Reversing valproic acid-induced autism-like behaviors through a combination of low-frequency repeated transcranial magnetic stimulation and superparamagnetic iron oxide nanoparticles.

Transcranial magnetic stimulation (TMS) is a neurostimulation device used to modulate brain cortex activity. Our objective was to enhance the therapeutic effectiveness of low-frequency repeated TMS (LF-rTMS) in a rat model of autism spectrum disorder (ASD) induced by prenatal valproic acid (VPA) exposure through the injection of superparamagnetic iron oxide nanoparticles (SPIONs). For the induction of ASD, we administered prenatal VPA (600 mg/kg, I.P.) on the 12.5th day of pregnancy. At postnatal day 30, SPIONs were injected directly into the lateral ventricle of the brain. Subsequently, LF-rTMS treatment was applied for 14 consecutive days. Following the treatment period, behavioral analyses were conducted. At postnatal day 60, brain tissue was extracted, and both biochemical and histological analyses were performed. Our data revealed that prenatal VPA exposure led to behavioral alterations, including changes in social interactions, increased anxiety, and repetitive behavior, along with dysfunction in stress coping strategies. Additionally, we observed reduced levels of SYN, MAP2, and BDNF. These changes were accompanied by a decrease in dendritic spine density in the hippocampal CA1 area. However, LF-rTMS treatment combined with SPIONs successfully reversed these dysfunctions at the behavioral, biochemical, and histological levels, introducing a successful approach for the treatment of ASD.

Anxiety, concerns and COVID-19: Cross-country perspectives from families and individuals with neurodevelopmental conditions.

Background: The COVID-19 pandemic had a major impact on the mental health and well-being of children with neurodevelopmental conditions (NDCs) and of their families worldwide. However, there is insufficient evidence to understand how different factors (e.g., individual, family, country, children) have impacted on anxiety levels of families and their children with NDCs developed over time. Methods: We used data from a global survey assessing the experience of 8043 families and their children with NDCs (mean of age (m) = 13.18 years, 37% female) and their typically developing siblings (m = 12.9 years, 45% female) in combination with data from the European Centre for Disease Prevention and Control, the University of Oxford, and the Central Intelligence Agency (CIA) World Factbook, to create a multilevel data set. Using stepwise multilevel modelling, we generated child-, family- and country-related factors that may have contributed to the anxiety levels of children with NDCs, their siblings if they had any, and their parents. All data were reported by parents. Results: Our results suggest that parental anxiety was best explained by family-related factors such as concerns about COVID-19 and illness. Children's anxiety was best explained by child-related factors such as children's concerns about loss of routine, family conflict, and safety in general, as well as concerns about COVID-19. In addition, anxiety levels were linked to the presence of pre-existing anxiety conditions for both children with NDCs and their parents. Conclusions: The present study shows that across the globe there was a raise in anxiety levels for both parents and their children with NDCs because of COVID-19 and that country-level factors had little or no impact on explaining differences in this increase, once family and child factors were considered. Our findings also highlight that certain groups of children with NDCs were at higher risk for anxiety than others and had specific concerns. Together, these results show that anxiety of families and their children with NDCs during the COVID-19 pandemic were predicted by very specific concerns and worries which inform the development of future toolkits and policy. Future studies should investigate how country factors can play a protective role during future crises.

Cognitive Prerequisites in Development of Childhood Anxiety: An Integrative Literature Review and Thematic Analysis.

It has been suggested that cognitive development affects the emotional experience of children, including anxiety. However, an evidence review is needed to extract cognitive prerequisites that contribute to the development of anxiety in children. The purpose of the study is to explore evidence on cognitive prerequisites involved in experiencing anxiety in children. Four electronic databases of Scopus, OVID-PsycINFO, PubMed, and ScienceDirect were comprehensively searched for 1900 to 2018, yielding 4,618 articles. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and inclusion and exclusion criteria, 25 articles were found as eligible. The analysis of literature identified 3 themes, including threat perception, future thinking, and generalization. It is suggested that these cognitive abilities may underlie anxiety. These results have important implications for better understanding the effect of cognitive prerequisites in anxiety phenomena and also could shed light on the explanation of anxiety in some disorders characterized by deficits in cognitive development.

Excessive audio-visual stimulation leads to impaired social behaviour with an effect on amygdala: Early life excessive exposure to digital devices in male rats.

Today, the effect of extreme early-life exposure to digital devices is suggested as a risk factor for neurodevelopmental disorders. However, the multitude of factors that influence brain development with subsequent behavioural abnormalities have not been fully elucidated. Herein, we simulated extreme early-life exposure to digital devices in rats by audio and visual stimulation and investigated its effects on autism-related behaviours and brain structural alteration. Male rat pups were exposed to excessive audio-visual stimulation (EAVS) from PND (post-natal day) 12 to PND 35, with and without maternal separation (MS). Autism-related behaviours including abnormal sociability, stereotype behaviours, anxiety and locomotor dysfunction were tested at PND 42. Brain structural alternation was examined by considering the amygdala, mPFC (medial prefrontal cortex) and hippocampal regions while performing 3D quantitative stereological analysis. We found that EAVS led to social behaviour deficit and higher locomotion in rats, which were associated with increases in the number of neurons and volume of the amygdala. We also showed that MS did not exaggerate the effect of extreme sensory stimulation on behaviour and the structure of the brain. This study proposed EAVS in rats as an animal model of early exposure to digital devices for investigating possible neurobiological alternations underlying autistic-like behaviours with an emphasis on the amygdala area.

A systematic review of program circumstances in training social skills to adolescents with high-functioning autism.

Despite many programs for educating social skills to adolescents with autism, insufficient attention has been paid to examine the optimal conditions and strategies that are important for improvement and generalization of the learned skills. So after reviewing and searching for three PubMed, Scopus, and ProQuest databases, 20 studies were finally analyzed and shared conditions were extracted. The results showed that the most important condition is parental involvement. The rehearsal and practice of social skills, attention to developmental trajectories, strengths and weaknesses of the individual and use of quantitative and qualitative tools are the other circumstances. In conclusion, taking into account these conditions for improvement, generalization and durability of the skills can be helpful.

Electrophysiological Markers of Fairness and Selfishness Revealed by a Combination of Dictator and Ultimatum Games.

Individual behavior during financial decision making is motivated by fairness, but an unanswered question from previous studies is whether particular patterns of brain activity correspond to different profiles of fairness. Event Related Potentials (ERPs) were recorded from 39 participants who played the role of allocators in a Dictator Game (DG) and responders in an Ultimatum Game (UG). Two very homogeneous groups were formed by fair and selfish individuals. At fronto-central cortical sites, the latency of ERP early negativity (N1) was 10 ms shorter in selfish participants than in fair participants. In fair DG players, the subsequent positive wave P2 suggested that more cognitive resources were required when they allocated the least gains to the other party. P2 latency and amplitude in the selfish group supported the hypothesis that these participants tended to maximize their profit. During UG, we observed that medial frontal negativity (MFN) occurred earlier and with greater amplitude when selfish participants rejected less favorable endowment shares. In this case, all players received zero payoffs, which showed that MFN in selfish participants was associated with a spiteful punishment. At posterior-parietal sites, we found that the greater the selfishness, the greater the amplitude of the late positive component (LPC). Our results bring new evidence to the existence of specific somatic markers associated with the activation of distinct cerebral circuits by the evaluation of fair and unfair proposals in participants characterized by different expressions of perceived fairness, thus suggesting that a particular brain dynamics could be associated with moral decisions.

ADHD subtypes: Do they hold beyond core symptoms? A multilevel testing of an additive model.

Attention Deficit Hyperactivity Disorder (ADHD) is characterized as a behavioral syndrome with core symptoms of inattention and/or hyperactivity/impulsivity that constitute, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), predominantly Inattentive and Hyperactive-Impulsive and a combined (additive) presentation that fulfills both criteria. The question remains if the pathophysiological background of both factors is also separate at levels of investigation beyond core symptoms. This would allow a clearer understanding and a more focused treatment approach even with tools derived from these levels. Hence, we assumed that an implicit additive diagnostic model also holds at the levels of associated psychopathology, neuropsychological performance and brain oscillations. We investigated this hypothesis using data of 61 boys (7-12 years old) with ADHD and 43 typically developing children. There were no significant differences in age and IQ between groups. Children were examined with Child Behavior Checklist (CBCL), the Integrated Visual and Auditory Test (IVA), and brain oscillations during eyes closed resting state. Inattention characteristics were associated with more pronounced internalizing problems, lower attention, and vigilance during IVA performance and at the Electroencephalography level with elevated Theta and diminished Beta power during eyes closed rest. In contrast, hyperactivity/impulsivity characteristics led to general psychopathology problems and showed at the neuropsychological level faster response speed and deficits in cognitive control and performance consistency, but were on the electroencephalography level without any deficits in EEG power. Considering differences in behavioral, neuropsychology, and electroencephalography levels in each subtype, separate clinical approaches should be recommended for them and an additive model for their combination.

Priming Global Processing Strategy Improves the Perceptual Performance of Children with Autism Spectrum Disorders.

We investigated (1) if the perceptual integration performance is different in children with ASD in comparison with their typically developed (TD) counterparts; and (2) if activating- priming- the global processing strategy, could benefit the integration performance of children with ASD in the subsequent task. We observed that in comparison with the TD group, children with ASD had lower performance in an information integration task that required identification of illusory shapes. Additionally, we observed that priming the global processing strategy increased the correct identification of the illusory shapes in the subsequent task. We suggested that studies on priming effect shed light on the different aspects of perceptual properties of ASD, and could also be used in developing new rehabilitation plans.

Enhanced reading abilities is modulated by faster visual spatial attention.

Research has shown improved reading following visual magnocellular training in individuals with dyslexia. Many studies have demonstrated how the magnocellular pathway controls visual spatial attention. Therefore, we have investigated the relationship between magnocellular pathway and visual spatial attention deficits in dyslexia in order to better understand how magnocellular-based interventions may help children to learn to read. Magnocellular function, visual spatial attention, and reading abilities of thirty elementary school students with dyslexia, aged between 8 and 10, were measured. The experimental group received magnocellular-based visual motion training for 12 sessions, while the control group received neutral sessions. All tests were repeated at the end of the training and after 1 month. The magnocellular functioning, visual spatial attention, and reading abilities of the experimental group improved significantly compared to the controls. Additionally, improvement in reaction time of invalid conditions predicted improvements in saccadic eye movements. We conclude that visual magnocellular training improved saccadic eye movement control, visual spatial orientation, and reading ability.

Classifying ADHD subtypes/presentations considering the joint effect of three levels of investigation.

AIM: Discriminant validity of the Attention Deficits/Hyperactive Disorders (ADHD) subtypes/presentations is not yet clear. The purpose of this study was to investigate joint contribution of the strongest factors of the three dimensions, namely psychopathology, neuropsychology and electrophysiology for subtyping of presentations. METHOD: A sample of 104 boys aged 7-12 years was subdivided into three groups with ADHD combined (n = 22), inattentive (n = 25) and hyperactive/impulsive subtype (n = 14), and 43 typically developing controls (TDC). Children were investigated regarding the Child Behavior Checklist (CBCL), the Integrated Visual and Auditory Test (IVA), and EEG spectral power during eyes closed resting state. Subsequently, statistical analysis included discriminant functional analysis and principle component analysis. RESULTS: Neuropsychological parameters had the highest contribution in classifying of the groups. EEG parameters had no effect on differentiation of the groups, and among the psychopathological parameters, only the oppositional behavioral disorder score contributed to correctly classify 74.3% of the groups. Furthermore, we found four factors with eigenvalues higher than 1 in the ADHD and typical groups, with one factor characterized by four CBCL scales, another one by auditory and visual vigilance, speed and beta band power, the third by auditory and visual prudence, and forth by theta band power. CONCLUSIONS: Our results demonstrated that ADHD subtypes/presentations can be differentiated from each other at different levels of investigation despite some clinical symptoms overlap. The results suggested that not only psychopathology but also the impairment of sensory processing should be assessed in children with ADHD in order to use this additional information for a jointly multilevel clinical intervention, which may improve treatment success.

Dual Profile of Environmental Enrichment and Autistic-Like Behaviors in the Maternal Separated Model in Rats.

BACKGROUND: Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well as number of conflicting results, urge for further examination of the therapeutic potential of EE in autism. Therefore, the aim of this study was to examine the effects of environmental enrichment on autism-related behaviors which were induced in the maternal separation (MS) animal model. MATERIAL AND METHODS: Maternally separated (post-natal day (PND) 1-14, 3h/day) and control male rats were at weaning (PND21) age equally divided into rats housed in enriched environment and normal environment. At adolescence (PND42-50), the four groups were behaviorally tested for direct social interaction, sociability, repetitive behaviors, anxiety behavior, and locomotion. Following completion of the behavioral tests, the blood and brain tissue samples were harvested in order to assess plasma level of brain derived neurotrophic factor (BDNF) and structural plasticity of brain using ELISA and stereological methods respectively. RESULTS: We found that environmental enrichment reduced repetitive behaviors but failed to improve the impaired sociability and anxiety behaviors which were induced by maternal separation. Indeed, EE exacerbated anxiety and social behaviors deficits in association with increased plasma BDNF level, larger volume of the hippocampus and infra-limbic region and higher number of neurons in the infra-limbic area (p < 0.05). Conclusion: We conclude that environmental enrichment has a significant improvement effect on the repetitive behavior as one of the core autistic-like behaviors induced by maternal separation but has negative effect on the anxiety and social behaviors which might have been modulated by BDNF.

Early screening of autism spectrum disorder using cry features.

The increase in the number of children with autism and the importance of early autism intervention has prompted researchers to perform automatic and early autism screening. Consequently, in the present paper, a cry-based screening approach for children with Autism Spectrum Disorder (ASD) is introduced which would provide both early and automatic screening. During the study, we realized that ASD specific features are not necessarily observable in all children with ASD and in all instances collected from each child. Therefore, we proposed a new classification approach to be able to determine such features and their corresponding instances. To test the proposed approach a set of data relating to children between 18 to 53 months which had been recorded using high-quality voice recording devices and typical smartphones at various locations such as homes and daycares was studied. Then, after preprocessing, the approach was used to train a classifier, using data for 10 boys with ASD and 10 Typically Developed (TD) boys. The trained classifier was tested on the data of 14 boys and 7 girls with ASD and 14 TD boys and 7 TD girls. The sensitivity, specificity, and precision of the proposed approach for boys were 85.71%, 100%, and 92.85%, respectively. These measures were 71.42%, 100%, and 85.71% for girls, respectively. It was shown that the proposed approach outperforms the common classification methods. Furthermore, it demonstrated better results than the studies which used voice features for screening ASD. To pilot the practicality of the proposed approach for early autism screening, the trained classifier was tested on 57 participants between 10 to 18 months. These 57 participants consisted of 28 boys and 29 girls and the results were very encouraging for the use of the approach in early ASD screening.

Brain connectivity analysis in fathers of children with autism.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in which changes in brain connectivity, associated with autistic-like traits in some individuals. First-degree relatives of children with autism may show mild deficits in social interaction. The present study investigates electroencephalography (EEG) brain connectivity patterns of the fathers who have children with autism while performing facial emotion labeling task. Fifteen biological fathers of children with the diagnosis of autism (Test Group) and fifteen fathers of neurotypical children with no personal or family history of autism (Control Group) participated in this study. Facial emotion labeling task was evaluated using a set of photos consisting of six categories (mild and extreme: anger, happiness, and sadness). Group Independent Component Analysis method was applied to EEG data to extract neural sources. Dynamic causal connectivity of neural sources signals was estimated using the multivariate autoregressive model and quantified by using the Granger causality-based methods. Statistical analysis showed significant differences (p value < 0.01) in the connectivity of neural sources in recognition of some emotions in two groups, which the most differences observed in the mild anger and mild sadness emotions. Short-range connectivity appeared in Test Group and conversely, long-range and interhemispheric connections are observed in Control Group. Finally, it can be concluded that the Test Group showed abnormal activity and connectivity in the brain network for the processing of emotional faces compared to the Control Group. We conclude that neural source connectivity analysis in fathers may be considered as a potential and promising biomarker of ASD.

Discrimination of ADHD Subtypes Using Decision Tree on Behavioral, Neuropsychological, and Neural Markers.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is a well-known neurodevelopmental disorder. Diagnosis and treatment of ADHD can often lead to a developmental trajectory toward positive results. The present study aimed at implementing the decision tree method to recognize children with and without ADHD, as well as ADHD subtypes. METHODS: In the present study, the subjects included 61 children with ADHD (subdivided into ADHD-I (n=25), ADHD-H (n=14), and ADHD-C (n=22) groups) and 43 typically developing controls matched by IQ and age. The Child Behavior Checklist (CBCL), Integrated Visual And Auditory (IVA) test, and quantitative EEG during eyes-closed resting-state were utilized to evaluate the level of behavioral, neuropsychology, and electrophysiology markers using a decision tree algorithm, respectively. RESULTS: Based on the results, excellent classification accuracy (100%) was obtained to discriminate children with ADHD from the control group. Also, the ADHD subtypes, including combined, inattention, and hyperactive/impulsive subtypes were recognized from others with an accuracy of 80.41%, 84.17%, and 71.46%, respectively. CONCLUSION: Our results showed that children with ADHD can be recognized from the healthy controls based on the neuropsychological data (sensory-motor parameters of IVA). Also, subtypes of ADHD can be distinguished from each other using behavioral, neuropsychiatric and electrophysiological parameters. The findings suggested that the decision tree method may present an efficient and accurate diagnostic tool for the clinicians.

Autistic-like behaviours and associated brain structural plasticity are modulated by oxytocin in maternally separated rats.

BACKGROUND: Early psycho-social experiences influence the developing brain and possible onset of various neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). ASD is characterized by a variety of brain abnormalities, including alteration of oxytocin receptors in the brain. Recently, early life adverse experiences, such as maternal separation (MS), have been shown to constitute risk factors for ASD in preclinical studies. Therefore, the main aims of the current study were to i) explore the association between onset of autistic-like behaviours and molecular/structural changes in the brain following MS, and ii) evaluate the possible beneficial effects of oxytocin treatment on the same parameters. METHOD AND MATERIAL: Male rats were exposed to the maternal separation from post-natal day (PND) 1 to PND14. After weaning, daily injections of oxytocin (1 mg/kg, ip) were administered (PND 22-30), followed by examination of autism-related behaviours at adolescence (PND 42-50). Brain structural plasticity was examined using stereological methods, and the plasma level of brain derived neurotrophic factor (BDNF) was analysed using ELISA. RESULTS: We found that maternal separation induced autistic-like behaviours, which was associated with increase in the hippocampal CA1 stratum radiatum (CA1.SR) volume. In addition, we observed increase in the infralimbic brain region volume and in the number of the pyramidal neurons in the same brain region. Maternal separation significantly increased the plasma BDNF levels. Treatment with oxytocin improved autistic like behaviours, normalized the number of neurons and the volume of the infralimbic region as well as the plasma BDNF level (p < 0.05). CONCLUSION: Maternal separation induced autistic-like behaviours, brain structural impairment together with plasma BDNF level abnormality, which could be improved by oxytocin treatment.

Common elements of parent management training programs for preschool children with autism spectrum disorder.

Parent management training is a general set of interventions used as a part of a variety of clinical approaches to reduce behavioral problems of children. These behavioral problems in children with special needs (such as autism spectrum disorder) take a more complex form. The objective is to present elements, needed to develop parent management training program to reduce behavioral problems in preschool children with autism spectrum disorder. At first, all parent management training programs for reducing behavioral problems of preschool children were collected. Subsequently, all programs were reviewed from the perspective of having a systematic review or meta-analysis, confirming the effectiveness of this program at preschool age. After that, interviews with experts and parents were conducted to identify effective elements on development of this program. In the next step, a set of components was obtained using information about parent management training programs as well as items obtained from interviews with experts and parents. At this stage, 10 experts were asked to rate the items according to their importance using the Delphi method. The items that achieved the required scores were introduced as main items. The number of them was 13 and included items such as full assessment of the child and appropriate communication with the child. Considering the characteristics of children with autism spectrum disorder will require changes in some parts of parent management training program, therefore, it is necessary to develop a specific program for these children to cover all of their characteristics.

Global precedence changes by environment: A systematic review and meta-analysis on effect of perceptual field variables on global-local visual processing.

Perceptual organization and, in particular, visual processing have been debated for many years. The global precedence effect in local-global visual processing, as introduced by David Navon, refers to the condition that global aspects of a scene are processed more rapidly than are local details. This perceptual dynamic is influenced by many factors that can be divided into two major categories: subjective or internal factors (e.g., age, disorder, culture) and the external factors called perceptual field variables (PFVs; e.g., stimulus size, eccentricity, sparsity). The aim of the current study was to identify the latter factors using a meta-analysis followed by a systematic literature review. In accordance of the standard framework suggested by PRISMA, 28 PFVs were observed through a literature search on articles published from 1982 to 2019, among which 10 factors have been qualified to be included in a meta-analysis. Subsequently, the random effects model proposed by Hedges and Olkin was used to estimate pooled effect sizes of PFVs. These effect sizes were used to compare and sort the PFVs on the basis of their intensity. According to Cohen's index, our analyses show that relevance, sparsity, and solidness type are categorized as small effects; visual field, level repetition, spatial frequency, and shape type are categorized as medium effects; and congruency, eccentricity, and size as large effect PFVs on global precedence.

A pilot study of family-based management of behavioral excesses in young Iranian children with autism spectrum disorder.

OBJECTIVE: Parent-mediated early behavioral interventions are considered as effective approaches in the treatment of children with Autism Spectrum Disorder (ASD). The majority of these interventions focus on social-communication deficits rather than behavioral excesses which severely irrupt child and family social life as well as the child's appearance behavior and learning processes. The study examines the effectiveness and feasibility of Family-based Management of Behavioral Excesses of Autism Program (FMBEAP) on Iranian families. METHOD: This pre-post and follow-up intervention study involved 17 parents of children with DSM-5 diagnosis of ASD recruited from Tehran Autism Center. All parents conducted FMBEAP on their children while receiving 10-weekly group supervision on top of everyday on-line individual coaching. The study's measures were Repetitive Behavior Scale-R, video-monitoring of child-parent Interaction, Clinical Global Impression-Improvement Scale, Parental Self-Efficacy and Parenting Stress Index-short form. The measures were applied to the sample three times: pre and post-intervention and at one-month follow-up. RESULTS: The Results showed high and low order behavioral excesses significantly decreased at post-intervention and the follow-up. 15 out of 17 children reached to recovered or highly recovered at post-test. Parents showed significant improvements in self-efficacy and parenting stress scales. The intervention was highly accepted by them. CONCLUSION: FMBEAP is shown to be a feasible, acceptable and effective intervention to improve autistic behavioral. The parents should also benefit from the program in terms of self-efficacy and parenting stress. FMBEAP is highly recommended for overcoming behavioral excesses along with those interventions focus on behavioral deficits in ASD.