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Background: Prenatal maternal stress is increasingly recognized as a risk factor for offspring mental health challenges. DNA methylation may be a mechanism, but few studies directly tested mediation. These few integrative studies are reviewed along with studies from three research areas: prenatal maternal stress and child mental health, prenatal maternal stress and child DNA methylation, and child mental health and DNA methylation.Methods: We conducted a narrative review of articles in each research area and the few published integrative studies to evaluate the state of knowledge.Results: Prenatal maternal stress was related to greater offspring internalizing and externalizing symptoms and to greater offspring peripheral DNA methylation of the NR3C1 gene. Youth mental health problems were also related to NR3C1 hypermethylation while epigenome-wide studies identified genes involved in nervous system development. Integrative studies focused on infant outcomes and did not detect significant mediation by DNA methylation though methodological considerations may partially explain these null results.Limitations: Operationalization of prenatal maternal stress and child mental health varied greatly. The few published integrative studies did not report conclusive evidence of mediation by DNA methylation.Conclusions: DNA methylation likely mediates the association between prenatal maternal stress and child mental health. This conclusion still needs to be tested in a larger number of integrative studies. Key empirical and statistical considerations for future research are discussed. Understanding the consequences of prenatal maternal stress and its pathways of influence will help prevention and intervention efforts and ultimately promote well-being for both mothers and children. [ABSTRACT FROM AUTHOR]

Background and Objectives: Depression has been associated with alterations in social functioning. Decoding and understanding others' mental states and adaptive reasoning are important for social functioning. This study examined theory of mind (ToM) and socio-moral reasoning (SMR) in adolescent girls with and without depression. Within the depression group, we examined associations between relevant clinical features (depression severity, anxiety symptoms and borderline personality traits) and ToM and SMR.Methods: A cross-sectional study was conducted, whereby 43 adolescent girls (mean age = 16.19, SD = 1.24) meeting full or subthreshold criteria for depression and 40 adolescent girls (mean age = 15.44, SD = 1.24) with no psychiatric diagnosis were recruited. ToM was assessed using the Movie for the Assessment of Social Cognition; SMR was evaluated via the Socio-Moral Reasoning Aptitude Level task.Results: Analyses of covariance indicated that adolescents with depression did not differ from controls in ToM abilities but showed lower socio-maturity scores on the SMR task. This difference disappeared after controlling for the number of words used to justify responses. Amongst adolescents with depression, multiple linear regression analyses revealed that higher levels of borderline personality traits were associated with lower levels of mentalization (ToM task), and more severe depressive symptoms were associated with lower socio-moral maturity stages (SMR task) LIMITATIONS: Directional associations were not studied, and the sample included only girls.Conclusions: Findings may help to explain clinical heterogeneity in social cognitive functioning observed in individuals with depression. [ABSTRACT FROM AUTHOR]

• Adolescents with depression were marginally faster than those in the comparison group to recognise sadness, although this trend disappeared once covarying for age and use of antidepressant medication. • Within the depression group, severity of depression symptoms and borderline personality features were associated with poorer emotional facial expression recognition (EFER) performance. • Discrepancies between group and within-group differences may explain some of the clinical heterogeneity observed in studies of EFER amongst adolescents with depression. • Studying clinical features in relation to EFER in adolescents with depression allows for a more nuanced understanding of social difficulties that may be experienced in depression. Studies have reported that emotional facial expression recognition (EFER) may be altered in individuals with depression. This study examined EFER in adolescent girls with and without depression and further examined associations between relevant clinical features of depression and EFER. Fifty adolescent girls aged 12 to 19 years old meeting criteria for depression or subthreshold levels of symptomatology and 55 adolescent girls with no psychiatric diagnosis completed EFER tasks. Reaction time and accuracy for recognising expressions at high and low intensities, and sensitivity in recognising happiness, sadness, anger and fear were assessed. Data were analysed using linear mixed models. Adolescents with depression were marginally faster than those in the comparison group to recognize sadness, although this trend disappeared once covarying for age and antidepressant use. Amongst adolescents with depression, clinical features were associated with poorer EFER performance. In contrast, anxiety symptoms were linked to better accuracy and heightened sensitivity towards happiness. A better understanding of EFER in adolescent girls with and without depression, and how clinical features might be associated with altered patterns of EFER could help to explain clinical heterogeneity observed in such studies of adolescents with depression. Knowledge of socio-cognitive alterations associated with depression will help to better develop and tailor interventions. [ABSTRACT FROM AUTHOR]

• Prenatal PBDE exposure can interfere with children's neurodevelopment. • PBDE blood concentrations in Canada are less than half those in the U.S.A. • We measured PBDEs in maternal blood and assessed IQ for 592 3-year-old children. • Prenatal PBDE exposure was related to lower IQ scores, but only among boys. • It suggests sex-specific neurotoxicity at the low PDBE levels in Canada. Prenatal exposure to polybrominated diphenyl ethers (PBDEs) has been associated with adverse neurodevelopmental outcomes in children, but evidence remains mixed regarding sex differences in this association. To examine the prospective association between prenatal PBDE exposure and cognitive ability in young children, as well as potential sex differences. The study was conducted in a multi-site Canadian pregnancy cohort recruited in 2008–11. PBDEs were measured in maternal plasma samples collected early in pregnancy. Cognitive ability was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) in children at age 3 years (mean = 3.4). Multiple linear regression was used to analyze the association between maternal PBDE plasma concentrations (lipid-standardized and log10-transformed) and Verbal, Performance, and Full Scale IQ scores on the whole sample and stratified by sex, adjusting for confounders. The sample was composed of 592 children (291 boys and 301 girls). A tenfold increase in maternal blood PBDE concentration (sum of BDE-47, −99, −100, and −153) was associated with lower Full Scale scores in boys (−3.4 points; 95% CI: −7.0, 0.1), after adjusting for confounders. BDE-47 was the congener with the highest concentrations in maternal blood and a tenfold increase in exposure was associated with significantly lower Full Scale IQ scores in boys (−4.4 points; 95% CI: −7.9, −0.9), after adjusting for confounders. Verbal and Performance IQ scores were similarly associated with PBDE exposure. Maternal blood PBDE concentrations were not associated with IQ scores in girls. Prenatal exposure to background levels of PBDEs, especially BDE-47, was associated with lower IQ scores in boys, but not in girls. Our results support that exposure to PBDEs during early development may be sex-dependent and detrimental to a child's neurodevelopmental trajectory. [ABSTRACT FROM AUTHOR]

Highlights • Daily life stress is associated with HPA-axis related gene methylation. • DNA methylation in HPA-axis genes is stable over time in healthy volunteers. • DNA methylation-brain associations are gene and tissue specific. • Measuring methylation in different tissues in the same persons can be recommended. Abstract Environmental factors can influence gene expression via epigenetic modifications such as DNA methylation. DNA methylation levels of regulatory regions in Hypothalamo-Pituitary-Adrenal (HPA) axis-related genes assessed from brain tissues as well as from surrogate, peripheral tissues have been associated with vulnerability to stress-related psychopathologies. Commonly used peripheral samples to assess DNA methylation in living humans are derived from blood, saliva or buccal cells. Although psychiatric epigenetic studies are increasingly relying on peripheral measures of DNA methylation, it is still unknown to what extent methylation patterns across peripheral tissues are associated with each other and with measures of brain processes and behavioural stress. In the present study, with a sample of 51 healthy adults, we assessed cross-tissue correlations of DNA methylation patterns in the glucocorticoid receptor (NR3C1) 1 F promoter and the FK506 Binding Protein 5 (FKBP5) gene intron 7 region using saliva and buccal cell samples, and assessed two-year stability in both tissues in a male subsample (N = 14). We also investigated associations between peripherally-derived DNA methylation and measures of neural function and perceived daily stress, and compared the extent of these associations across tissue samples. DNA methylation cross-tissue correlations were highly significant for FKBP5 , but not significant for NR3C1. DNA methylation in both genes remained stable for two years. Tissue- and gene-specific associations were found for brain resting state connectivity and neural responses to sadness, thereby suggesting that saliva- and buccal cell-derived DNA methylation levels of NR3C1 -1 F and FKBP5 gene regions might differently capture different measures of putatively related brain processes. It was also found that greater buccal cell- (but not saliva-) derived NR3C1 -1 F methylation was associated with lower perceived daily life demands. Results of the present study may inform the design of future epigenetic studies on FKBP5 -intron-7 and NR3C1 -1 F-promoter methylation in relation to neuro-imaging and behavioural measures, and provide insight for the development of peripheral DNA methylation correlates of stress sensitivity and resilience. [ABSTRACT FROM AUTHOR]

Despite intense ongoing research efforts, the etiology of psychiatric disorders remains incompletely understood. Among biological factors playing a role in Major Depressive Disorder (MDD) and Anxiety Disorders (ANX), emerging evidence points to the relevance of different types of glia cells and efficient neuron-glia interactions. Here, we review recent findings highlighting the involvement of central nervous system (CNS) glia in MDD and ANX etiology and treatment response. Additionally, several relatively underexplored topics will be discussed: (1) glial response to non-pharmacological therapies, (2) impact of early life adversity on glia, (3) influence of lifestyle factors on glia in the context of MDD and ANX, and (4) monitoring glial functions in patients. It can be concluded that despite the sequence of events is still unclear, alterations in glial cell types are common and somewhat overlapping in ANX, MDD and corresponding animal models. Furthermore, glia are responsive to a variety of treatment and lifestyle options. Looking forward, new research developments can lead to novel types of therapeutic or symptom-relieving approaches targeting glia. [ABSTRACT FROM AUTHOR]

Stress during early development produces lasting effects on psychopathological outcomes. We analysed the impact of prior intermittent, physical stress (IPS) during early adolescence (PD 22–33) on anxiety-like behaviour of female rats in adulthood. After behavioural testing, we used immunohistochemistry for the 5-HT transporter (SERT) to evaluate 5-HT innervation profiles in the medial prefrontal cortex (mPFC) and ventral hippocampus (VH). Administration of IPS (i.e., water immersion, elevated platform, foot shock) in early adolescence increased rats’ anxiety-like behaviour in the elevated plus-maze but had no effects in the shock-probe burying test. In the social interaction test, IPS decreased social interaction, and this effect was driven by selective decreases in the frequency of playfighting with no evident changes in contact and investigative behaviours. Selective stress-induced increases in the density of SERT- ir positive fibres were found in the infralimbic (IL) subregion of the mPFC but not in the cingulate or prelimbic (PL) subregions. IPS in early adolescence did not affect 5-HT innervation profiles in any sub-fields of the VH. Our findings confirm and extend on earlier evidence that stress during early adolescence promotes the emergence of an anxious phenotype and provide novel evidence that these effects are associated with increased 5-HT innervation of the IL mPFC. [ABSTRACT FROM AUTHOR]

Objective Posttraumatic stress disorder (PTSD) is a disorder with significant sleep morbidity and limited treatment options. Prazosin may constitute a novel management approach and has been tested recently in a number of trials. We conducted a meta-analysis to examine the effectiveness of prazosin for nightmares and other sleep disturbances in adults with PTSD. Method A systematic review of databases for randomized, double-blind, placebo-controlled trials of adults diagnosed with PTSD and reporting sleep disturbances that were treated with prazosin was conducted in January 2015. No limitations were placed on language or year of publication. Results Six randomized controlled trials of prazosin for sleep disturbances in patients with PTSD were included (sample n = 240). We found that prazosin was statistically significantly more effective than placebo in improving sleep quality [ g = 0.987, 95% confidence interval (CI): 0.324–1.651] and in reducing overall PTSD symptoms ( g = 0.699, 95% CI: 0.139–1.260) and sleep disturbances in particular ( g = 0.799, 95% CI: 0.391–1.234). Conclusions Prazosin showed medium-to-large and statistically significant effects on PTSD symptoms in general and sleep disturbances in particular. While promising, results should be interpreted with caution given the limited total number of participants and the limitations induced by the majority of participants being male and noncivilian. [ABSTRACT FROM AUTHOR]

Background: Subthreshold depression is highly prevalent in adolescence, but compared to major depressive disorder, the clinical impact is under-researched. The aim of this review was to compare subthreshold depression and major depressive disorder in adolescents by reviewing available literature on epidemiology, risk factors, illness trajectories, brain anatomy and function, genetics, and treatment response.Methods: We conducted a scoping review of papers on subthreshold depression and major depressive disorder in adolescence published in English. Studies in adults were included when research in adolescence was not available.Results: We found that individuals with subthreshold depression were similar to individuals with major depressive disorder in several regards, including female/male ratio, onset, functional impairment, comorbidity, health care utilization, suicidal ideation, genetic predisposition, brain alterations, and treatment response. Further, subthreshold depression was about two times more common than major depressive disorder.Limitations: The definition of subthreshold depression is highly variable across studies. Adolescent-specific data are limited in the areas of neurobiology and treatment.Conclusions: The findings of the current review support the idea that subthreshold depression is of clinical importance and provide evidence for a spectrum, versus categorical model, for depressive symptomatology. Given the frequency of subthreshold depression escalating to major depressive disorder, a greater recognition and awareness of the significance of subthreshold depression in research, clinical practice and policy-making may facilitate the development and application of early prevention and intervention. [ABSTRACT FROM AUTHOR]

Screening is done to improve health outcomes by identifying and effectively treating individuals with unrecognized conditions. Depression screening has been proposed to identify previously unrecognized depression cases. Including individuals already diagnosed or treated for depression in screening test accuracy studies could exaggerate accuracy and the yield of new cases from screening. The present study investigated (1) the proportion of depression screening tool accuracy primary studies published in 2018–2021 that excluded individuals with a confirmed depression diagnosis or who were already undergoing treatment; and (2) whether this has improved since the last review of studies published in 2013–2015, which found that five of 89 (5.6%) primary studies appropriately excluded such individuals. MEDLINE was searched from January 1, 2018 through May 21, 2021 for primary studies on depression screening tool accuracy. Eighteen of 106 (17.0%; 95% Confidence Interval [CI], 11.0% to 25.3%) primary studies excluded currently diagnosed or treated individuals. This was 11.4% (95% CI, 2.8% to 20.0%) greater than in similar studies published in 2013–2015. There has been an improvement since 2015, but the proportion of studies that exclude individuals already known to have depression remains low. This may bias research findings intended to inform clinical practice. [ABSTRACT FROM AUTHOR]

Over the past decade, psychiatric research has been on an important hunt for biomarkers of psychiatric disease. In psychiatry, the term "biomarker" is a broad umbrella term used to identify any biological variable that can be objectively measured and applied to a diagnosis; this includes genetic and epigenetic assessments, hormone levels, measures of neuro-anatomy and many other scientific modalities. However, despite hundreds of studies on the topic being published yearly and other medical specialties having success in discovering biomarkers, clinical psychiatric practice has not had the same success. This paper aims to consolidate the many opinions on the search for psychiatric biomarkers to suggest key methodological and clinical challenges that psychiatric biomarker research faces. Psychiatry as a specialty has many fundamental differences compared to other medical specialties in methods of diagnosing, underlying etiology and disease pathologies that may be limiting the success of biomarker research in itself and puts strict requirements on the research being conducted. The academic and clinical environment in which the research is being conducted also heavily influences the translation of the findings. Finally, once biomarkers are identified, more often than not they are inapplicable to clinical settings, unable to integrate into clinical practice and fail to outperform current diagnostic practices and guidelines. We also make six recommendations for more promising future research in psychiatric biomarkers. • For biomarker research to be successful, multiple techniques must be combined. • There are intricacies unique to psychiatry that make successful biomarker identification difficult. • Improved research methodologies that are easily combined are needed. • Multidisciplinary teams should be involved at all stages of biomarker research. [ABSTRACT FROM AUTHOR]

Background: Studies in adult depressed patients have indicated that altered DNA methylation patterns at genes related to serotonin and HPA axis functioning (e.g., SLC6A4, FKBP5) are associated with changes in frontolimbic functional connectivity and structure. Here, we examined whether these associations can be generalized to adolescents.Methods: 25 adolescents with depression (Mean age = 15.72 ± 0.94 SD; 20 girls) and 20 healthy controls (Mean age = 16.05 ± 1.5 SD; 16 girls) underwent a functional and structural magnetic resonance imaging protocol, which included a resting-state assessment and measures of brain morphometry. DNA was obtained from saliva. Levels of SLC6A4 and FKBP5 methylation were determined using pyrosequencing.Results: SLC6A4 methylation was linked to amygdala-frontal operculum resting-state functional connectivity (rs-FC), regardless of diagnosis, and was differentially associated with inferior orbitofrontal gyrus (IFOG) gray matter (GM) volume in adolescents with depression and controls. Replicating and extending previous findings in adults, FKBP5 methylation was associated with IFOG GM volume in depressed and healthy adolescents, as well as orbitofrontal cortex (OFC)-rostral prefrontal cortex (RPFC) connectivity in healthy adolescents only.Limitations: Effects of medication use or genotype cannot be ruled out. Further, the relatively small sample size and predominately female sample may limit generalizability.Conclusions: These findings suggest that previously observed associations between SLC6A4 and FKBP5 methylation and frontolimbic processes in adult depressed patients can be in part generalized to adolescent patients. Further, findings suggest that measuring peripheral methylation at these genes deserves further attention as potential markers of typical and atypical development. [ABSTRACT FROM AUTHOR]

• Sadness involves reduction of cortical control over evolutionarily ancient brain systems. • Basic emotion theorists have identified a SADNESS circuit, based on animal research. • Psychological constructionists have identified patterns of activity that dependent on context. • Competing models may relate to different levels on a phylogenetic hierarchy. • Dedicated funding to facilitate collaborative and transdisciplinary opportunities is needed. Sadness is typically characterized by raised inner eyebrows, lowered corners of the mouth, reduced walking speed, and slumped posture. Ancient subcortical circuitry provides a neuroanatomical foundation, extending from dorsal periaqueductal grey to subgenual anterior cingulate, the latter of which is now a treatment target in disorders of sadness. Electrophysiological studies further emphasize a role for reduced left relative to right frontal asymmetry in sadness, underpinning interest in the transcranial stimulation of left dorsolateral prefrontal cortex as an antidepressant target. Neuroimaging studies – including meta-analyses – indicate that sadness is associated with reduced cortical activation, which may contribute to reduced parasympathetic inhibitory control over medullary cardioacceleratory circuits. Reduced cardiac control may – in part – contribute to epidemiological reports of reduced life expectancy in affective disorders, effects equivalent to heavy smoking. We suggest that the field may be moving toward a theoretical consensus, in which different models relating to basic emotion theory and psychological constructionism may be considered as complementary, working at different levels of the phylogenetic hierarchy. [ABSTRACT FROM AUTHOR]

Background: Peer victimization is associated with increased risk for depression, as well as increased neural response to social exclusion in the anterior cingulate cortex (ACC) and the amygdala. Altered functional connectivity (FxC) of fronto-limbic circuitry is associated with risk for various affective disorders. The present study examined the relationship between fronto-limbic FxC during social exclusion, prior peer victimization experience and depressive symptoms.Methods: Three mutually exclusive groups were formed: peer victimized (with a history of peer victimization), defenders (history of defending peers), and controls (no prior peer victimization experience) (n = 15/group; Mage = 17.7 years). Functional Magnetic Resonance Imaging data were collected while participants completed the Cyberball paradigm (simulating the experience of social exclusion). FxC between the Medial Prefrontal Cortex (MPFC), ACC, right insula and left amygdala, was compared between groups and examined in relation to depressive symptoms.Results: Prior peer victimization experience was associated with differences in fronto-limbic FxC across social inclusion and exclusion. Defenders displayed distinct shifts in FxC across the transition from being included to excluded. Peer victimized individuals exhibited a unique pattern of amygdala-specific FxC during inclusive interaction with peers, and in the continuous FxC across inclusion and exclusion. FxC of the MPFC-amygdala across inclusion and exclusion moderated the relationship between peer victimization and depressive symptoms.Limitations: Small sample size and cross-sectional design limit interpretation of the findings.Conclusions: Peer victimized individuals who exhibit continuous positive FxC of the MPFC-left amygdala across inclusion and exclusion may be at greater risk for depressive symptoms. [ABSTRACT FROM AUTHOR]

Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin synthesis. The TPH2 gene has frequently been investigated in relation to psychiatric morbidity. The aim of the present review is to integrate results from association studies between TPH2 single nucleotide polymorphisms (SNPs) and various psychiatric disorders, which we furthermore quantified with meta-analysis. We reviewed 166 studies investigating 69 TPH2 SNPs in a broad range of psychiatric disorders, including over 30,000 patients. According to our meta-analysis, TPH2 polymorphisms show strongest associations with mood disorders, suicide (attempt) and schizophrenia. Despite small effect sizes, we conclude that TPH2 SNPs in the coding and non-coding areas (rs4570625, rs11178997, rs11178998, rs10748185, rs1843809, rs4290270, rs17110747) are each associated with one or more psychopathological conditions. Our findings highlight the possible common serotonergic mechanisms of the investigated psychiatric disorders. Yet, the functional relevance of most TPH2 polymorphisms is unclear. Characterizing how exactly the different TPH2 variants influence the serotonergic neurotransmission is a next necessary step in understanding the psychiatric disorders where serotonin is implicated. [ABSTRACT FROM AUTHOR]

Exposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce. To quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex. We measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics. Geometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10–2.50), 4.97 (3.20–6.20) and 1.09 (0.67–1.60) μg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p <.01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = −2.80, 95% CI: −4.92, −0.68; PFOS: B = −2.64, 95% CI: −4.77, −0.52; PFHxS: B = −2.92, 95% CI: −4.72, −1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = −3.16, 95% CI: −4.90, −1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: −0.99, 2.26). No significant associations were found for EF in either males or females. Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific. • We assessed associations between PFAS and child neurodevelopment. • PFOS, PFOS and PFHxS were inversely associated with nonverbal IQ in males. • In mixture models, PFHxS was identified as a chemical of concern. • We observed no associations between PFAS and executive functioning. • The association between PFAS and IQ may be sex and domain-specific. [ABSTRACT FROM AUTHOR]

Depression is associated with alterations in hypothalamic–pituitary–adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene ( NR3C1 ) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance. [ABSTRACT FROM AUTHOR]

Existing studies suggest that dehydroepiandrosterone (DHEA) may be important for human brain development and cognition. For example, molecular studies have hinted at the critical role of DHEA in enhancing brain plasticity. Studies of human brain development also support the notion that DHEA is involved in preserving cortical plasticity. Further, some, though not all, studies show that DHEA administration may lead to improvements in working memory in adults. Yet these findings remain limited by an incomplete understanding of the specific neuroanatomical mechanisms through which DHEA may impact the CNS during development. Here we examined associations between DHEA, cortico-hippocampal structural covariance, and working memory (216 participants [female=123], age range 6–22 years old, mean age: 13.6 +/−3.6 years, each followed for a maximum of 3 visits over the course of 4 years). In addition to administering performance-based, spatial working memory tests to these children, we also collected ecological, parent ratings of working memory in everyday situations. We found that increasingly higher DHEA levels were associated with a shift toward positive insular-hippocampal and occipito-hippocampal structural covariance. In turn, DHEA-related insular-hippocampal covariance was associated with lower spatial working memory but higher overall working memory as measured by the ecological parent ratings. Taken together with previous research, these results support the hypothesis that DHEA may optimize cortical functions related to general attentional and working memory processes, but impair the development of bottom-up, hippocampal-to-cortical connections, resulting in impaired encoding of spatial cues. [ABSTRACT FROM AUTHOR]

Early adversity can influence gene expression via epigenetic mechanisms, including DNA methylation. Peripheral tissues are essential in psychiatric epigenetics, as methylation generally cannot be assessed in the living human brain. Several magnetic resonance imaging (MRI) studies show associations of peripheral serotonin transporter gene (SLC6A4) methylation with function and/or structure of frontal-limbic circuits and brain's resting-state. Commonly used samples are derived from blood, saliva or buccal cells. However, little is known regarding which peripheral tissue is most strongly associated with human brain processes. The aim of the current study was to compare the extent of the association between peripheral SLC6A4 promoter methylation and frontal-limbic function, structure and resting-state in healthy individuals across peripheral tissues. Forty healthy prospectively-followed adults underwent anatomical, resting-state and functional MRI. Saliva-, blood- and buccal-derived DNA methylation was assessed by pyrosequencing. Blood-derived SLC6A4 methylation was positively associated with superior frontal gray matter (GM) volume and with right lateral parietal area (RLP)-frontal pole regional resting-state functional connectivity (rsFC). Saliva-derived SLC6A4 methylation was positively associated with superior frontal GM volume. Buccal-derived SLC6A4 methylation was positively associated with superior and inferior frontal and anterior cingulate cortical (ACC) GM volumes, and with RLP-ACC, frontal pole and medial prefrontal regional rsFC. Current results confirmed the relevance of peripheral methylation for frontal-limbic processes in humans. Buccal cells may be the most sensitive cell type when studying SLC6A4 promoter methylation and its associated risk for neural vulnerability and resilience for psychopathologies in which serotonin is implicated. These data should be further validated in clinical populations. [ABSTRACT FROM AUTHOR]

Numerous studies have been using peripheral tissues (e.g., blood or saliva) for DNA methylation analyses in psychiatric epigenetics. The glucocorticoid receptor gene (NR3C1) was among the first ones to show DNA methylation changes due to adverse social environment. Importantly, the NR3C1 gene has several alternative promoters, out of which the 1-F showed increased DNA methylation level at a transcription factor binding site. Afterwards, its co-chaperone molecule, FK506-binding protein 5 (FKBP5) gained interest, showing allele-specific demetylation in its glucocorticoid response element of the 7th intron. This decreased methylation at FKBP5 can lead to NR3C1 resistance, because of an impaired intracellular negative feedback loop. While it is now standard for epigenome-wide DNA methylation analyses to control for cell heterogeneity using cell count estimates derived from the DNA methylation profiles, this important technical variable of cell composition is rarely included in candidate gene analyses. Therefore, we aimed to (1) develop a panel of pyrosequencing assays for cell-specific CG-sites, and (2) evaluate the effect of cell ratio on DNA methylation levels of candidate gene regions in frequently used peripheral tissues, such as Whole Blood (WB), Peripheral Blood Mononuclear Cell (PBMC), as well as non-invasively collected buccal, mouthwash, and saliva samples in two cohorts. Samples were collected from 51 adults participating in a Montreal-based longitudinal cohort, out of which 16 men had been assessed twice. In addition, 38 female patients with borderline personality disorder and 21 control women were recruited at a psychiatric clinic in Budapest. Candidate gene regions of the NR3C1-1F and FKBP5-intron7, as well as tissue-specific CG-sites were assessed by pyrosequencing at both sites. The DNA methylation level of the CG-island in the NR3C1-1F promoter region showed little variance in all of the tissue types we investigated. However, the low CG-density region of FKBP5-intron7 was highly variable across samples, especially in saliva. Notably, methylation level of the epithelial cell marker PTPN7 cg18384097 varied widely among the mouth-related samples in both cohorts (ranging from 9%-95%), even in buccal swab samples, where there was ~ 80% buccal cell ratio on average with 10–12% SD. The effect of epithelial cell composition was substantial on FKBP5-intron7 methylation levels in saliva and mouthwash samples (r=0.5–0.7), but it was less pronounced in buccal swab samples (r=0.2–0.4). Higher ratio of epithelial cells resulted in lower methylation level at the studied FKBP5 CG-sites. Importantly, the stability of the DNA methylation level of this gene region was significant both in saliva and buccal swab samples (r=0.6–0.8, p<0.01). In addition, methylation level of the T lymphocyte marker CD3E cg06164961 also showed correlation with FKBP5-intron7 methylation in blood samples (WB: r=0.5–0.7, PBMC: r=0.3–0.5). Our preliminary results show that cell composition should be taken into account at candidate gene DNA methylation analyses, especially when measuring low CG-density regions in heterogeneous peripheral tissues, such as whole blood or saliva. Using more homogeneous biological samples, e.g., PBMC or purified leukocytes would result in less technical variability. The non-invasively obtained buccal swabs can also yield a relatively homogeneous surrogate sample in psychiatric epigenetics. [ABSTRACT FROM AUTHOR]