Early-life social stress induces permanent alterations in plasticity and perineuronal nets in the mouse anterior cingulate cortex.

Child maltreatment disrupts trajectories of brain development, but the underlying pathways are unclear. Stressful stimuli in early life interfere with maturation of local inhibitory circuitry and deposition of perineuronal nets (PNNs), specialized extracellular matrix structures involved in the closure of critical periods of development. Alterations in cortical PNN and parvalbumin (PV) following early-life stress (ELS) have been detected in human and animal studies. Aberrations in the anterior cingulate cortex (ACC) are the most consistent neuroimaging findings in maltreated people, but the molecular mechanisms linking ELS with ACC dysfunctions are unknown. Here, we employed a mouse model of early social threat to test whether ELS experienced in a sensitive period for ACC maturation could induce long-term aberrations of PNN and PV development in the ACC, with consequences on plasticity and ACC-dependent behavior. We found that ELS increased PNN but not PV expression in the ACC of young adult mice. This was associated with reduced frequency of inhibitory postsynaptic currents and long-term potentiation impairments and expression of intense object phobia. Our findings provide information on the long-term effects of ELS on ACC functionality and PNN formation and present evidence for a novel neurobiological pathway underlying the impact of early adversity on the brain.

Microglial alterations induced by psychoactive drugs: A possible mechanism in substance use disorder?

Recently, the xenobiotic hypothesis has implicated the immune system in targeting substances of abuse as foreign molecules and stimulating inflammatory responses. Microglial cells are the resident immune cells of the central nervous system and function in homeostatic surveillance. Microglial changes that are induced by exposure to substances of abuse appear to mediate in part the establishment of addiction and the persistence of drug-mediated biological and behavioral changes. In this context, interest in the study of drug-microglia interactions has increased recently. This review summarizes the most recent preclinical rodent and clinical studies on the interaction between microglia and various classes of drugs of abuse, such as ethanol, psychostimulants, and opioids. The principal biological mechanisms of the communication between substances of abuse and microglia will be described to consider putative mechanisms of the establishment of drug addiction and future potential targets for treating substance use disorder.

Early life stress exposure worsens adult remote microglia activation, neuronal death, and functional recovery after focal brain injury.

Trauma to the central nervous system (CNS) is a devastating condition resulting in severe functional impairments that strongly vary among patients. Patients' features, such as age, social and cultural environment, and pre-existing psychiatric conditions may be particularly relevant for determining prognosis after CNS trauma. Although several studies demonstrated the impact of adult psycho-social stress exposure on functional recovery after CNS damage, no data exist regarding the long-term effects of the exposure to such experience at an early age. Here, we assessed whether early life stress (ELS) hampers the neuroinflammatory milieuand the functional recovery after focal brain injury in adulthood by using a murine model of ELS exposure combined with hemicerebellectomy (HCb), a model of remote damage. We found that ELS permanently altered microglia responses such that, once experienced HCb, they produced an exaggerated remote inflammatory response - consistent with a primed phenotype - associated with increased cell death and worse functional recovery. Notably, prevention of microglia/macrophages activation by GW2580 treatment during ELS exposure significantly reduced microglia responses, cell death and improved functional recovery. Conversely, GW2580 treatment administered in adulthood after HCb was ineffective in reducing inflammation and cell death or improving functional recovery. Our findings highlight that ELS impacts the immune system maturation producing permanent changes, and that it is a relevant factor modulating the response to a CNS damage. Further studies are needed to clarify the mechanisms underlying the interaction between ELS and brain injury with the aim of developing targeted treatments to improve functional recovery after CNS damage.

Beyond the dyad: the role of mother and father in newborns' global DNA methylation during the first month of life-a pilot study.

The study aimed to longitudinally explore the effects of parental prenatal attachment and psychopathological symptomatology on neonatal global DNA methylation (5-mC) variation between birth and the first month of life. Eighteen mothers and thirteen fathers were assessed before childbirth (t0) by Perceived Stress Scale (PSS), Prenatal-Attachment Inventory, and Paternal Antenatal Attachment Scale; 48 hr after childbirth (t1) by SCL-90-R; and one month after childbirth (t2) by PSS. At t1 and t2, buccal swabs from parents and newborns were collected. In newborns' 5-mC and single nucleotide polymorphisms (SNPs) of DAT, MAOA, BDNF, and 5-HTTLPR genes were detected, while in parents only SNPs were measured. At t1, newborns' 5-mC was negatively associated with maternal psychopathological symptoms, while at t2, newborns' 5-mC was positively associated with paternal psychopathological symptoms and negatively with paternal prenatal attachment. The variation of newborns' 5-mC from t1 to t2 was predicted by paternal psychopathological symptoms. No significant correlations among parental SNPs and 5-mC levels were found. Results highlight parent-specific influences on newborn's DNA methylation. At birth, maternal psychological symptoms seem to have an effect on newborns' 5-mC, while after one month of life, paternal psychological characteristics could have a specific role in modulating the newborns' epigenetic responses to the environment.

Affective Saturation Index: A Lexical Measure of Affect.

Affect plays a major role in the individual's daily life, driving the sensemaking of experience, psychopathological conditions, social representations of phenomena, and ways of coping with others. The characteristics of affect have been traditionally investigated through physiological, self-report, and behavioral measures. The present article proposes a text-based measure to detect affect intensity: the Affective Saturation Index (ASI). The ASI rationale and the conceptualization of affect are overviewed, and an initial validation study on the ASI's convergent and concurrent validity is presented. Forty individuals completed a non-clinical semi-structured interview. For each interview transcript, the ASI was esteemed and compared to the individual's physiological index of propensity to affective arousal (measured by heart rate variability (HRV)); transcript semantic complexity (measured through the Semantic Entropy Index (SEI)); and lexical syntactic complexity (measured through the Flesch-Vacca Index (FVI)). ANOVAs and bi-variate correlations estimated the size of the relationships between indexes and sample characteristics (age, gender), then a set of multiple linear regressions tested the ASI's association with HRV, the SEI, and the FVI. Results support the ASI construct and criteria validity. The ASI proved able to detect affective saturation in interview transcripts (SEI and FVI, adjusted R2 = 0.428 and adjusted R2 = 0.241, respectively) and the way the text's affective saturation reflected the intensity of the individual's affective state (HRV, adjusted R2 = 0.428). In conclusion, although the specificity of the sample (psychology students) limits the findings' generalizability, the ASI provides the chance to use written texts to measure affect in accordance with a dynamic approach, independent of the spatio-temporal setting in which they were produced. In doing so, the ASI provides a way to empower the empirical analysis of fields such as psychotherapy and social group dynamics.

The impact of adolescent stress experiences on neurobiological development.

Adolescence is considered a developmental period of heightened vulnerability to many psychological dysfunctions-primarily due to the high structural neuronal plasticity that accompanies the associated physical and cognitive gains, rendering an individual highly susceptible to environmental stressors during this time. Recently, interest has been generated in the study of neuronal and behavioral adaptation to adverse experiences during adolescence. This review will provide an overview of the principal neurobehavioral changes that occur during adolescence and describe what happens when the maturation of these functions is altered by stressful environmental stimuli.

Social threat exposure in juvenile mice promotes cocaine-seeking by altering blood clotting and brain vasculature.

Childhood maltreatment is associated with increased severity of substance use disorder and frequent relapse to drug use following abstinence. However, the molecular and neurobiological substrates that are engaged during early traumatic events and mediate the greater risk of relapse are poorly understood and knowledge of risk factors is to date extremely limited. In this study, we modeled childhood maltreatment by exposing juvenile mice to a threatening social experience (social stressed, S-S). We showed that S-S experience influenced the propensity to reinstate cocaine-seeking after periods of withdrawal in adulthood. By exploring global gene expression in blood leukocytes we found that this behavioral phenotype was associated with greater blood coagulation. In parallel, impairments in brain microvasculature were observed in S-S mice. Furthermore, treatment with an anticoagulant agent during withdrawal abolished the susceptibility to reinstate cocaine-seeking in S-S mice. These findings provide novel insights into a possible molecular mechanism by which childhood maltreatment heightens the risk for relapse in cocaine-dependent individuals.

Repetitive transcranial magnetic stimulation reduces remote apoptotic cell death and inflammation after focal brain injury.

BACKGROUND: After focal brain injuries occur, in addition to the effects that are attributable to the primary site of damage, the resulting functional impairments depend highly on changes that occur in regions that are remote but functionally connected to the site of injury. Such effects are associated with apoptotic and inflammatory cascades and are considered to be important predictors of outcome. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique that is used to treat various central nervous system (CNS) pathologies and enhance functional recovery after brain damage. OBJECTIVE: This study examined the efficacy of rTMS in mitigating remote degeneration and inflammation and in improving functional recovery in a model of focal brain damage. METHODS: Rats that were undergoing hemicerebellectomy (HCb) were treated with an rTMS protocol for 7 days, and neuronal death indices, glial activation, and functional recovery were assessed. RESULTS: rTMS significantly reduced neuronal death and glial activation in remote regions and improved functional recovery. CONCLUSIONS: Our finding opens up a completely new scenario for exploiting the potential of rTMS as an anti-apoptotic and anti-inflammatory treatment.

To Be Frail or Not to Be Frail: This Is the Question-A Critical Narrative Review of Frailty.

Many factors have contributed to rendering frailty an emerging, relevant, and very popular concept. First, many pandemics that have affected humanity in history, including COVID-19, most recently, have had more severe effects on frail people compared to non-frail ones. Second, the increase in human life expectancy observed in many developed countries, including Italy has led to a rise in the percentage of the older population that is more likely to be frail, which is why frailty is much a more common concern among geriatricians compared to other the various health-care professionals. Third, the stratification of people according to the occurrence and the degree of frailty allows healthcare decision makers to adequately plan for the allocation of available human professional and economic resources. Since frailty is considered to be fully preventable, there are relevant consequences in terms of potential benefits both in terms of the clinical outcome and healthcare costs. Frailty is becoming a popular, pervasive, and almost omnipresent concept in many different contexts, including clinical medicine, physical health, lifestyle behavior, mental health, health policy, and socio-economic planning sciences. The emergence of the new "science of frailty" has been recently acknowledged. However, there is still debate on the exact definition of frailty, the pathogenic mechanisms involved, the most appropriate method to assess frailty, and consequently, who should be considered frail. This narrative review aims to analyze frailty from many different aspects and points of view, with a special focus on the proposed pathogenic mechanisms, the various factors that have been considered in the assessment of frailty, and the emerging role of biomarkers in the early recognition of frailty, particularly on the role of mitochondria. According to the extensive literature on this topic, it is clear that frailty is a very complex syndrome, involving many different domains and affecting multiple physiological systems. Therefore, its management should be directed towards a comprehensive and multifaceted holistic approach and a personalized intervention strategy to slow down its progression or even to completely reverse the course of this condition.

A sex-specific pathway linking early life maltreatment, vagal activity, and depressive symptoms.

Background: Experiences of early life maltreatment (ELM) are alarmingly common and represent a risk factor for the development of psychopathology, particularly depression. Research has focused on alterations in autonomic nervous system (ANS) functioning as a mediator of negative mental health outcomes associated with ELM. Early alterations in autonomic vagal activity (vmHRV) may moderate the relationship between ELM and depression, particularly when considering forms of emotional maltreatment. Recent evidence suggests that the relationships of both ELM and vmHRV with depression may be non-linear, particularly considering females.Objective: Building on and extending theoretical considerations and previous work, the present work aims to further the current understanding of the complex relationships between ELM exposure, vmHRV, and depression.Methods: This study uses an adaptive modelling approach, combining exploratory network-based analyses with linear and quadratic moderation analyses, drawing on a large sample of males and females across adolescence (total N = 213; outpatient at-risk sample and healthy controls) and adulthood (total N = 85; community-based convenience sample).Results: Exploratory network-based analyses reveal that exposure to emotional abuse is particularly central within a network of ELM subtypes, depressive symptoms, and concurrent vmHRV in both adolescents and adults. In adults, emotional neglect shows strong associations with both emotional abuse and vmHRV and is highly central as a network node, which is not observed in adolescents. Moderator analyses reveal significant interactions between emotional maltreatment and vmHRV predicting depressive symptoms in adult females. Significant quadratic relationships of emotional maltreatment and vmHRV with depression are observed in both adolescent and adult females.Conclusions: The present findings contribute to the understanding of the psychological and physiological mechanisms by which ELM acts as a risk factor for the development of depression. Ultimately, this will contribute to the development of targeted and effective intervention strategies to mitigate the detrimental effects of early adversity.

Early exposure to chronic and severe adversity, which includes experiences of maltreatment, defined by the World Health Organization as physical, sexual, emotional abuse and/or neglect of children under the age of 18, is highly prevalent in the general population (estimated at 40­50 percent), and is a well-documented risk factor for depression.The present work combines network-based analyses with tests of different functions (i.e. linear, nonlinear quadratic) in moderator analyses to further explore the complex relationships among ELM exposure, vmHRV, and depression.The present findings contribute to the understanding of the psychological and physiological mechanisms by which early exposure to chronic and severe maltreatment acts as a risk factor for the development of depression.Ultimately, this will contribute to the development of targeted and effective intervention strategies to mitigate the detrimental effects of early adversity.

I Got it. Perceived Infectability and Germ Aversion after Covid-19 Infection.

Objective: The COVID-19 pandemic has offered a unique opportunity to test evolutionary hypotheses on the functionality of the behavioral immune system. The aim of the present study was to ascertain if a previous infection with COVID-19 was associated with increased levels of perceived infectability and germ aversion. Based on the calibration hypothesis, we predicted that the activation of the behavioral immune system was greater in those participants who had been infected compared to those who reported no previous COVID-19 infection. Method: The sample included 2072 participants who completed an online survey between March 1 and April 10, 2022 when the Italian population was facing the third wave of the COVID-19 pandemic. To measure the activation of the behavioral immune system, we used the Perceived Vulnerability to Disease (PVD) scale. Results: Perceived infectability was significantly greater in those participants who had been infected compared to those who reported no previous COVID-19 infection but there was no significant difference between the two groups in terms of germ aversion.Conclusions Overall, our findings suggest that individual differences in the activation of the behavioral immune system were marginally affected by a personal history of COVID-19 infection. A possible explanation is that the environmental sensitivity of the behavioral immune system is tuned more on chronic disease threat (i.e., ecologies with higher pathogen load) than on situational disease threat (e.g., a pandemic or disease outbreak like the COVID-19 pandemic).

COVID-19 vaccination and the behavioral immune system: The newcomer and the old friend get along in preventing infection.

Despite its old evolutionary history and emotional relevance, the behavioral immune system is one of the less studied individual predictors of vaccine uptake. To fill the gap, we conducted a large online study (2072 participants) during the spring 2022 when the great majority of the Italian population had already received at least one dose of the COVID-19 vaccine. Hierarchical binary logistic regression showed that, after controlling for the confounding effects of demographic and personality factors, there was a significant and positive association between pathogen disgust sensitivity and COVID-19 vaccine uptake (OR, 1.68; 95% CI, 1.42-1.99). The likelihood of being vaccinated for a participant with the highest possible score on the PVD Germ Aversion scale was approximately 12 times higher than the likelihood for a participant with the lowest possible score. Public health messaging could leverage the activation of the behavioral immune system as an emotional driver of vaccine uptake.

Organ donation: psychosocial factors of the decision-making process.

Organ donation has a crucial impact on patient care and survival, of which the worldwide gap between organ demand and supply is currently one of the most challenging issues. Brain-dead patients are the main source of organs that can be donated, but donation requires the consent of family members-a choice that is often complex and stressful and leads to refusal of consent. This mini-review aims to provide an overview of the current knowledge on the impact of certain psychosocial factors on the decision-making process with regard to organ donation by family members. In particular, the influence of several aspects is emphasized, such as sociodemographic factors, knowledge of the organ donation process, religious beliefs, concerns that are related to the choice to donate, and mode of communication. Consistent with this evidence, we emphasize the need to examine these aspects further through interventions and guidelines that improve the organ donation application process and ensure a positive experience for the family that has to make the decision.

The long-term impact of early adverse experience on adaptive functioning: a pilot study integrating measures of mental status, nonverbal communication, and heart rate variability.

Background: Childhood maltreatment (CM) can disrupt the development of behavioural and physiological systems, increasing the risk of physical and psychological adverse outcomes across the lifespan. CM may cause interpersonal dysfunctions that impair social communication and lead to dysfunctional activation of the autonomic nervous system. The present exploratory study analyzed the long-term impact of CM from an integrated perspective through the simultaneous assessment of psychological symptoms, social and behavioural communication, and physiological regulation.Methods: Participants were 55 healthy university students (9 males and 46 females; mean age ± SD = 25.26 ± 2.83 years), who filled out a battery of questionnaires to assess the presence of CM (Childhood Trauma Questionnaire) and psychopathological symptoms (Symptom Check-List-90 Item Revised). Participants were then subjected to a videotaped interview for the assessment of non-verbal behaviour (Ethological Coding System for Interviews) and measurement of tonic heart rate variability (HRV), a measure of physiological adaptability to the environment. We performed Pearson's correlation analysis to evaluate the associations between non-verbal behaviour, HRV, and CM variables. Multiple regression analysis was used to evaluate the independent associations between CM variables on HRV and nonverbal behaviour.Results: We found an association between more severe CM, increased symptoms-related distress (ps < .001), less submissive behaviour (ps < .018), and decreased tonic HRV (ps < .028). As a result of multiple regression analysis, participants with a history of emotional abuse (R² = .18, p = .002) and neglect (R² = .10, p = .03) were more likely to display decreased submissive behaviour during the dyadic interview. Moreover, early experience of emotional (R² = .21, p = .005) and sexual abuse (R² = .14, p = .04) was associated with decreased tonic HRV.Conclusion: Our preliminary findings show the utility of analyzing the long-term effects of adverse early experiences at different levels of 'adaptive functioning' (the capabilities needed to respond effectively to environmental demands).

Substantial traumatic experiences during childhood, such as emotional abuse, emotional neglect, and sexual abuse were associated with lower heart rate variability levels in a sample of young adults.Young adults with a history of emotional abuse and neglect were more likely to display decreased submissive behaviour (ethological behaviour) during the dyadic interview.Severe childhood maltreatment was associated with increased symptoms-related distress, less submissive behaviour (ethological behaviour), and decreased tonic heart rate variability in young adults.

Anxiety Symptoms, COVID-19-Related Stress Reactions in the Italian General Population, and Validation of the Italian COVID Stress Scales (CSS-I).

Background. The COVID Stress Scales (CSS) assess COVID-related stress experienced in the past week related to danger and contamination fears, socioeconomic consequences, xenophobia, compulsive checking, and reassurance seeking, and traumatic stress symptoms. Our objective was to provide a translation into Italian, replication, and psychometric validation of the CSS in the general population. Moreover, we aimed to test the convergent and discriminant validity of the Italian CSS (CSS-I) with respect to anxiety, stress, and depressive symptoms in the general Italian population. Method. Adult participants (n = 935) over the age of 18 years were recruited from the general population in Italy. Psychological status was assessed using multiple validated measures, including the CSS, Depression, Anxiety and Stress Scales-21 (DASS-21), and the Prejudice Against Immigrants Scale (PAIS). Results. Our confirmatory factor analysis supported a 6-factor model, including danger fears (DAN), socioeconomic consequences (SEC), xenophobia (XEN), compulsive checking and reassurance seeking (CHE), contamination fears (CON), and traumatic stress symptoms (TSS). Strong reliability of the CSS-I (Cronbach's α = 0.863-0.936) and convergent validity with the DASS-21 and PAI were established with positive correlations between total and scale scores across measures. Conclusions. The CSS-I is a valid and reliable instrument to measure COVID-19-related distress in the Italian population.

The behavioral immune system in action: Psychological correlates of pathogen disgust sensitivity in healthcare professionals working in a COVID-19 hospital.

The behavioral immune system includes a set of proactive mechanisms that inhibit contact with pathogens in the first place. These mechanisms offer a sort of psychological and behavioral prophylaxis against infection. The aim of this study was to assess the functionality of the behavioral immune system under conditions of strong ecological validity. Our hypothesis was that the emotional and more primitive component of the behavioral immune system (i.e. pathogen disgust sensitivity) acts as a powerful predictor of fear of infection. The sample was made up of 101 healthcare professionals working in a COVID-19 hospital when vaccination was not yet available. We conducted a hierarchical regression analysis to assess the role of germ-related disgust in modulating levels of fear. After controlling for the significant effects of depressive symptoms and exposure to people with a confirmed diagnosis of COVID-19, we found that fear of infection was more intense in those healthcare workers who reported higher levels of germ-related disgust. Fear of infection was not related to perceived infectability, an individual variable informed by more rational cognitive appraisals. These findings show that, even in healthcare workers who can take advantage of their professional knowledge and acquired skills for rational appraisals, the most primitive component of the behavioral immune system still plays a major role in eliciting fear of COVID-19. It is likely that the psychological reactions elicited by the behavioral immune system promote preventive health behaviors in modern environments as well.

Psychological Health in Intensive Care Unit Health Care Workers after the COVID-19 Pandemic.

BACKGROUND: Although the COVID-19 pandemic had an impact on the general population, health care workers (HCWs) constituted one of the groups that were most adversely affected by the associated risks, owing to the significant consequences on their mental health. This study examined these psychological effects on HCWs who cared for COVID-19 patients who were admitted to the intensive care unit in an Italian hospital. METHODS: Subjects were administered several self-reported questionnaires: Kessler 10 Psychological Distress Scale (K10), Perceived Stress Scale-10 (PSS), Impact of Event Scale Revised (IES-R), and Post-traumatic Growth Inventory (PTGI), as well as two open-ended questions oriented toward understanding their positive and negative emotional experience and differentiating between two phases of the emergency. RESULTS: Overall, 45% of HCWs showed medium-to-high anxiety/depressive symptoms, whereas 60% presented with medium-to-high levels of perceived stress. In addition, 37% of subjects developed symptoms of PTSD and 50% showed post-traumatic growth in the "appreciation of life" and "new possibilities" dimensions. With regard to the open-ended questions, three themes were identified: quality of workplace relationships, sense of emotional-relational competence, and sense of clinical-technical competence. In addition, two macrocategories of responses were identified in the answers: growth and block. CONCLUSIONS: The mental health of HCWs who are involved in the front line of COVID-19 was significantly impacted by this experience, showing high levels of post-traumatic stress and anxiety and depressive symptoms more than 1 year after the emergency began. A qualitative analysis of staff experiences can be a useful guide for structuring interventions and prevention.

Psychological health in COVID-19 patients after discharge from an intensive care unit.

Along with physical changes, psychological changes are detectable in patients with COVID-19. In these patients, the stressful experience of intensive care unit (ICU) hospitalization may aggravate psychological conditions. Our study examines the short- and long-term psychological consequences of COVID-19 in ICU patients. COVID-19 patients completed the self-rating questionnaires Kessler 10 Psychological Distress Scale (K10), Perceived Stress Scale-10 (PSS), Impact of Event Scale Revised (IES-R), and Post-traumatic Growth Inventory (PTGI) and were clinically interviewed 1 and 6 months after discharge. Altered behavioral-psychological symptoms and patients' strategies (adaptive vs. maladaptive) for coping with stress during and after hospitalization were coded during clinical interviews. Between 20 and 30% of patients showed moderate symptoms of depression or anxiety and perceived stress 1 and 6 months after discharge. Sleep problems, difficulty concentrating, confusion in placing events, and fear of reinfection were observed in many (6-17%) patients. At 6 months, only 7% of patients showed PTSD symptoms, and 50% showed post-traumatic growth in the "appreciation of life" sub-scale. Finally, 32% of subjects were classified as "maladaptive coping patients," and 68% as "adaptive coping patients." Patients who adopted "adaptive" coping strategies showed significantly lower levels of anxious-depressive symptoms and perceived stress when compared to subjects with "maladaptive" strategies at both time points. Coping strategy had no effect on PTSD symptoms or post-traumatic growth at 6 months. These findings clarify the short- and long-term psychological effects of intensive care due to COVID-19 infection and demonstrate that patient characteristics, particularly strategies for coping with stress, seem to play a critical role in psychological outcomes.