd2 we observed ~20% and ~7% respective decreases in respiration in female and male Immp2lKD-/- KO mice over time. Together these findings suggest that the respiratory related functions of mGpd2 and Cyc1 have been compromised to different degrees in different tissues in the Immp2lKD-/- KO mouse. Structural analyses using AlphaFold2-Multimer further predicted that the interaction between Cyc1 and mitochondrial encoded cytochrome b (Cyb) in Complex III had been altered as had the homodimeric structure of the mGpd2 enzyme within the inner mitochondrial membrane of the Immp2lKD-/- KO mouse. mGpd2 functions as an integral component of the glycerol phosphate shuttle (GPS) which positively regulates both mitochondrial respiration and glycolysis. Interestingly, we found that nonmitochondrial respiration (NMR) was also dramatically lowered in the Immp2lKD-/- KO mouse. Primary mouse embryonic fibroblast (MEF) cell lines derived from the Immp2lKD-/- KO mouse displayed a ~27% decrease in total respiration comprised of a ~50% decrease in NMR and a ~12% decrease in total mitochondrial respiration where the latter was consistent with the decreases in substrate specific mitochondrial respiration reported here. This study is the first to report the role of Immp2l in enhancing Gpd2 structure and function, mitochondrial respiration, nonmitochondrial respiration, organ size and homeostasis.

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother’s obesity as potentially environmental factors of ASD. The purpose of the present analysis is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.

The involvement of the prefrontal cortical dopaminergic system in psychopathology of epilepsies and comorbid conditions such as autism spectrum disorder (ASD) still needs to be explored. We used autoradiography to study the D1-like (D1DR) and D2-like (D2DR) receptor binding density in the prefrontal cortex of normal Wistar rats and Wistar-derived strains with generalized convulsive and/or nonconvulsive epilepsies. WAG/Rij rats served as a model for non-convulsive absence epilepsy, WAG/Rij-AGS as a model of mixed convulsive/non-convulsive forms, and KM strain was a model for convulsive epilepsy comorbiding with ASD-like behavioral phenotype. Prefrontal cortex of rats with any of epileptic pathology studied, demonstrated profound decreases in binding densities to both D1DR, D2DR; the effects were localized in the primary and secondary anterior cingulate cortexi, and adjacent regions. The local decreased D1DR and D2DR binding densities were independent (not correlated) from each other. The particular group of epileptic rats with ASD-like phenotype (KM strain), displayed changes in the lateral prefrontal cortex and adjacent regions: D1DR were lowered, but those to D2DR elevated, in anterior dysgranular insular cortex and adjacent regions. Thus, epilepsy-related changes in the dopaminergic system of rat archeocortex were localized in the medial regions, whereas ASD-related candidates were seen in the lateral aspects. The findings point to putative local dopaminergic dysfunctions, associated with generalized epilepsies and/or ASD.

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases, and psychiatric disorders. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants, and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses, and chronic diseases. KYN, kynurenic acid, xanthurenic acid, and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2, 3-oxygenases, and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines, and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia, and autism spectrum disorder.

Neurodegeneration is a major problem in neuroscience and medicine as it causes and worsens many neurological and psychiatric disorders. It involves gradual loss of neurons at different levels of the brain, affecting cognition, emotion, behavior, consciousness, and attention. Understanding the causes and consequences of neurodegeneration is crucial for identifying the risk factors, biomarkers, and treatments. However, the current therapies are mostly symptomatic and ineffective. Therefore, new and innovative methods, such as noninvasive brain stimulation (NIBS), are needed to modulate brain activity and plasticity in a safe and reversible manner. This field is rapidly developing, with a focus on exploring new clinical applications, mechanisms, and combinations of NIBS and drugs. This special issue covers the latest progress and challenges in the study of neurodegeneration in cognitive impairment and mood disorders from the experimental, clinical, and translational perspectives. It addresses the complexity and diversity of these conditions, the lack of disease-modifying treatments, the ethical and practical issues of conducting research in vulnerable and diverse populations, the integration and interpretation of data from multiple sources and modalities, and the development and validation of novel methods such as NIBS, artificial intelligence, and drug repurposing. Collaborative efforts among various stakeholders are needed to improve our knowledge and treatment of neurodegeneration underlying cognitive impairment and mood disorders.