Setting a research agenda for examining early risk for elevated cognitive disengagement syndrome symptoms using data from the ABCD cohort.

Background: Little research has examined early life risk for symptoms of cognitive disengagement syndrome (CDS) despite a well-established literature regarding co-occurring outcomes (e.g., attention-deficit/hyperactivity disorder). The current study estimated bivariate associations between early life risk factors and CDS in a large and representative sample of U.S. children. Methods: We conducted secondary analyses of baseline data from the Adolescent Brain Cognitive Development (ABCD) study (N = 8,096 children, 9-10 years old). Birthing parents reported early life risk factors on a developmental history questionnaire, including parental, prenatal, delivery and birth, and developmental milestone information. They also completed the Child Behavior Checklist, which includes a CDS subscale that was dichotomized to estimate the odds of elevated CDS symptoms (i.e., T-score > 70) in children related to risk indices. Results: We observed significantly elevated odds of CDS related to parental risk factors (i.e., unplanned pregnancy, pregnancy awareness after 6 weeks, teenage parenthood), birthing parent illnesses in pregnancy (i.e., severe nausea, proteinuria, pre-eclampsia/toxemia, severe anemia, urinary tract infection), pregnancy complications (i.e., bleeding), prenatal substance exposures (i.e., prescription medication, tobacco, illicit drugs), delivery and birth risk factors (i.e., child blue at delivery, child not breathing, jaundice, incubation after delivery), and late motor and speech milestones in children. Conclusions: Several early-life risk factors were associated with elevated odds of CDS at ages 9-10 years; study design prevents the determination of causality. Further investigation is warranted regarding early life origins of CDS with priority given to risk indices that have upstream commonalities (i.e., that restrict fetal growth, nutrients, and oxygen).

Association of Childhood Exposure to School Racial Segregation with Late-Life Cognitive Outcomes among Older Americans.

IMPORTANCE: Disparities in cognition, including dementia occurrence, persist between White and Black older adults, and are possibly influenced by early educational differences stemming from structural racism. However, the relationship between school racial segregation and later-life cognition remains underexplored. OBJECTIVE: To investigate the association between childhood contextual exposure to school racial segregation and cognitive outcomes in later life. DESIGN SETTING AND PARTICIPANTS: Data from 16,625 non-Hispanic White (hereafter, White) and 3,335 non-Hispanic Black (hereafter, Black) Americans aged 65 or older were analyzed from the Health and Retirement Study. EXPOSURES: State-level White-Black dissimilarity index for public elementary schools in the late 1960s (range: 0-100) was used to measure school segregation. States were categorized into high segregation (383.6) and low segregation (<83.6) based on the top quintile. MAIN OUTCOMES AND MEASURES: Cognitive scores, cognitive impairment (with or without dementia), and dementia were assessed using the Telephone Interview for Cognitive Status (TICS) and proxy assessment. Multilevel regression analyses were conducted, adjusting for demographic covariates, socioeconomic status, and health factors. Stratified analyses by race were performed. RESULTS: The mean (SD) age of participants was 78.5 (5.7) years, and 11,208 (56.2%) were female. Participants exposed to high segregation exhibited lower cognitive scores (12.6 vs. 13.6; P<0.001) and higher prevalence of cognitive impairment (50.8% vs 41.4%; P<0.001) and dementia (26.0% vs. 19.5%; P<0.001), compared to those with low segregation exposure. Multilevel analyses revealed a significant negative association between school segregation and later-life cognitive even after adjusting sequentially for potential confounders, and these associations were stronger among Black than White participants. Notably, in the fully adjusted model, Black participants exposed to high segregation displayed significantly lower cognitive scores (-0.51; 95% CI: -0.94, -0.09) and higher likelihood of cognitive impairment (adjusted Odds Ratio [aOR]: 1.45, 95% CI: 1.22, 1.72) and dementia (aOR: 1.31, 95% CI: 1.06, 1.63). CONCLUSIONS AND RELEVANCE: Our study underscores that childhood exposure to state-level school segregation is associated with late-life cognition, especially for Black Americans. Given the rising trend of school segregation in the US, educational policies aimed at reducing segregation are crucial to address health inequities. Clinicians can leverage patients' early-life educational circumstances to promote screening, prevention, and management of cognitive disorders.

Famine exposure in early life increases risk of cataracts in elderly stage.

Background: Epidemiological studies have shown that early-life nutritional deficiencies are associated with an increased risk of diseases later in life. This study aimed to explore the correlation between famine exposure during the early stages of life and cataracts. Methods: We included 5,931 participants from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) 2018 cross-sectional data in our study. Subjects were categorized into three groups by their age during the famine: adulthood group, school age famine exposure group, and teenage famine exposure group. Utilizing binary logistic regression models, we investigated the relationship between early-life famine exposure and cataracts. Results: Compared to the adulthood group, both the school age exposure group (OR = 2.49, 95%CI = 1.89-3.27) and teenage exposure group (OR = 1.45, 95%CI = 1.20-1.76) had a heightened risk of developing cataracts in elderly stage. And the sex differences in the impact of famine during early years on elderly cataract risk were observed, particularly indicating a higher risk among women who experienced childhood famine compared to men with similar exposure. Conclusion: Famine exposure during the early stages of life is associated with a heightened risk of developing cataracts in old age. To prevent cataracts in elderly individuals, particularly in females, measures should be taken to address nutritional deficiencies in these specific periods.

Global incidence trends of early-onset colorectal cancer and related exposures in early-life: an ecological analysis based on the GBD 2019.

Background: The incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019. Methods: Data on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0-4, 5-9, 10-14 and 15-19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC. Results: The global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0-4, 5-9, 10-14 and 15-19 years were also associated with the incidences, particularly for the exposures at ages 15-19 years. Conclusion: The global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.

The oral microbiome is associated with HPA axis response to a psychosocial stressor.

Intense psychosocial stress during early life has a detrimental effect on health-disease balance in later life. Simultaneously, despite its sensitivity to stress, the developing microbiome contributes to long-term health. Following stress exposure, HPA-axis activation regulates the "fight or flight" response with the release of glucose and cortisol. Here, we investigated the interaction between the oral microbiome and the stress response. We used a cohort of 115 adults, mean age 24, who either experienced institutionalisation and adoption (n = 40) or were non-adopted controls (n = 75). Glucose and cortisol measurements were taken from participants following an extended socially evaluated cold pressor test (seCPT) at multiple time points. The cohort´s oral microbiome was profiled via 16S-V4 sequencing on microbial DNA from saliva and buccal samples. Using mixed-effect linear regressions, we identified 12 genera that exhibited an interaction with host's cortisol-glucose response to stress, strongly influencing intensity and clearance of cortisol and glucose following stress exposure. Particularly, the identified taxa influenced the glucose and cortisol release profiles and kinetics following seCPT exposure. In conclusion, our study provided evidence for the oral microbiome modifying the effect of stress on the HPA-axis and human metabolism, as shown in glucose-cortisol time series data.

Strengths of fertilizer and litter effects on seedling recruitment and growth of grassland species differ depending on functional groups and seed size.

Agricultural grasslands play an important role in conserving the biodiversity of the European cultural landscape. Both, litter cover and soil nutrient availability, change with grassland management, but it is not well-studied how seedling recruitment and growth of multiple grassland species are influenced by their single or combined effects. Therefore, we studied the effects of nitrogen fertilization (100 kg N per year and ha) and litter cover (250 gdw per m2) on seedling recruitment and growth of 75 temperate grassland species (16 graminoid species, 51 forb species, 8 legume species) in a full factorial microcosm experiment. Overall, fertilizer reduced seedling emergence, while litter cover increased it even when combined with fertilization. Fertilization increased seedling height and biomass, and the combination of fertilizer and litter resulted in even stronger responses. Litter cover alone did not influence seedling biomass or seedling height. While the overall direction of treatment effects was similar across functional groups, their strengths were mostly weaker in graminoids than in non-legume forbs and legumes. Positive litter effects on seedling emergence were stronger in large-seeded species. Positive fertilization effects on seedling growth were stronger in small-seeded species, while their seedling biomass was negatively affected by litter cover. In summary, our results show for multiple grassland species that the combination of litter cover and fertilization modulates their single effects. The varying sensitivity of how grassland species representing different functional groups and seed sizes respond with their seedling emergence and growth to litter cover and nitrogen fertilization indicates that the consequences of land-use change on grassland diversity and composition already start to manifest in the earliest stages of the plant life cycle.

Individual longitudinal changes in DNA-methylome identify signatures of early-life adversity and correlate with later outcome.

Adverse early-life experiences (ELA) affect a majority of the world's children. Whereas the enduring impact of ELA on cognitive and emotional health is established, there are no tools to predict vulnerability to ELA consequences in an individual child. Epigenetic markers including peripheral-cell DNA-methylation profiles may encode ELA and provide predictive outcome markers, yet the interindividual variance of the human genome and rapid changes in DNA methylation in childhood pose significant challenges. Hoping to mitigate these challenges we examined the relation of several ELA dimensions to DNA methylation changes and outcome using a within-subject longitudinal design and a high methylation-change threshold. DNA methylation was analyzed in buccal swab/saliva samples collected twice (neonatally and at 12 months) in 110 infants. We identified CpGs differentially methylated across time for each child and determined whether they associated with ELA indicators and executive function at age 5. We assessed sex differences and derived a sex-dependent 'impact score' based on sites that most contributed to methylation changes. Changes in methylation between two samples of an individual child reflected age-related trends and correlated with executive function years later. Among tested ELA dimensions and life factors including income to needs ratios, maternal sensitivity, body mass index and infant sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, high early-life unpredictability interacted with methylation changes to presage executive function. Thus, longitudinal, within-subject changes in methylation profiles may provide a signature of ELA and a potential predictive marker of individual outcome.

The right educational environment: Oral tolerance in early life.

Oral tolerance promotes the suppression of immune responses to innocuous antigen and is primarily mediated by regulatory T cell (Tregs). The development of oral tolerance begins in early life during a "window of tolerance," which occurs around weaning and is mediated by components in breastmilk. Herein, we review the factors dictating this window and how Tregs are uniquely educated in early life. In early life, the translocation of luminal antigen for Treg induction is primarily dictated by goblet cell-associated antigen passages (GAPs). GAPs in the colon are negatively regulated by maternally-derived epidermal growth factor and the microbiota, restricting GAP formation to the "periweaning" period (postnatal day 11-21 in mice, 4-6 months in humans). The induction of solid food also promotes the diversification of the bacteria such that bacterially-derived metabolites known to promote Tregs-short-chain fatty acids, tryptophan metabolites, and bile acids-peak during the periweaning phase. Further, breastmilk immunoglobulins-IgA and IgG-regulate both microbial diversity and the interaction of microbes with the epithelium, further controlling which antigens are presented to T cells. Overall, these elements work in conjunction to induce a long-lived population of Tregs, around weaning, that are crucial for maintaining homeostasis in adults.

Macroscopic and microscopic morphological characteristics of gelatinous egg masses (egg veils) of yellow goosefish Lophius litulon (Lophiiformes; Lophiidae).

We recorded the morphological characteristics and effect of preservation methods on the structure of the egg veils of Lophius litulon found in field investigations. The egg veils were characterized as translucent sheet-shape with parallel opaque creases spaced approximately 2 cm apart. The egg veils were found to be composed of pentagonal or hexagonal chambers with rounded corners arranged in one layer, and each chamber enveloped one to three embryos. Cryopreservation is recommended to prevent structural changes in the egg veil rather than ethanol solution and neutral buffered formalin solution.

Consortium Profile: The Methylation, Imaging and NeuroDevelopment (MIND) Consortium.

Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (Npooled DNAm = 11,299; Npooled neuroimaging = 10,133; Npooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.

Exploring perceptions of vulnerability among women facing psychosocial adversity before, during and after pregnancy: A qualitative interview-study using thematic analysis.

OBJECTIVE: The term 'vulnerable' is often used to describe women facing psychosocial adversity during pregnancy, implying a heightened risk of experiencing suboptimal pregnancy outcomes. While this label might facilitate the pathway to appropriate care, it can be perceived as stigmatizing by the women it intends to help, which could deter their interaction with healthcare services. This study explores how women facing psychosocial adversity before, during and after pregnancy perceive the concept of vulnerability and experience being labeled as such. METHODS: We conducted a thematic analysis of semi-structured, in-depth interviews. Through purposive sampling targeting maximum variation, ten women of diverse backgrounds were included. RESULTS: Three central themes emerged: defining vulnerability, embracing vulnerability and the feeling of being stigmatized. Women perceived vulnerability as an inability to adequately care for themselves or their children, necessitating additional support alongside routine antenatal care. Acceptance of the 'vulnerable' label came when it also acknowledged their proactive efforts and strengths to improve their situation. Conversely, if discussions surrounding vulnerability failed to recognize women's agency - specifically, their personal journeys and the courage needed to seek support - the label was perceived as stigmatizing. CONCLUSIONS: Addressing vulnerability effectively in maternity care requires a nuanced, patient-centered approach, acknowledging both the challenges and strengths of women facing psychosocial adversities. Emphasizing personal narratives and their courage in seeking support can mitigate the stigmatizing effects of the 'vulnerable' label. Integrating these narratives into maternal healthcare practices can foster deeper connections with the women involved, enhancing the overall quality of care.

Threat, Emotion Dysregulation, and Parenting in a Clinical Sample of Children with Disruptive Behaviour.

Early-life adversity is associated with the development of internalizing and externalizing problems in children. Despite this, there is a need to understand the mechanisms linking these experiences to psychopathology, especially in clinical samples. This cross-sectional study tested emotion dysregulation as a mechanism linking early-life threat to psychopathology in a clinical sample of children with disruptive behavior problems. We also explored parental positive reinforcement as a protective factor in these pathways. A clinical sample of 606 children aged 6-12 years, referred to a mental healthcare hospital, were included. Parent-reported child threat, and parent- and teacher-reported child emotion dysregulation and psychopathology, were collected. Path analysis was used to explore the mediating effect of emotion dysregulation in the relation between threat and psychopathology. The moderating effects of parental positive reinforcement were explored through moderated-mediation analyses. Emotion dysregulation partially mediated the association between threat and both internalizing (ß = .18, P = .006) and externalizing (ß = .19, P = .002) problems. Positive reinforcement did not buffer the association between threat and emotion dysregulation (ß = .09, P = .62) or the association between emotion dysregulation and internalizing (ß = - .003, P = .20) or externalizing (ß = - .002, P = .35). Poor emotion regulation may be a transdiagnostic mechanism linking early-threat with internalizing and externalizing problems in clinic-referred children with disruptive behaviors. Factors aside from parental positive reinforcement should be explored as protective factors in these pathways, including those directly implicated in the purported mechanisms linking these factors over time.

Individual- and community-level social determinants of health are associated with cognition in older adults with focal epilepsy.

OBJECTIVE: Epilepsy is associated with significant health disparities, including access to specialized care and adverse outcomes that have been associated with several social determinants of health (SDOH). We sought to examine the relationship between individual- and community-level SDOH and cognitive outcomes in older adults with epilepsy. MATERIALS AND METHODS: We collected clinical, SDOH, and neuropsychological data in 57 older adults with epilepsy. Individual-level SDOH included patient factors (quality of education, income, insurance, marital status) and early-life environmental factors (parental education and occupation, childhood employment). Neighborhood deprivation was measured with the Area Deprivation Index (ADI). Stepwise regressions were conducted to examine the independent contribution of individual-level SDOH to cognitive performance, and Spearman rho correlations were conducted to examine the relationship between ADI and cognitive performance. The SDOH profiles of patients who met the criteria for cognitive impairment were examined. RESULTS: After controlling for clinical variables, patient factors (public health insurance, poorer quality of education) and early-life environmental factors (lower mother's education, lower father's and mother's occupational complexity, history of childhood employment) were significant predictors of lower performance on measures of global cognition, verbal learning and memory, processing speed, and executive function. Higher ADI values (greater disadvantage) were associated with lower scores on global cognitive measures, verbal learning and memory, and executive function. Patients who met criteria for cognitive impairment had, on average, a greater number of adverse SDOH, including lower household incomes and father's education, and higher ADI values compared to those who were cognitively intact. CONCLUSION: We provide new evidence of the role of individual- and community-level SDOH on cognitive outcomes in older adults with epilepsy. This emerging literature highlights the need to examine SDOH beyond epilepsy-related clinical factors. These data could inform the development of interventions focused on increasing access to epilepsy care, education, and resources and promoting brain and cognitive health within the most at-risk communities.

Intracranial Volume Is Driven by Both Genetics and Early Life Exposures: The SOL-INCA-MRI Study.

Intracranial volume (ICV) reflects maximal brain development and is associated with later-life cognitive abilities. We quantified ICV among first- and second-generation Hispanic and Latino adults from the Study of Latinos-Investigation of Cognitive Aging - MRI (SOL-INCA-MRI), estimated ICV heritability, and tested its associations with previously reported genetic variants, both individually and as a genetic risk score (GRS). We also estimated the association of ICV with early life environmental measures: nativity or age of immigration and parental education. The estimated heritability of ICV was 19% (95% CI, 0.1%-56%) in n=1781 unrelated SOL-INCA-MRI individuals. Four of 10 tested genetic variants were associated with ICV and an increase of 1 SD of the ICV-GRS was associated with an increase of 10.37 cm3 in the ICV (95% CI, 5.29-15.45). Compared to being born in the continental United States, immigrating to the United States at age 11 years or older was associated with 24 cm3 smaller ICV (95% CI, -39.97 to -8.06). Compared to both parents having less than high-school education, at least 1 parent completing high-school education was associated with 15.4 cm3 greater ICV (95% CI, 4.46-26.39). These data confirm the importance of early life health on brain development.

Paternal adverse childhood experiences are associated with a low risk of atopy in the offspring.

AIM: Parental adverse childhood experiences (ACE) might affect the offspring health through intergenerational inheritance. The aim of this study was to investigate how paternal ACE associate with offspring sensitisation and allergic rhinitis (AR). METHODS: The study included 590 Finnish father-child dyads from the FinnBrain Birth Cohort Study. Outcomes were offspring sensitisation against allergens and AR at age 5.5 years. Paternal ACE up to 18 years were assessed using the Trauma and Distress Scale (TADS) with the lowest quarter as the reference group. RESULTS: Of the children, 317 (54%) were males. Sensitisation occurred in 162/533 (30%) and AR in 122/590 (21%). Paternal TADS (median 17 points; interquartile range 11-27) was inversely associated with the risk of sensitisation. Children whose fathers scored the highest quarter had the lowest risk of sensitisation (adjusted odds ratio 0.42; 95% confidence interval 0.24-0.75), followed by those in the second highest quarter (0.58; 0.34-0.99). The association between the highest quarter and reduced risk of AR was similar. CONCLUSION: Paternal ACE were associated with a low risk of offspring sensitisation and AR, suggesting paternal childhood stress might influence immune responses in their offspring.

Maternal gestational diabetes mellitus associates with altered gut microbiome composition and head circumference abnormalities in male offspring.

The impact of gestational diabetes mellitus (GDM) on maternal or infant microbiome trajectory remains poorly understood. Utilizing large-scale longitudinal fecal samples from 264 mother-baby dyads, we present the gut microbiome trajectory of the mothers throughout pregnancy and infants during the first year of life. GDM mothers had a distinct microbiome diversity and composition during the gestation period. GDM leaves fingerprints on the infant's gut microbiome, which are confounded by delivery mode. Further, Clostridium species positively correlate with a larger head circumference at month 12 in male offspring but not females. The gut microbiome of GDM mothers with male fetuses displays depleted gut-brain modules, including acetate synthesis I and degradation and glutamate synthesis II. The gut microbiome of female infants of GDM mothers has higher histamine degradation and dopamine degradation. Together, our integrative analysis indicates that GDM affects maternal and infant gut composition, which is associated with sexually dimorphic infant head growth.

Early life malnutrition and risk of T2DM adulthood: evidence from the lower socioeconomic status of northwest Chinese population.

Objective: This study aimed to explore whether famine exposure during early life are associated with a high risk of Type 2 Diabetes Mellitus (T2DM) in adulthood and the role of socioeconomic status (SES) on this effect. Materials and methods: We conducted a secondary data analysis based on data from a cross-sectional survey, collected 3,355 participants born between January 1, 1941 and December 31, 1966. Participants were categorized into four groups based on their date of birth, unexposed (individuals born in 1963-1966), infant exposed (individuals born in 1959-1962), childhood exposed (individuals born in 1949-1958), and adolescent exposed (born in 1941-1948). The association of famine exposure with T2DM risk in adults and conducted separately in plain area and mountain area was assessed using logistics regression model. Result: 22.35% of participants were diagnosed with T2DM, of which 43.47% were from the childhood famine-exposed group, representing the highest proportion among all subgroups (p < 0.001). Participants exposed to famine during childhood and adolescence from the lower SES mountain areas showed a significantly higher prevalence of T2DM in adulthood than those from the plain areas (p < 0.001). The adolescence stage exposed famine will increase the risk of T2DM in the mountain area (OR 2.46, 95% CI 1.61, 3.77). Conclusion: No strong evidence demonstrates that exposure to famine during the early life stage increases the risk of developing T2DM in adulthood. However, populations with lower SES are likely to be exposed to more risk factors for T2DM.

The effects of buprenorphine and morphine during pregnancy: Impact of exposure length on maternal brain, behavior, and offspring neurodevelopment.

The escalating incidence of opioid-related issues among pregnant women in the United States underscores the critical necessity to understand the effects of opioid use and Medication for Opioid Use Disorders (MOUDs) during pregnancy. This research employed a translational rodent model to examine the impact of gestational exposure to buprenorphine (BUP) or morphine on maternal behaviors and offspring well-being. Female rats received BUP or morphine before conception, representing established use, with exposure continuing until postnatal day 2 or discontinued on gestational day 19 to mimic treatment cessation before birth. Maternal behaviors - including care, pup retrieval, and preference - as well as hunting behaviors and brain neurotransmitter levels were assessed. Offspring were evaluated for mortality, weight, length, milk bands, surface righting latency, withdrawal symptoms, and brain neurotransmitter levels. Our results reveal that regardless of exposure length (i.e., continued or discontinued), BUP resulted in reduced maternal care in contrast to morphine-exposed and control dams. Opioid exposure altered brain monoamine levels in the dams and offspring, and was associated with increased neonatal mortality, reduced offspring weight, and elevated withdrawal symptoms compared to controls. These findings underscore BUP's potential disruption of maternal care, contributing to increased pup mortality and altered neurodevelopmental outcomes in the offspring. This study calls for more comprehensive research into prenatal BUP exposure effects on the maternal brain and infant development with the aim to mitigate adverse outcomes in humans exposed to opioids during pregnancy.

Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.