Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity.

Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions.

Acute stress symptoms in general population during the first wave of COVID lockdown in Italy: Results from the COMET trial.

BACKGROUND: The coronavirus disease of 2019 (COVID-19) pandemic is an unprecedented traumatic event that has severely impacted social, economic, and health well-being worldwide. The COvid Mental hEalth Trial was specifically designed to evaluate the impact of the COVID-19 pandemic and its containment measures on the mental health of the Italian general population in terms of COVID-19-related acute stress disorder (ASD) symptoms. METHODS: The present cross-sectional study is based on an online survey carried out in the period March-May 2020. Italian general adult population was invited to compile an anonymous survey, which included the severity of acute stress symptoms scale/National Stressful Events Survey Short Scale to investigate the occurrence and severity of ASD symptoms. RESULTS: The final sample consisted of 20,720 participants. During the lockdown, subjects with pre-existing mental health problems reported a statistically significant higher risk of acute post-traumatic symptoms compared to the general population (B: 2.57; 95% CI:2.04-3.09; p < .0001) and health care professionals (B: .37; 95% CI: .02-0.72; p < .05). According to multivariate regression models, the levels of acute post-traumatic symptoms (p < .0001) were higher in younger and female respondents. Social isolation and sleep disorder/insomnia represented positive predictors of acute stress (B = 3.32, 95% CI = 3.08-3.57). CONCLUSIONS: Concerns about the risk of infection as well as social isolation caused a higher incidence of acute post-traumatic stress symptoms that may predict the subsequent development of post-traumatic stress disorder symptoms in the long term.

The predictive role of proinflammatory and neuroendocrine factors in the acute phases of bipolar disorder: study protocol of a longitudinal controlled trial.

INTRODUCTION AND AIMS: Bipolar disorder (BD) is a severe and recurring mental illness associated with a significant personal and social burden. It has been recently hypothesized that increased levels of pro-inflammatory cytokines and cortisol, which is also associated with a reduced expression of the brain-derived neurotrophic factor (BDNF), may influence affective recurrences in BD. Our study aims to: 1) assess changes in the levels of peripheral cytokines, BDNF and salivary cortisol during acute and euthymic phases of bipolar disorder, compared to that of a sample oh healthy controls; 2) evaluate whether these changes represent a biosignature for the different phases of the illness. MATERIALS AND METHODS: Patients aged 18-65 years old, with a diagnosis of BD I or II types, will be enrolled during an acute episode, according to DSM-5 criteria, together with age- and gender-matched healthy controls. Blood and salivary samples will be collected at baseline and after 3 and 6 months. Validated assessment instruments will be administered to all participants for the evaluation of symptom severity, global functioning, suicidal risk, stress levels and physical comorbidities. EXPECTED RESULTS: We expect changes in inflammatory and neuroendocrine indices to be predictive of the onset of an acute phase of bipolar disorder and that overall levels of cytokines, cortisol and BDNF are overall significantly different between BD patients and healthy controls. CONCLUSIONS: The longitudinal design of the study will allow to assess whether the presence of acute affective symptoms in BD patients correlates with significantly higher levels of cytokines and salivary cortisol and with reduced BDNF levels compared to euthymic phases. Moreover, the comparison with healthy control subjects will allow to understand if inflammatory mediators as well as the hypothalamic-pituitary-adrenal (HPA) axis are chronically elevated in BD patients and are independent from mood swings.

Reduction in the use of green spaces during the COVID-19 pandemic and its impact on mental health.

Our study examined the use of green spaces before and during the pandemic in a large cohort of Italian twins and evaluated its impact on measures of mental health (depressive, anxiety, stress symptoms). Twins were analysed as individuals and as pairs. A twin design approach was applied to minimize confounding by genetic and shared environmental factors. Questionnaires from 2,473 twins enrolled in the Italian Twin Registry were screened. Reduced green space use was associated with significantly higher levels of depression, anxiety and distress. Being a woman, residing in urban areas, and having a high perceived risk of the outbreak resulted in a higher likelihood to modify green space use, with a negative impact on mental health.

The effect of social media and infodemic on mental health during the COVID-19 pandemic: results from the COMET multicentric trial.

On January 30, 2020, the World Health Organization (WHO) declared the status of pandemic due to the COVID-19 infection. The initial phases of the pandemic were characterized by uncertainty and public fears. In order to cope with such unexpected conditions, people adopted different coping strategies, including search for information, accessing Internet, and using social media. The present study based on the COMET collaborative research network aims to: (1) assess use of Internet and of social media among the Italian general population; (2) explore differences in web usage between people with pre-existing mental disorders and the general population; (3) identify changes over time in social media usage along the phase 1 of the pandemic; (4) identify the clinical, socio-demographic and contextual predictors of excessive use of social media. A significant increase in time spent on Internet, with an average time of 4.8 ± 0.02 h per day, was found in the global sample of 20,720 participants. Compared with the general population, Internet use was significantly higher in people with pre-existing mental disorders (5.2 ± 0.1 h vs. 4.9 ± 0.02; p < 0.005). According to the multivariate logistic regression model, the risk of excessive use of social media and Internet was significantly higher in people with moderate levels of depressive symptoms (OR: 1.26, CI 95%: 0.99 to 1.59, p < 0.0.005); while protective factors were being students (OR: 0.72, CI 95%: 0.53 to 0.96, p < 0.0029) and living in central Italy (OR: 0.46, CI 95%: 0.23 to 0.90, p < 0.002). The evaluation of social media and Internet use by the general population represents a first step for developing specific protective and supportive interventions for the general population, including practical suggestions on how to safely use Internet and social media.

Rosmarinic Acid Improves Cognitive Abilities and Glucose Metabolism in Aged C57Bl/6N Mice While Disrupting Lipid Profile in Young Adults in a Sex-Dependent Fashion.

A growing body of evidence suggests that regular consumption of natural products might promote healthy aging; however, their mechanisms of action are still unclear. Rosmarinic acid (RA) is a polyphenol holding anti-inflammatory, antioxidant and neuroprotective properties. The aim of this study was to characterise the efficacy of an oral administration of RA in promoting healthspan in a mouse model of physiological aging. Aged C57Bl/6 male and female (24-month-old) mice were either administered with RA (500 mg/Kg) or a vehicle in drinking bottles for 52 days while 3-month-old mice receiving the same treatment were used as controls. All subjects were assessed for cognitive abilities in the Morris water maze (MWM) and for emotionality in the elevated-plus maze test (EPM). Brain-derived Neurotrophic Factor (BDNF) protein levels were evaluated in the hippocampus. Since the interaction between metabolic signals and cerebral functions plays a pivotal role in the etiopathogenesis of cognitive decline, the glycaemic and lipid profiles of the mice were also assessed. RA enhanced learning and memory in 24-month-old mice, an effect that was associated to improved glucose homeostasis. By contrast, the lipid profile was disrupted in young adults. This effect was associated with worse glycaemic control in males and with reduced BDNF levels in females, suggesting powerful sex-dependent effects and raising a note of caution for RA administration in young healthy adult subjects.

Use of social network as a coping strategy for depression among young people during the COVID-19 lockdown: findings from the COMET collaborative study.

BACKGROUND: Use of social media (SM) has exponentially grown particularly among youths in the past two years, due to COVID-19-related changing lifestyles. Based on the Italian COvid Mental hEalth Trial (COMET), we investigated the association between SM use and depressive symptoms among Italian young adults (aged 18-24). METHODS: The COMET is a nationwide multi-center cross-sectional study that investigated socio-demographic data, social networking addiction (BSNAS), depression, anxiety, and stress (DASS-21), as well as impulsiveness (BIS-15) and aggressiveness (AQ) in a large sample of youngsters, in order to assess the association between BSNAS and DASS-21 indices. Mediation analyses were performed to evaluate the role of impulsiveness and aggressive personality traits in the association between SM use (SMU) and depression. RESULTS: 75.8% of the sample (n = 491) had a problematic SMU. SMU was reduced by high AQ and high DASS-21 scores (F = 42.338, p < 0.001, R2 = 0.207). Mediation analyses showed that SMU negatively predicted depressive symptomatology with the interaction mediated by AQ total (ß = - 0.1075), physical (ß = - 0.207) and anger (ß = - 0.0582), BIS-15 total (ß = - 0.0272) and attentional (ß = - 0.0302). High depressive levels were predicted by high AQ scores, low SMU levels, low verbal and physical AQ, and low attentional BIS-15 (F = 30.322, p < 0.001, R2 = 0.273). Depressive symptomatology negatively predicted SMU with their interaction mediated by AQ total (ß = - 0.1640), verbal (ß = 0.0436) and anger (ß = - 0.0807), BIS-15 total (ß = - 0.0448) and attentional (ß = - 0.0409). CONCLUSIONS: SMU during the early phases of the COVID-19 pandemic could have a beneficial role in buffering negative consequences linked to social isolation due to quarantine measures, despite this association being mediated by specific personality traits.

Depressive Anxiety Symptoms in Hospitalized Children with Chronic Illness during the First Italian COVID-19 Lockdown.

COVID-19 is continuing to spread around the world, having a direct impact on people's daily lives and health. Although the knowledge of the impact of the COVID-19 pandemic on mental health in the general population is now well established, there is less information on its effect on specific and vulnerable populations, such as children with chronic illness (CI). We conducted a multi-centered cross-sectional study among pediatric patients in six public children's hospitals in Italy during the first lockdown, with the aim of assessing the proportion of children with CI presenting anxiety and depressive symptoms, and the clinical and demographic characteristics affecting such symptomatology. We included children with at least one chronic condition, with no cognitive delay, aged between 11 and 18 years. Brief standardized questionnaires were administered during medical scheduled visits to screen anxiety and depressive symptoms. We found a very high proportion of children showing mild to severe depressive and anxiety symptomatology (approximately 68% and 63%, respectively). Our results highlight the need of ensuring tailored psychological interventions to protect children with CI from the effect of the pandemic (and related restrictive measures such as quarantine and social distancing), with the final aim of promoting mental health and psychological well-being in this vulnerable population.

Inflammatory Signatures of Maternal Obesity as Risk Factors for Neurodevelopmental Disorders: Role of Maternal Microbiota and Nutritional Intervention Strategies.

Obesity is a main risk factor for the onset and the precipitation of many non-communicable diseases. This condition, which is associated with low-grade chronic systemic inflammation, is of main concern during pregnancy leading to very serious consequences for the new generations. In addition to the prominent role played by the adipose tissue, dysbiosis of the maternal gut may also sustain the obesity-related inflammatory milieu contributing to create an overall suboptimal intrauterine environment. Such a condition here generically defined as "inflamed womb" may hold long-term detrimental effects on fetal brain development, increasing the vulnerability to mental disorders. In this review, we will examine the hypothesis that maternal obesity-related gut dysbiosis and the associated inflammation might specifically target fetal brain microglia, the resident brain immune macrophages, altering neurodevelopmental trajectories in a sex-dependent fashion. We will also review some of the most promising nutritional strategies capable to prevent or counteract the effects of maternal obesity through the modulation of inflammation and oxidative stress or by targeting the maternal microbiota.

Insomnia and related factors in patients with pre-existing psychiatric disorders compared to the general population during the COVID-19 lockdown: Findings from the multicentric COMET study.

BACKGROUND: The COVID-19 pandemic has heavily impacted social, economic and health systems worldwide. Necessary confinement measures have, in turn, contributed to the occurrence of several stress-related conditions and deterioration of pre-existing mental conditions, including insomnia. OBJECTIVE: The present study sought to investigate the occurrence and severity of insomnia during the COVID-19 lockdown among psychiatric patients and in the general population in the largest Italian sample examined to date. Potential factors associated with a risk of developing insomnia in the global sample were examined as well. METHODS: A sample of 20,720 people (5.5% of them being psychiatric patients) was assessed through an online survey conducted during lockdown between March and May 2020. To investigate the occurrence and severity of sleep related issues, the Insomnia Severity Index (ISI) was used. In order to evaluate factors associated with the severity of insomnia in the global sample, multivariate linear regression models were performed. RESULTS: During the lockdown, patients with pre-existing mental disorders reported a mean higher score on the ISI scale (p < 0.001) compared to the general population. According to the multivariate regression models, the first three weeks of lockdown were significantly associated with a higher risk of insomnia, but the risk disappeared in the fourth week. Other associated factors included: the presence of a pre-existing mental disorder, ages 24 to 64 years old, and/or being female (p < 0.001). CONCLUSIONS: Although containment measures represent essential public health strategies to avoid the spread of the COVID-19 pandemic, sleep was one of the aspects affected during the early stages of the lockdown in both people with pre-existing mental disorders and general population. As an integral part of COVID-19 intervention, it is useful to raise awareness about these issues and to adopt both preventive and therapeutic interventions.

Time moderates the interplay between 5-HTTLPR and stress on depression risk: gene x environment interaction as a dynamic process.

The serotonin-transporter-linked promoter region (5-HTTLPR) has been widely investigated as contributing to depression vulnerability. Nevertheless, empirical research provides wide contrasting findings regarding its involvement in the etiopathogenesis of the disorder. Our hypothesis was that such discrepancy can be explained considering time as moderating factor. We explored this hypothesis, exploiting a meta analytic approach. We searched PubMed, PsychoINFO, Scopus and EMBASE databases and 1096 studies were identified and screened, resulting in 22 studies to be included in the meta-analyses. The effect of the 5-HTTLPR x stress interaction on depression risk was found to be moderated by the following temporal factors: the duration of stress (i.e. chronic vs. acute) and the time interval between end of stress and assessment of depression (i.e. within 1 year vs. more than 1 year). When stratifying for the duration of stress, the effect of the 5-HTTLPR x stress interaction emerged only in the case of chronic stress, with a significant subgroup difference (p = 0.004). The stratification according to time interval revealed a significant interaction only for intervals within 1 year, though no difference between subgroups was found. The critical role of time interval clearly emerged when considering only chronic stress: a significant effect of the 5-HTTLPR and stress interaction was confirmed exclusively within 1 year and a significant subgroup difference was found (p = 0.01). These results show that the 5-HTTLPR x stress interaction is a dynamic process, producing different effects at different time points, and indirectly confirm that s-allele carriers are both at higher risk and more capable to recover from depression. Overall, these findings expand the current view of the interplay between 5-HTTLPR and stress adding the temporal dimension, that results in a three-way interaction: gene x environment x time.

Were anxiety, depression and psychological distress associated with local mortality rates during COVID-19 outbreak in Italy? Findings from the COMET study.

BACKGROUND: The mental health of the Italian population declined at the onset of the COVID-19 pandemic. However, nationwide population prevalence estimates may not effectively reproduce the heterogeneity in distress responses to the pandemic. In particular, contextual determinants specific to COVID-19 pandemic need to be considered. We thus aimed to explore the association between local COVID-19 mortality rates and mental health response among the general population. METHODS: We capitalised on data (N = 17,628) from a large, cross-sectional, national survey, the COMET study, run between March and May 2020. While psychological distress was measured by General Health Questionnaire-12 (GHQ-12), the Depression, Anxiety and Stress Scale-21 Items (DASS-21) was used to assess relevant domains. In addition, a Covid-19 mortality ratio was built to compare single regional mortality rates to the national estimate and official statistics were used to control for other area-level determinants. RESULTS: Adjusted ordered regression analyses showed an association between mortality ratio and moderate (OR = 1.10, 95%CI 1.03-1.18) and severe (OR = 1.11, 95%CI 1.03-1.21) DASS-21 anxiety levels. No effects of mortality ratio on GHQ-12 scores and DASS-21 depression and stress levels, uniformly high across the country, were estimated. CONCLUSIONS: Although we could not find any association between regional COVID-19 mortality ratio and depression or psychological distress, anxiety levels were significantly increased among subjects from areas with the highest mortality rates. Local mortality rate seems a meaningful driver for anxiety among the general population. Considering the potentially long-lasting scenario, local public health authorities should provide neighbouring communities with preventive interventions reducing psychological isolation and anxiety levels.

Psychopathological burden and coping strategies among frontline and second-line Italian healthcare workers facing the COVID-19 emergency: Findings from the COMET collaborative network.

BACKGROUND: The aim of this study was to explore the psychopathological burden related to COVID-19 together with coping strategies in healthcare workers, focusing on differences between frontline and second-line workers. METHODS: This is a cross-sectional study part of the COvid Mental hEalth Trial (COMET). Participants' socio-demographic and COVID-19-related information was collected through an online survey. Psychiatric symptoms and coping strategies were also investigated. Multivariate analyses, corrected for demographic characteristics, were adopted to assess differences between frontline and second-line workers. RESULTS: The sample consisted of 20,720 individuals. Healthcare workers (n = 2907) presented with significantly higher risk for mental health disturbances as compared to the rest of the sample (p < 0.001). Healthcare professionals working versus not working on the front line differed in living in severely impacted areas (p < 0.001), precautionary isolation by COVID-19 (p < 0.001), infection by COVID-19 (p < 0.001). Frontline workers also reported significantly increased insomnia (p < 0.001), depression (p = 0.007), anxiety (p < 0.001), obsessive-compulsive symptoms (p < 0.001), non-specific chronic and acute traumatic stress (p < 0.001; p < 0.001), as well as more adaptive coping strategies (p = 0.001). LIMITATIONS: The survey was conducted between March and June 2020, at the peak of the COVID-19 outbreak in Italy. Accordingly, the mental health impact of the COVID-19 pandemic might have changed over time. The survey design involved online invitation and it was not possible to assess the participation rate. CONCLUSIONS: To our knowledge, this is the largest study addressing the psychopathological burden of Italian healthcare professionals during the COVID-19 outbreak and associated coping strategies. Empowering supportive interventions is crucial for the whole healthcare workforce.

Ion-Pairing Chromatography and Amine Derivatization Provide Complementary Approaches for the Targeted LC-MS Analysis of the Polar Metabolome.

Liquid chromatography coupled to mass spectrometry is a key metabolomics/metabonomics technology. Reversed-phase liquid chromatography (RPLC) is very widely used as a separation step, but typically has poor retention of highly polar metabolites. Here, we evaluated the combination of two alternative methods for improving retention of polar metabolites based on 6-aminoquinoloyl-N-hydroxysuccinidimyl carbamate derivatization for amine groups, and ion-pairing chromatography (IPC) using tributylamine as an ion-pairing agent to retain acids. We compared both of these methods to RPLC and also to each other, for targeted analysis using a triple-quadrupole mass spectrometer, applied to a library of ca. 500 polar metabolites. IPC and derivatization were complementary in terms of their coverage: combined, they improved the proportion of metabolites with good retention to 91%, compared to just 39% for RPLC alone. The combined method was assessed by analyzing a set of liver extracts from aged male and female mice that had been treated with the polyphenol compound ampelopsin. Not only were a number of significantly changed metabolites detected, but also it could be shown that there was a clear interaction between ampelopsin treatment and sex, in that the direction of metabolite change was opposite for males and females.

Curcumin: A Promising Tool to Develop Preventive and Therapeutic Strategies against Non-Communicable Diseases, Still Requiring Verification by Sound Clinical Trials.

Curcumin is a pleiotropic compound found in the rhizome of Curcuma longa (turmeric) [...].