Stressful Newborn Memories: Pre-Conceptual, In Utero, and Postnatal Events

Early-life stressful experiences are critical for plasticity and development, shaping adult neuroendocrine response and future health. Stress response is mediated by the autonomous nervous system and the hypothalamic–pituitary–adrenal (HPA) axis while various environmental stimuli are encoded via epigenetic marks. The stress response system maintains homeostasis by regulating adaptation to the environmental changes. Pre-conceptual and in utero stressors form the fetal epigenetic profile together with the individual genetic profile, providing the background for individual stress response, vulnerability, or resilience. Postnatal and adult stressful experiences may act as the definitive switch. This review addresses the issue of how preconceptual in utero and postnatal events, together with individual differences, shape future stress responses. Putative markers of early-life adverse effects such as prematurity and low birth weight are emphasized, and the epigenetic, mitochondrial, and genomic architecture regulation of such events are discussed

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.publishedVersio

Normative modeling of brain morphometry in clinical high risk for psychosis

Importance The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)–derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < −1.96) or supranormal (z > 1.96) scores. Results Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = −0.08; 95% CI, −0.13 to −0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk

Investigation of genetic, epigenetic and protein parameters in individuals with First Episode in Psychosis and in Animal Models

Schizophrenia is a debilitating disorder that affects 1% of the population worldwide. The onset of the disease is usually characterized by a First Episode in Psychosis (FEP) and includes delusions, hallucinations and disorganized speech. It is commonly observed in young adults and lasts lifelong. The purpose of this PhD thesis was to investigate the molecular, stress-associated underpinnings of the disease in peripheral blood of individuals with FEP, as well as in a control sample of the general population. First and foremost, polymorphisms associated with the response to stress were genotyped in order to investigate the contribution of risk alleles in the development of the disease. Specifically, the presence of the risk polymorphisms was associated with higher scores at the PANSS-N scale and lower scores at the PANSS-G scale for the FEP individuals. Furthermore, the mRNA levels of molecular stress mediators, namely NR3C1 and NR3C2 that encode for the glucocorticoid (GR) and mineralocorticoid (MR) receptors were analyzed and the mRNA levels of NR3C2 were found diminished in FEP individuals before and after the treatment with second generation antipsychotics. Also, the mRNA levels of GR targets FKBP5 and GILZ were examined and found higher. The aforementioned genes mediate the stress response via the Hypothalamic-Pituitary-Adrenal axis, as well as the maintenance of homeostasis. Furthermore, the levels of FKBP5 protein were assessed and found diminished in an independent cohort of FEP individuals, as well as the methylation status of the CpG island in the promoter region of FKBP5 gene, which was observed to be unmethylated. The stress response was also studied in a model of unpredictable repeated restraint stress in C57BL/6 mice. The mRNA levels of NR3C1, NR3C2, FKBP5, GILZ and BDNF genes were assessed in prefrontal cortices of stressed and control mice. The mRNA levels of NR3C2 and BDNF were found lower in stressed mice compared to controls. The behavioral response was assessed with the use of a battery of behavioral tests, including the Forced Swim test, the Social Preference/Avoidance test and the Dark/Light Box test.Η σχιζοφρένεια αποτελεί μια σημαντική νευροψυχιατρική νόσο και επηρεάζει το 1% του γενικού πληθυσμού. Η έναρξη της νόσου είναι οξεία και θεαματική ή βραδεία με προϊούσα πορεία. Τα συμπτώματά της περιλαμβάνουν ψευδαισθήσεις, παραληρητικές ιδέες και αποδιοργανωμένο λόγο, ενώ στην παθολογία της νόσου συμπεριλαμβάνονται ψυχωτικά επεισόδια. Στην εργασία αυτή μελετήθηκαν σε περιφερικό αίμα ατόμων με Πρώτο Ψυχωτικό Επεισόδιο (ΠΨΕ) και σε δείγμα ελέγχου γενικού πληθυσμού, παράγοντες που διαμεσολαβούν την απόκριση στο στρες. Συγκεκριμένα, διερευνήθηκαν τα επίπεδα mRNA των μορίων-τελεστών που διαμεσολαβούν την απόκριση στο στρες μέσω του άξονα Υποθαλάμου-Υπόφυσης-Επινεφριδίων (ΥΥΕ) και είναι υπεύθυνα για την επαναφορά του οργανισμού στην ομοιόσταση κατόπιν έκθεσης σε στρεσογόνα περιβαλλοντικά ερεθίσματα. Αρχικά γονοτυπήθηκαν πολυμορφισμοί των γονιδίων SLC6A4 και FKBP5 που φαίνεται να επηρεάζουν την απόκριση στο στρες και βρέθηκαν στατιστικά σημαντικές διαφορές μεταξύ των αλληλομόρφων στα δείγματα με ΠΨΕ και στο γενικό πληθυσμό. Επιπλέον, η παρουσία των αλληλομόρφων κινδύνου συσχετίστηκε με υψηλότερα σκορ στην κλίμακα PANSS-N και χαμηλότερα σκορ στην κλίμακα PANSS-G. Μελετήθηκαν έπειτα τα επίπεδα των γονιδίων NR3C1 και NR3C2 που κωδικοποιούν τους υποδοχείς γλυκοκορτικοειδών (GR) και αλατοκορτικοειδών (MR) αντίστοιχα και παρατηρήθηκαν μειωμένα επίπεδα mRNA του γονιδίου NR3C2 στα δείγματα με ΠΨΕ πριν και μετά τη θεραπεία με δεύτερης γενιάς αντιψυχωτικά, ενώ η έρευνα των γονιδίων FKBP5 και GILZ, που αποτελούν μεταγραφικούς στόχους του GR, αποκάλυψε αυξημένα τα επίπεδα των mRNA τους. Επιπροσθέτως, διερευνήθηκαν τα επίπεδα της πρωτεΐνης FKBP5 που λειτουργεί ως συμπαράγοντας του GR σε ανεξάρτητο δείγμα ατόμων με ΠΨΕ και βρέθηκαν σημαντικά μειωμένα, καθώς και τα επίπεδα μεθυλίωσης της νησίδας CpG του υποκινητή του γονιδίου FKBP5, τα οποία υποδεικνύουν μια μη μεθυλιωμένη περιοχή. Επιπλέον, οι ίδιοι παράγοντες του στρες μελετήθηκαν σε επίπεδο mRNA σε ένα μοντέλο απρόβλεπτου επαναλαμβανόμενου στρες περιορισμού σε μύες. Η απόκριση στο στρες μελετήθηκε μέσω συμπεριφορικών δοκιμασιών, συμπεριλαμβανομένης της δοκιμασίας Εξαναγκασμένης Κολύμβησης, της δοκιμασίας Κοινωνικής Προτίμησης/Αποφυγής και της δοκιμασίας Σκοτεινού/Φωτεινού πεδίου στους μύες που υπέστησαν στρες και σε δείγμα ελέγχου. Τα μοριακά ευρήματα στο μοντέλο τρωκτικών συμφωνούν με τα ευρήματα των ατόμων με ΠΨΕ. Συγκεκριμένα, παρατηρήθηκαν μειωμένα επίπεδα των γονιδίων NR3C2 και BDNF και αυξημένα επίπεδα του γονιδίου FKBP5 στον προμετωπιαίο φλοιό τρωκτικών που υπέστησαν επαναλαμβανόμενο στρες περιορισμού. Τα ευρήματα αυτά καθιστούν την ανάγκη για περαιτέρω διερεύνηση των μοριακών τελεστών του στρες στο ΠΨΕ επιτακτική

Developmental Dyslexia: Environment Matters

Developmental dyslexia (DD) is a multifactorial, specific learning disorder. Susceptibility genes have been identified, but there is growing evidence that environmental factors, and especially stress, may act as triggering factors that determine an individual’s risk of developing DD. In DD, as in most complex phenotypes, the presence of a genetic mutation fails to explain the broad phenotypic spectrum observed. Early life stress has been repeatedly associated with the risk of multifactorial disorders, due to its effects on chromatin regulation, gene expression, HPA axis function and its long-term effects on the systemic stress response. Based on recent evidence, we discuss the potential role of stress on DD occurrence, its putative epigenetic effects on the HPA axis of affected individuals, as well as the necessity of early and appropriate intervention, based on the individual stress-associated (endo)phenotype

COVID-19 Pandemic: Prevention and Protection Measures to be Adopted at the Workplace

INTRODUCTION: SARS-CoV-2, identified in Wuhan, China, for the first time in December 2019, is a new viral strain, which has not been previously identified in humans; it can be transmitted both by air and via direct and indirect contact; however, the most frequent way it spreads is via droplets. Like the other viruses belonging to the same family of coronaviruses, it can cause from mild flu-like symptoms, such as cold, sore throat, cough and fever, to more severe ones such as pneumonia and breathing difficulties, and it can even lead to death. Since no effective specific drug therapy has been found yet, nor any vaccine capable of limiting the spread of this pathogen, it is important for ways of preventing the spread of this infection to be established. METHODS: the purpose of our research was to provide a protocol to prevent the spread of SARS-CoV-2 infection in light of the limited information related to this coronavirus. In detail, we analysed and searched targeted evidence-based guidelines issued in the various countries affected by this epidemic up till now. In addition, we analyzed the recommendations for the prevention and control of other epidemics caused by other pathogens belonging to the same family of coronaviruses or others that present the same mechanisms of transmission. DISCUSSION: general organizational measures regarding the containment and management of the epidemiological emergency of COVID-19 have been imposed by the competent authorities for an adequate and proportionate management of the evolution of the epidemiological situation. The prevention and protection organizational measures therefore aim to minimize the probability of being exposed to SARS-CoV-2. For this purpose, measures must also be taken at work to avoid new infections or even the spread of the virus where it has already been present. Furthermore, environmental measures are aimed at reducing the risk of transmission of SARS-CoV-2 to individuals through contact with infected subjects, objects, equipment, or contaminated environmental surfaces. CONCLUSION: protective devices must be used whenever there is potentially close contact with a suspect case, especially when the potentially infected person does not wear a surgical mask that could reduce the spread of viruses in the environment. By adopting this specific prevention and protection measures recommended in the workplace, it will be possible to help overcome this COVID-19 pandemic

Polygenic risk scores across the extended psychosis spectrum

As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke's pseudo-R$^{2}$: 1.3-7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare

Developmental Dyslexia: Insights from EEG-Based Findings and Molecular Signatures—A Pilot Study

Developmental dyslexia (DD) is a learning disorder. Although risk genes have been identified, environmental factors, and particularly stress arising from constant difficulties, have been associated with the occurrence of DD by affecting brain plasticity and function, especially during critical neurodevelopmental stages. In this work, electroencephalogram (EEG) findings were coupled with the genetic and epigenetic molecular signatures of individuals with DD and matched controls. Specifically, we investigated the genetic and epigenetic correlates of key stress-associated genes (NR3C1, NR3C2, FKBP5, GILZ, SLC6A4) with psychological characteristics (depression, anxiety, and stress) often included in DD diagnostic criteria, as well as with brain EEG findings. We paired the observed brain rhythms with the expression levels of stress-related genes, investigated the epigenetic profile of the stress regulator glucocorticoid receptor (GR) and correlated such indices with demographic findings. This study presents a new interdisciplinary approach and findings that support the idea that stress, attributed to the demands of the school environment, may act as a contributing factor in the occurrence of the DD phenotype

Polygenic risk scores across the extended psychosis spectrum

As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke's pseudo-R-2: 1.3-7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.ISSN:2158-318