The correlation between brain structure characteristics and emotion regulation ability in children at high risk of autism spectrum disorder.

As indicated by longitudinal observation, autism has difficulty controlling emotions to a certain extent in early childhood, and most children's emotional and behavioral problems are further aggravated with the growth of age. This study aimed at exploring the correlation between white matter and white matter fiber bundle connectivity characteristics and their emotional regulation ability in children with autism using machine learning methods, which can lay an empirical basis for early clinical intervention of autism. Fifty-five high risk of autism spectrum disorder (HR-ASD) children and 52 typical development (TD) children were selected to complete the skull 3D-T1 structure and diffusion tensor imaging (DTI). The emotional regulation ability of the two groups was compared using the still-face paradigm (SFP). The classification and regression models of white matter characteristics and white matter fiber bundle connections of emotion regulation ability in the HR-ASD group were built based on the machine learning method. The volume of the right amygdala (R2 = 0.245) and the volume of the right hippocampus (R2 = 0.197) affected constructive emotion regulation strategies. FA (R2 = 0.32) and MD (R2 = 0.34) had the predictive effect on self-stimulating behaviour. White matter fiber bundle connection predicted constructive regulation strategies (positive edging R2 = 0.333, negative edging R2 = 0.334) and mother-seeking behaviors (positive edging R2 = 0.667, negative edging R2 = 0.363). The emotional regulation ability of HR-ASD children is significantly correlated with the connections of multiple white matter fiber bundles, which is a potential neuro-biomarker of emotional regulation ability.

Heritability of abnormalities in limbic networks of autism spectrum disorder children: Evidence from an autism spectrum disorder twin study.

Although the limbic system is closely related to emotion and social behaviors, little is known about the integrity of limbic pathways and how genetics influence the anatomical abnormalities of limbic networks in children with autism spectrum disorder (ASD). Therefore, we used an ASD twin study design to evaluate the microstructural integrity and autism-related differences in limbic pathways of young children with ASD and to estimate the heritability of limbic tracts microstructure variance. We obtained diffusion tensor imaging scans from 33 pairs of twins with ASD aged 2-9 years and 20 age-matched typically developing children. The ACE model was used to estimate the relative effects of additive genetic factors (A), shared environmental factors (C) and specific environmental factors (E) on the variability of diffusivity measurements. We found a significant decrease in fractional anisotropy (FA) in the bilateral fornix and uncinate fasciculus (UF), as well as increased mean diffusivity (MD) and radial diffusivity (RD) in the bilateral fornix and right UF of ASD children. Correlation analysis showed that FA, MD, and lateralization indices of UF were correlated with autism diagnostic observation schedule scores. The ACE model revealed that genetic effects may drive some of the variability of microstructure in the bilateral fornix, cingulum, and left UF. In conclusion, in children with ASD, there are abnormalities in the white matter microstructure of the limbic system, which is related to the core symptoms; these abnormalities may be related to the relative contribution of genetic and environmental effects on specific tracts. LAY SUMMARY: Autism spectrum disorder (ASD) children have abnormal white matter structure in limbic system related to ASD symptoms, and genetic factors play an important role in the development of limbic tracts.

The characteristics and factors of the internalizing and externalizing behaviours of children at high risk for autism spectrum disorder.

BACKGROUND: The behavioral characteristics of children with autism spectrum disorder (ASD) are not only affected by their disease, but also by their parenting environment. HR-ASD has the risk of developing internalization and externalization problems. How the early development of these behavioral problems is affected by parent-child interaction is worth exploring. We tested whether parent-child interactions and parenting characteristics were associated with behavioural problems during the infant periods. METHODS: This study collected data from 91 infants at high risk for ASD and 68 matched typically developing (TD) infants, about their internalizing and externalizing behavioural problems and engagement states (i.e. positive, negative, and parent-child interactions), using free play paradigm. Parent measures were assessed using the Broad Autism Phenotypic Questionnaire (BAPQ) and Parenting Stress Index Short Form (PSI-SF) questionnaire. The core symptoms of ASD were assessed using the the Autism Diagnostic Observational Schedule (ADOS). RESULTS: During free play, infants in the HR-ASD group showed more internalizing (P < 0.001) and externalizing (P < 0.05) behaviours and less positive engagement (P < 0.01) than the TD group. In the regression analysis, we found that parenting stress had an impact on the infants' externalizing behaviours (△R2 = 0.215). Parent negative engagement had an impact on the infants' internalizing behaviours (△R2 = 0.451). CONCLUSIONS: The present study revealed that children at high risk for ASD exhibited more severe internalizing and externalizing behavioural problems than TD group. The parent negative engagement is associated with behavioural problems. The findings on the contribution of parents' factors to behavioural problems suggests that the parenting stress and parent-child interactions are important factors for mitigating behavioural problems.

The relationships between the topological properties of the whole-brain white matter network and the severity of autism spectrum disorder: A study from monozygotic twins.

Twins provide a valuable perspective for exploring the pathological mechanism of autism spectrum disorder (ASD). We aim to analyze differences in the topological properties of the white matter (WM) network between monozygotic twins with ASD (MZCo-ASD) and children with typical development (TD). We enrolled 67 subjects aged 2-9 years. Twenty-three pairs of MZCo-ASD and 21 singleton children with TD completed clinical assessments and diffusion tensor imaging (DTI). Graph theory was used to compare the topological properties of the WM network between the two groups, and analyzed their correlations with the severity of clinical symptoms. We found that the global efficiency (Eg) of MZCo-ASD is weaker than that of TD children, while the shortest path length (Lp) of MZCo-ASD is longer than that of TD children, and MZCo-ASD have three unique hubs (the bilateral dorsolateral superior frontal gyrus and right insula). Eg and Lp were both correlated with the repetitive behavior scores of the Autism Diagnostic Interview-Revised (ADI-R) in the MZCo-ASD group, and the nodal efficiency of the dorsal superior frontal gyrus (SFGdor) was correlated with the ADI-R scores of repetitive behaviors. Left SFGdor nodal efficiency was correlated with Repetitive Behavior and Communication, two core symptoms of autism. The results implicated that MZCo-ASD had atypical brain structural network attributes and node distributions. Using MZCo-ASD, we found that the WM topological properties that correlate with the severity of ASD core symptoms were Eg, Lp, and the nodal efficiency of the SFGdor.

Bisphenol A induces ovarian cancer cell proliferation and metastasis through estrogen receptor-α pathways.

Bisphenol A (BPA) is a widely used raw material that can be detected both in the environment and in the human body. Due to its estrogen-like effects, wide concerns have been raised about the potential role of BPA in the initiation and development of hormone-dependent cancers. Ovarian cancer is the most common reproductive system cancer and has a high mortality rate in women. Despite recent investigations into BPA's carcinogenic effects, studies on its role in ovarian cancer development remain limited. In this study, we aimed to assess the effect of BPA at various environmentally relevant concentrations on proliferation and metastasis of ovarian cancer cells. We discovered that BPA can stimulate proliferation of OVCAR-3 ovarian cancer cells after exposure for up to 5 days. Strikingly, BPA enhanced ovarian cancer cell migration, invasion, and adhesion (to vascular endothelial cells) through upregulation of matrix metalloproteinase-2 (MMP-2), MMP-9, and intercellular cell adhesion molecule-1 (IMAC-1). The stimulatory effects of BPA on cancer cell proliferation and metastasis were reversed by treatment with an ERα inhibitor, but not by treatment with an ERß inhibitor. Together, these results suggest that BPA induces proliferation and metastasis of ovarian cancer cells through ERα signaling pathways. This study provides new insights into the carcinogenic effects of BPA with regard to ovarian cancer.

Atypical Neural Responses of Cognitive Flexibility in Parents of Children With Autism Spectrum Disorder.

Impaired cognitive flexibility has been repeatedly demonstrated in autism spectrum disorder (ASD). There is strong evidence for genetic involvement in ASD. First-degree relatives of individuals with ASD may show mild deficits in cognitive inflexibility. The present study investigated cognitive flexibility and its neuroelectrophysiological mechanisms in first-degree relatives of individuals with ASD to assess its potential familiality. Forty-five biological parents of individuals/children with ASD (pASD) and thirty-one biological parents of typically developing individuals/children (pTD), matched by gender, age, and IQ, were enrolled. The broad autism phenotype questionnaire (BAPQ) and cognitive flexibility inventory (CFI) were used to quantitatively assess autistic traits and cognitive flexibility in daily life, respectively. The task-switching paradigm was used to evaluate the behavioral flexibility in a structured assessment situation. Event-related potentials (ERPs) induced by this paradigm were also collected. Results showed that compared with the pTD group, the pASD group had lower CFI scores (t = -2.756, p < 0.01), while both groups showed an equivalent "switch cost" in the task-switching task (p > 0.05). Compared with the pTD group, the pASD group induced greater N2 amplitude at F3, F4, Fz, and C4 (F = 3.223, p < 0.05), while P3 amplitude and latency did not differ between the two groups. In addition, there was a significant negative correlation between the CFI total scores and BAPQ total scores in the pASD group (r = -0.734, p < 0.01). After controlling for age and IQ, the N2 amplitude in the frontal lobe of pASD was negatively correlated with the CFI total scores under the repetition sequence (r = -0.304, p = 0.053). These results indicated that pASD had deficit in cognitive flexibility at the self-reported and neurological levels. The cognitive flexibility difficulties of parents of children with ASD were related to autistic traits. These findings support that cognitive flexibility is most likely a neurocognitive endophenotype of ASD, which is worthy of further investigation.

Predictors of Change in Play-Based Communication and Behavior Intervention for High-Risk ASD: The Role of Mother-Child Dyadic Synchrony.

Background: Interindividual variability is important in the evolution of adaptative profiles of children with ASD having benefited from an early intervention make up for deficits in communication, language and social interactions. Therefore, this paper aimed to determine the nature of factors influencing the efficacy variability of a particular intervention technique i.e., "Play-based communication and behavior intervention" (PCBI). Methods: The participants comprised 70 13-30-month-old toddlers with ASD enrolled in PCBI for 12 weeks. The Autism Treatment Evaluation Checklist (ATEC) was used to evaluate the efficacy of PCBI. Video recordings of 5 min of free-play before and after PCBI were used to examine behaviors of mothers and children and parent-child dyadic synchrony. Hierarchical multiple regression analyses and machine learning algorithms were performed to explore the effect of these potential predictors (mothers' factors, children's factors and videotaped mother-child interaction) of intervention efficacy. Results: The hierarchical regression analysis and the machine learning algorithms indicated that parenting stress, level of completion of training at home and mother-child dyadic synchrony were crucial factors in predicting and monitoring the efficacy of PCBI. Conclusions: In summary, the findings suggest that PCBI could be particularly beneficial to children with ASD who show a good performance in the mother-child dyadic synchrony evaluation. A better dyadic mother-child synchrony could enhance the PCBI efficacy through adapted emotional and behavioral responses of the mother and the child and has a beneficial influence on the child's psychological development.

Differential Regulation of DNA Methylation at the CRMP2 Promoter Region Between the Hippocampus and Prefrontal Cortex in a CUMS Depression Model.

Current evidence supports the idea that neural plasticity is a potential cause of depression. Abundant studies indicate that CRMP2 has important roles in neural plasticity. Moreover, CRMP2 may contribute to the etiology of depression. However, the regulatory mechanisms underlying the role of CRMP2 remain unclear. DNA methylation alteration is generally acknowledged to be involved in the development of depression. The aim of this study was to explore the relationship between the expression and DNA methylation of CRMP2 in the hippocampus and prefrontal cortex of a rat depression model. Chronic unpredictable mild stress (CUMS) was used to establish a rat depression model, and body weight and behavioral tests were used to evaluate the effects of stress. Real-time PCR and Western blotting were used to test CRMP2 mRNA and protein expression, respectively, in the hippocampus and prefrontal cortex of rats. DNA methylation levels of the CRMP2 promoter were analyzed by bisulfite sequencing PCR (BSP). CUMS caused depressive-like behavior in rats, as evidenced by: decreased body weight and sucrose preference rate; decreases in the total distance traveled, rearing frequency, velocity, and duration in the center in the open field test (OFT); and prolonged immobility in the forced swimming test (FST). CRMP2 mRNA and protein expression in the hippocampus and prefrontal cortex were significantly decreased in the CUMS group compared with the control group. The levels of CRMP2 promoter DNA methylation in the hippocampus of the CUMS group were significantly higher than those of the control group, while these changes were not observed in the prefrontal cortex of CUMS rats. Our data provide evidence that altered expression of CRMP2 in the hippocampus and prefrontal cortex is associated with the pathogenesis of depression. Moreover, the results also suggest regional differences in the regulation of DNA methylation in the CRMP2 promoter between the hippocampus and prefrontal cortex during the development of depression.

Longitudinal Study of Brain Asymmetries in Autism and Developmental Delays Aged 2-5 Years.

Some previous studies have demonstrated atypical brain lateralization in autism spectrum disorder (ASD). However, most of these reports have focused on language-related asymmetries in adults, and the developmental trajectory of hemispheric asymmetries in the important phase that occurs at 2-5 years of age remains unclear. Thus, we used structural magnetic resonance imaging and diffusion tensor imaging (DTI) in a longitudinal study of grey matter (GM) asymmetries across all cortical parcellation units (PUs) and white matter (WM) lateralization across the WM skeleton using voxel-based morphometry and tract-based spatial statistics (TBSS) in 34 toddlers with ASD and a matched group of 26 toddlers with developmental delay (DD) at 2-3 years old and with follow-up at 4-5 years of age. We found the total brain volume and fractional anisotropy (FA) of WM was higher in the ASD group than in the DD group at baseline and 2 years later. The ASD and DD groups showed a rightward asymmetry in a large number of cortical PUs and in the WM skeleton at both time points. GM lateralization was associated with the social and communicative disturbances observed in ASD at baseline, while WM asymmetry was significantly related to social disturbances and repetitive behaviours seen at 4-5 years of age. In conclusion, both ASD and DD toddlers had widespread rightward asymmetry, and the patterns of lateralization were similar across the groups. GM and WM showed asynchronous development of hemispheric asymmetries at 2-5 years of age, and this lateralization was associated with ASD symptoms.

DNA methylation of the Tacr2 gene in a CUMS model of depression.

Tacr2, the gene encoding the NK2 receptor, belongs to G protein-coupled receptors. Accumulating evidence has indicated that the tachykinin receptors may contribute to the pathophysiology of depression. During the last decade, some studies have shown that Tacr2 activation is involved in the modulation of emotional processes. However, the extent, to which stress impacts Tacr2 expression remains unclear. The molecular mechanisms underlying depression also remain poorly understood. In this study, we subjected adult male Sprague Dawley (SD) rats to chronic unpredictable mild stress (CUMS) to induce a depression-like phenotype. We then measured the body weight and performed the sucrose preference test, forced swimming test (FST) and open field test to detect the effects of stress on anhedonia and activity. Western blotting and real-time PCR were used to study the protein and mRNA expression levels of Tacr2, respectively, in the hypothalamus. To explore DNA methylation of the Tacr2 gene, we used methylated DNA immunoprecipitation sequencing (MeDIP-seq). Additionally, we used the bisulfite sequencing PCR (BSP) to further verify the DNA methylation levels of the Tacr2 receptor gene in rats. We found that the CUMS-sensitive rats exhibited a decrease in body weight and sucrose preference, a decrease in the distance traveled, rearing frequency and velocity in the open field test, and an increase in immobility time in the FST. Compared with the expression in the control rats, Tacr2 protein and mRNA expression in the hypothalamus significantly increased in the CUMS-sensitive rats; however, the DNA methylation levels of the Tacr2 gene were significantly lower than in the control rats. In summary, according to our findings, the stress-induced increase in Tacr2 expression in the hypothalamus correlated with a specific decrease in DNA methylation of the Tacr2 gene. These results may enrich the understanding of the pathological processes of depression and provide insights into therapeutic approaches for its treatment.

Reduced Prefrontal Activation During the Tower of London and Verbal Fluency Task in Patients With Bipolar Depression: A Multi-Channel NIRS Study.

Background: The Tower of London (TOL) task is one of the most commonly used tests for evaluating executive functions, and can indicate planning and problem-solving abilities. The aim of this study was to evaluate hemodynamic changes between the task period and rest period in patients with bipolar depression during the TOL task and the verbal fluency task (VFT) using near-infrared spectroscopy (NIRS). Methods: Forty-three patients with bipolar depression and 32 healthy controls (HCs) matched for sex, age, handedness, and years of education were enrolled in this study. All participants were aged between 16 and 50. All patients in our study were taking medications such as antidepressants, antipsychotics and mood stabilizers at the time of measurement. Changes in oxygenated hemoglobin (oxy-Hb) levels in frontal areas during the TOL task and VFT were evaluated using a 41-channel NIRS system. Results: During the TOL task, the patients with bipolar depression exhibited significantly smaller changes in the bilateral dorsal-lateral prefrontal cortex (DLPFC) than the HCs. During the VFT task, the patients with bipolar depression exhibited significantly smaller changes in the right ventrolateral prefrontal cortex (VLPFC), the right DLPFC and both the right and left prefrontal cortex (PFC) than the HCs. Limitations: Our sample size was small, and the effects of medication cannot be excluded. Conclusions: These results indicate that planning and problem solving dysfunction is related to the impairment of the prefrontal cortex in patients with bipolar depression, and NIRS can be used to assess planning and problem solving abilities, which are essential to daily life in patients with bipolar disorder.

Auditory P300 study in patients with convalescent bipolar depression and bipolar depression.

The aim of this study was to investigate the information-processing changes during an auditory oddball task among healthy controls (HCs), convalescent bipolar depression (BPC), and bipolar depression (BPD) patients. Thirty patients with BPD, 27 patients with BPC, and 30 HC were recruited in this study. The participants' performance (reaction time and accuracy) as well as P300 amplitude and latency during the tests were analyzed statistically. BPD and BPC showed poor task performance compared with HC. BPD had lower P300 amplitude and delayed P300 latency in the frontal, central, and parietal areas than HC. BPC had lower P300 amplitude, but no difference in P300 latency compared with the HC group. Further, P300 latency was significantly delayed over the right relative to the left region. In conclusion, bipolar patients had P300 abnormalities and deficits in cognitive processing of stimulus, and may be present even when emotional symptoms were relieved.