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Childhood trauma refers to trauma experiences encountered during childhood and adolescence. Maternal childhood trauma experiences have a lasting impact on the next generation, affecting their physical and mental well-being. The mechanisms involved include the hypothalamic-pituitary-adrenal axis, inflammatory factors, brain structure and function, gene interactions, and parenting styles. This paper systematically reviews the mechanisms of the impact of maternal childhood trauma on intergenerational transmission, providing insights for the prevention of intergenerational transmission of childhood trauma.

Oscillatory biomarkers of autism: evidence from the innate visual fear evoking paradigm.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with multiple associated deficits in both social and cognitive functioning. Diagnosing ASD usually relies on subjective clinical competencies, and research on objective criteria for diagnosing ASD in the early stage is still in its infancy. A recent animal study showed that the looming-evoked defensive response was impaired in mice with ASD, but whether the effect will be observed in human and contribute to finding a robust clinical neural biomarker remain unclear. Here, to investigate the looming-evoked defense response in humans, electroencephalogram responses toward looming and corresponding control stimuli (far and missing type) were recorded in children with ASD and typical developed (TD) children. Results revealed that alpha-band activity in the posterior brain region was strongly suppressed after looming stimuli in the TD group, but remained unchanged in the ASD group. This method could be a novel, objective way to detect ASD earlier. These findings suggest that further investigation of the neural mechanism underlying innate fear from the oscillatory view could be a helpful direction in the future. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09839-6.

Vitamin D deficiency worsens maternal diabetes induced neurodevelopmental disorder by potentiating hyperglycemia-mediated epigenetic changes.

Many studies have shown that vitamin D (VD) deficiency may be a risk factor for neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, although causative mechanisms remain unknown. In this study, we investigated the potential role and effect of VD on maternal diabetes induced autism-related phenotypes. The in vitro study found that enhancing genomic VD signaling by overexpressing the VD receptor (VDR) in human neural progenitor cells ACS-5003 protects against hyperglycemia-induced oxidative stress and inflammation by activating Nrf2 and its target genes, including SOD2 and HMOX1, and accordingly, VDR gene knockdown worsens the problem. In the two in vivo models we explored, maternal diabetes was used to establish an animal model of relevance to ASD, and mice lacking 25-hydroxyvitamin D 1-alpha-hydroxylase (the rate-limiting enzyme in the synthesis of 1,25(OH)2D3) were used to develop a model of VD deficiency (VDD). We show that although prenatal VDD itself does not produce ASD-relevant phenotypes, it significantly potentiates maternal diabetes induced epigenetic modifications and autism-related phenotypes. Postnatal manipulation of VD has no effect on maternal diabetes induced autism-related phenotypes. We conclude that VDD potentiates maternal diabetes induced autism-related phenotypes in offspring by epigenetic mechanisms. This study adds to other preclinical studies linking prenatal VDD with a neurodevelopmental disorder.

Urinary Metabonomic Profiling Discriminates Between Children with Autism and Their Healthy Siblings.

BACKGROUND Autism spectrum disorder (ASD) is a complicated neuropsychiatric disease that displays significant heterogeneity. The diagnosis of ASD is currently primarily dependent upon descriptions of clinical symptoms, and it remains urgent to find biological markers for the detection and diagnosis of autism. The current study applied the urinary metabolic profiling approach to characterize metabolic phenotypes in ASD. MATERIAL AND METHODS Urine was obtained from children with ASD and their matched healthy siblings. Samples were analyzed using 1H NMR-based methods designed to measure a broad range of metabolites. Partial least-square-discriminant analysis (PLS-DA) was used to develop models to identify metabonomic variations that can be used to distinguish between individuals with ASD and their unaffected siblings. RESULTS A significant difference was observed between the metabolomic profiles of children with ASD and that of their healthy siblings. An increase in the levels of tryptophan, hippurate, glycine, and creatine, and a decrease in trigonelline, melatonin, pantothenate, serotonin, and taurine were observed compared to the control group. We conclude that several metabolic pathways are affected by autism, which suggests that a gut-brain link may be important in the pathophysiology of ASD. CONCLUSIONS 1H NMR-based metabonomic analysis of the urine can determine perturbations of specific metabolic pathways related to ASD and help identify a characteristic metabolic fingerprint to better understand the disease and its causes.

Untargeted Metabolomic Profiling Using UHPLC-QTOF/MS Reveals Metabolic Alterations Associated with Autism.

Autism spectrum disorder (ASD) is a clinical spectrum of neurodevelopment disorder characterized by deficits in social communication and social interaction along with repetitive/stereotyped behaviors. The current diagnosis for autism relies entirely on clinical evaluation and has many limitations. In this study, we aim to elucidate the potential mechanism behind autism and establish a series of potential biomarkers for diagnosis. Here, we established an ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry- (UHPLC-QTOF/MS-) based metabonomic approach to discriminate the metabolic modifications between the cohort of autism patients and the healthy subjects. UHPLC-QTOF/MS analysis revealed that 24 of the identified potential biomarkers were primarily involved in amino acid or lipid metabolism and the tryptophan kynurenine pathway. The combination of nicotinamide, anthranilic acid, D-neopterin, and 7,8-dihydroneopterin allows for discrimination between ASD patients and controls, which were validated in an independent autism case-control cohort. The results indicated that UHPLC-QTOF/MS-based metabolomics is capable of rapidly profiling autism metabolites and is a promising technique for the discovery of potential biomarkers related to autism.

Prevalence and risk factors for depression in outpatient departments of three general hospitals in China: a cross-sectional study.

Objectives: To determine the prevalence and risk factors associated with depression of outpatients in three general hospitals in southern China.Methods: This hospital-based, cross-sectional descriptive study was conducted in outpatient departments of Neurology, Gastroenterology, Cardiology and Gynaecology of three general hospitals between March and June 2016. A total of 5294 adult respondents (≥18 years) in clinic waiting rooms were recruited, and 4976 were eligible to participate in the study. The nine-item Patient Health Questionnare-9 (PHQ-9) Scale was used to assess the presence of depressive symptoms. Binary logistic regression analysis was performed to identify the risk factors associated with depressive symptoms.Results: The prevalence of depressive symptoms among outpatients was 26.0% (95% CI: 24.8-27.3%). Risk factors associated with depressive symptoms included younger age (OR = 0.960; 95% CI: 0.95-0.971), social alcohol drinking (OR = 1.339; 95% CI: 1.074-1.668) and sleep disturbance (OR = 3.678; 95% CI: 3.025-4.471).Conclusions: This study provides evidence that depressive symptoms are prevalent among outpatients of general hospitals. Moreover, younger age, alcohol consumption and sleep disturbance may potentially be useful for targeted screening and prevention for outpatients with depression seen in general hospitals.KeypointsThe prevalence of self-reported depressive symptoms is common in outpatients in clinical settings.Younger age, current alcohol drinking and sleep disturbance are the associated risk factors for depression in outpatient population.Alcohol prevention and sleep quality improvement need to be incorporated into strategies aimed at the prevention and management of depression.

Regional differences in the risk of insomnia symptoms among patients from general hospital outpatient clinics.

BACKGROUND: Region-specific differences in the prevalence of insomnia symptoms in outpatient clinics in China have received little systematic study. This study was conducted preliminarily to examine region-specific differences in the risk of insomnia symptoms in Chinese outpatients. METHOD: In total, 4,399 adult outpatients (urban vs rural residents: 1,768 vs 2,631) who completed three questions focusing on insomnia symptoms were included. Their sociodemographic and clinical information were collected with standardized questionnaires. RESULTS: The prevalence of self-reported insomnia symptoms in urban residents (23.4%) was more frequent than the prevalence in rural residents (21.2%). The estimated prevalence of insomnia symptoms was significantly lower in rural than urban residents after adjusting for the potential confounders (P=0.015). Similarly, more urban (22.9%) than rural (13.4%) residents with insomnia symptoms had significantly higher treatment rates (χ 2=14.9, P<0.001). Multiple regression analyses showed that depressive symptoms, old age, and low education level were the most common risk factors for insomnia symptoms in both urban and rural residents. CONCLUSION: Our findings show that the prevalence of insomnia symptoms was relatively lower in rural than urban residents. Longitudinal studies are warranted to confirm the current findings.

Gender differences in the prevalence and clinical correlates of sleep disturbance in general hospital outpatients.

This study investigated gender differences in the prevalence of sleep disturbance and related demographic and clinical characteristics, including quality of life (QOL), in Chinese outpatients. Up to 4399 adult outpatients (2896 females, 1503 males) who visited the neurological, cardiovascular, gastrointestinal, and gynaecological outpatient clinics in four general hospitals were recruited. Demographic and clinical data including QOL were collected by using self-report questionnaires. The prevalence of sleep disturbance in female outpatients (671/2896, 23.2%) was significantly higher than in male outpatients (302/1503, 20.1%) and remained significant after adjusting for significant confounders in the regression analysis. In the regression analysis, divorced/widowed and unemployed status were independently associated with a higher frequency of sleep disturbance in females, while educational level was independently associated with males only. Among these factors, depressive symptoms and older age were the most common risk factors for sleep disturbance in both genders. Sleep disturbance was not associated with the mental domains of the QOL assessments in both genders. This study suggests that sleep disturbance is more frequent in female outpatients and is associated with multiple factors in both genders. A longitudinal study is warranted to confirm the current findings.

Prevalence of insomnia symptoms and their associated factors in patients treated in outpatient clinics of four general hospitals in Guangzhou, China.

BACKGROUND: Data on the prevalence of insomnia symptoms in medical outpatient clinics in China are lacking. This study examined the prevalence of insomnia symptoms and their socio-demographic correlates in patients treated at medical outpatient clinics affiliated with four general hospitals in Guangzhou, a large metropolis in southern China. METHOD: A total of 4399 patients were consecutively invited to participate in the study. Data on insomnia and its socio-demographic correlates were collected with standardized questionnaires. RESULTS: The prevalence of any type of insomnia symptoms was 22.1% (95% confidence interval (CI): 20.9-23.3%); the prevalence of difficulty initiating sleep was 14.3%, difficulty maintaining sleep was 16.2%, and early morning awakening was 12.4%. Only 17.5% of the patients suffering from insomnia received sleeping pills. Multiple logistic regression analysis revealed that male gender, education level, rural residence, and being unemployed or retired were negatively associated with insomnia symptoms, while lacking health insurance, older age and more severe depressive symptoms were positively associated with insomnia symptoms. CONCLUSIONS: Insomnia symptoms are common in patients attending medical outpatient clinics in Guangzhou. Increasing awareness of sleep hygiene measures, regular screening and psychosocial and pharmacological interventions for insomnia are needed in China. TRIAL REGISTRATION: ChiCTR-INR-16008066 . Registered 8 March 2016.

The profile of cognitive impairments in chronic ketamine users.

The aim of this study was to examine the cognitive function in chronic ketamine users. Factors correlated to cognition impairments were analyzed. Sixty-three chronic ketamine users and 65 healthy subjects were recruited. Cognitive function was assessed by using immediate/delayed visual reproduction (IVR/DVR) tasks, immediate/delayed logical memory (ILM/DLM) tasks, Stroop test, Wisconsin card sorting test (WCST), and continuous performance test (CPT). Psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). Ketamine users performed worse than controls on the IVR, ILM, DLM, Stroop and auditory CPT tests. IVR and DVR, color-naming and color-interference-reading scores were positively correlated with education level. In ketamine users ILM scores were negatively correlated with the negative subscale of PANSS. DLM score was positively correlated with average dose of ketamine use. Word-reading score was positively correlated with education level, and negatively correlated with duration of ketamine use. False hits in auditory CPT was positively correlated with duration of ketamine use. Number of trials to complete the first category and perseverative errors on WCST were positively correlated with the duration between the test and last ketamine use. Chronic ketamine users had cognitive impairments across multiple domains.

Association of sleep duration with sleep disturbances, quality of life, and sociodemographic factors in general hospital outpatients.

PURPOSE: To examine sleep duration and its demographic and clinical correlates in patients attending outpatient clinics attached to general hospitals. DESIGN AND METHODS: A total of 4,399 outpatients participated in the study. Sleep duration (short sleep, <7 h/day; long sleep, >8 h/day; and medium sleep, 7-8 h/day) was assessed. FINDINGS: The proportions of short and long sleep duration were 39.5% and 10.3%, respectively. Significant associations between short sleep and any type of sleep disturbances, age, education level, depressive symptoms, and rural residence were found. Long sleep was associated with age, education level, being unemployed, and depressive and anxiety symptoms. PRACTICE IMPLICATIONS: Short sleep duration is common among Chinese general hospital outpatients. Due to its negative effects, screening and interventions for short sleep are needed in this population.

Low serum level of epidermal growth factor in chronic ketamine users.

BACKGROUND: Growth factors play an important role in brain development. Whether epidermal growth factor (EGF) plays a role in the pathophysiology of ketamine related disorders is unexplored. In this study, we examined the serum levels of EGF in chronic ketamine users as compared with healthy controls. The possible correlation between serum EGF levels with the demographic, ketamine use characteristics and psychopathological symptoms were analyzed. METHODS: Sixty-seven chronic ketamine users and 40 healthy subjects were recruited. Serum EGF levels were measured by enzyme-linked immunosorbent assay. Psychopathological symptoms were assessed using Positive and Negative Syndrome Scale, Beck Depression Inventory and Beck Anxiety Inventory. RESULTS: The serum level of EGF in the chronic ketamine users was significantly lower than that of healthy subjects (22.34 ± 4.81 pg/ml vs. 87.10 ± 2.96 pg/ml, F = 15.169, p < 0.01). The serum EGF level was negatively correlated with the current average dose of ketamine consumption per day of use (p = 0.015), and positively associated with the Positive and Negative Syndrome Scale positive symptom score (p = .022). CONCLUSIONS: Serum level of EGF decreased in chronic ketamine users compared with healthy subjects, which may play a role in the pathophysiology of ketamine related disorders.

Major depressive disorder and suicide risk among adult outpatients at several general hospitals in a Chinese Han population.

BACKGROUND: Somatic complaints are often the presenting symptoms of major depressive disorder (MDD) in the outpatient context, because this may go unrecognized. It is well understood that MDD carries an increased risk of suicide. This study aimed to identify the risk factors and association with both MDD and suicidality among Han Chinese outpatients. METHODS: A multicenter study was carried out in 5189 outpatient adults (≥18 years old) in four general hospitals in Guangzhou, China. The 1392 patients who had the Patient Health Questionnaire-9 (PHQ-9) score ≥ 5, indicating depressive symptoms were offered an interview with a psychiatrist by the Mini International Neuropsychiatric Interview (MINI); 819 patients consented and completed the MINI interview. MINI module B was used to assess suicidality. Stepwise binary logistic models were used to estimate the relationship between a significant risk factor and suicide or MDD. According to with or without MDD, the secondary analysis was performed using the logistic regression model for the risk of suicidility. RESULTS: The current prevalence of MDD and the one month prevalence of suicidality were 3.7% and 2.3% respectively. The odds ratio of suicidality in women was more than twice that in men (OR = 2.62; 95% CI 1.45-4.76). Other risk factors which were significantly associated with suicidality were: living alone, higher education, self-reported depression, getting psychiatric diagnoses (MDD, anxiety disorders, and bipolar disorders). Significant risk factors for MDD were also noticed, such as comorbid anxiety disorders, self-reported anxiety, insomnia, suicidal ideation. LIMITATION: It's a cross-sectional study in outpatient clinics using self-report questionnaires. CONCLUSION: This study provides valuable data about the risk factors and association of MDD and suicide risk in adult outpatients in Han Chinese. Those factors allow better the employment of preventative measures.

Profiling the psychotic, depressive and anxiety symptoms in chronic ketamine users.

OBJECTIVE: Although concern about chronic ketamine abuse has grown, the characteristic symptomatology of chronic ketamine users has yet to be examined. This study aims to measure the psychotic, depressive and anxiety symptoms in chronic ketamine users. METHODS: A group of chronic ketamine users in Guangzhou, China were evaluated. The socio-demographic and drug use characteristics of subjects were documented. Symptoms of psychosis, depression, anxiety were evaluated by the Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). The severity of the symptoms was identified by standard severity cutoffs. RESULTS: The PANSS total score, positive symptom, negative symptom, general psychopathology subscale score were 45.3±8.4, 8.0±1.7, 13.2± 3.9 and 24.2± 4.9 respectively. BDI and BAI score was 13.1±6.5 and 15.7±9.6 respectively. 77.5% and 46.0% of the subjects showed moderate to severe depressive symptoms and anxiety symptoms respectively. The BDI score was positively correlated with ketamine use frequency. The BAI score was positively correlated with ketamine use frequency. CONCLUSIONS: Depressive symptoms were commonly presented in chronic ketamine users. The higher ketamine use frequency and dosage were associated with more severe depressive symptoms.

Relationship of serum levels of TNF-α, IL-6 and IL-18 and schizophrenia-like symptoms in chronic ketamine abusers.

OBJECTIVE: Exposing to NMDAR receptor antagonists, such as ketamine, produces schizophrenia-like symptoms in humans and deteriorates symptoms in schizophrenia patients. Meanwhile, schizophrenia is associated with alterations of cytokines in the immune system. This study aims to examine the serum TNF-α, IL-6 and IL-18 levels in chronic human ketamine users as compared to healthy subjects. The correlations between the serum cytokines levels with the demographic, ketamine use characteristics and psychiatric symptoms were also assessed. METHODS: 155 subjects who fulfilled the criteria of ketamine dependence and 80 healthy control subjects were recruited. Serum TNF-α, IL-6 and IL-18 levels were measured using an enzyme-linked immunosorbent assay (ELISA). The psychiatric symptoms of the ketamine abusers were assessed using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Serum IL-6 and IL-18 levels were significantly higher, while serum TNF-α level was significantly lower among ketamine users than among healthy controls (p<0.05). Serum TNF-α levels showed a significant negative association with PANSS total score (r=-0.210, p<0.01) and negative subscore (r=-0.300, p<0.01). No significant association was found between PANSS score and serum levels of IL-6 and IL-18. CONCLUSIONS: Serum levels of TNF-α, IL-6 and IL-18 were altered in chronic ketamine abusers which may play a role in schizophrenia-like symptoms in chronic ketamine abusers.

Development of a checklist of short-term and long-term psychological symptoms associated with ketamine use.

BACKGROUND: Ketamine is an increasingly popular drug of abuse in China but there is currently no method for classifying the psychological effects of ketamine in individuals with ketamine dependence. AIM: Develop a scale that characterizes the acute and long-term psychological effects of ketamine use among persons with ketamine dependence. METHODS: We developed a preliminary symptom checklist with 35 dichotomous ('yes' or 'no') items about subjective feelings immediately after ketamine use and about perceived long-term effects of ketamine use that was administered to 187 inpatients with ketamine dependence recruited from two large hospitals in Guangzhou, China. Exploratory factor analysis (EFA) was conducted on a randomly selected half of thesample to reduce the items and to identify underlying constructs. Confirmatory factor analysis (CFA) was conducted on the second half of the sample to assess the robustness of the identified factor structure. RESULTS: Among the 35 symptoms, the most-reported acute effects were 'floating or circling' (94%), 'euphoric when listening to rousing music' (86%), and 'feeling excited, talkative, and full of energy' (67%). The mostreported long-term symptoms were 'memory impairment' (93%), 'personality changes' (86%), and 'slowed reactions' (81%). EFA resulted in a final 22-item scale best modelled by a four-factor model: two factors representing chronic symptoms (social withdrawal and sleep disturbances), one about acute psychoticlike symptoms, and one that combined acute drug-related euphoria and longer-term decreased libido. CFA showed that these 4 factors accounted for 50% of the total variance of the final 22-item scale and that the model fit was fair (Goodness of Fit Index, GIF=83.3%; Root Mean Square Error of Approximation, RMSEA=0.072). CONCLUSION: A four-factor model including social withdrawal, sleep disturbance, psychotic-like symptoms, and euphoria at the time of drug use provides a fair description of the short-term and long-term psychological symptoms associated with ketamine use. Future work on the 22-item version of the scale with larger samples is needed to confirm the validity of this 4-factor structure, to assess the scale's test-retest reliability, and to determine whether or not it can be useful in the differential diagnosis and monitoring of treatment of individuals with ketamine dependence.

Serum level of vascular endothelial growth factor decreased in chronic ketamine abusers.

AIMS: To evaluate the serum level of vascular endothelial growth factor (VEGF) in a group of chronic ketamine abusers in comparison to healthy controls. METHODS: Eighty-one ketamine abusers who were hospitalized for the treatment of ketamine dependence and 39 healthy controls were recruited. Serum VEGF level was measured by enzyme linked immunosorbent assay (ELISA). Psychopathological symptoms were assessed using Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). RESULTS: Serum level of VEGF was significantly lower in chronic ketamine abusers compared to healthy controls (64.6±42.1 vs. 92.4±59.4pg/ml, F=7.243, p=0.008). CONCLUSIONS: Serum level of VEGF decreased in chronic ketamine abusers compared to healthy controls.

Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia.

OBJECTIVE: Studies of the effects of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, ketamine, have suggested similarities to the symptoms of schizophrenia. Our primary goal was to evaluate the dimensions of the Positive and Negative Syndrome Scale (PANSS) in ketamine users (acute and chronic) compared to schizophrenia patients (early and chronic stages). METHOD: We conducted exploratory factor analysis for the PANSS from four groups: 135 healthy subject administrated ketamine or saline, 187 inpatients of ketamine abuse; 154 inpatients of early course schizophrenia and 522 inpatients of chronic schizophrenia. Principal component factor analyses were conducted to identify the factor structure of the PANSS. RESULTS: Factor analysis yielded five factors for each group: positive, negative, cognitive, depressed, excitement or dissociation symptoms. The symptom dimensions in two schizophrenia groups were consistent with the established five-factor model (Wallwork et al., 2012). The factor structures across four groups were similar, with 19 of 30 symptoms loading on the same factor in at least 3 of 4 groups. The factors in the chronic ketamine group were more similar to the factors in the two schizophrenia groups rather than to the factors in the acute ketamine group. Symptom severities were significantly different across the groups (Kruskal-Wallis χ(2)(4) = 540.6, p < 0.0001). Symptoms in the two ketamine groups were milder than in the two schizophrenia groups (Cohen's d = 0.7). CONCLUSION: Our results provide the evidence of similarity in symptom dimensions between ketamine psychosis and schizophrenia psychosis. The interpretations should be cautious because of potential confounding factors.

Serum brain-derived neurotrophic factor and nerve growth factor decreased in chronic ketamine abusers.

AIMS: This study investigated the serum levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in a group of chronic ketamine abusers in comparison to healthy controls. The correlations between the serum BDNF, NGF level with the subjects' demographic, pattern of ketamine use were also examined. METHODS: 93 subjects who met the criteria of ketamine dependence and 39 healthy subjects were recruited. Serum BDNF and NGF levels were assayed by enzyme-linked immunosorbent assay (ELISA). Psychopathological symptoms were assessed using Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). RESULTS: Both serum levels of BDNF and NGF were significant lower in the ketamine users compared to the healthy control subjects (9.50±6.68 versus 14.37±6.07 ng/ml, p=0.019 for BDNF; 1.93±0.80 versus 2.60±1.07 ng/ml, p=0.011 for NGF). BDNF level was negatively associated with current frequency of ketamine use (r=-0.209, p=0.045). CONCLUSIONS: Both BDNF and NGF serum concentrations were significantly lower among chronic ketamine users than among health controls.