Epigenetic clock as a correlate of anxiety.

DNA methylation changes consistently throughout life and age-dependent alterations in DNA methylation can be used to estimate one's epigenetic age. Post-mortem studies revealed higher epigenetic age in brains of patients with major depressive disorder, as compared with controls. Since MDD is highly correlated with anxiety, we hypothesized that symptoms of anxiety, as well as lower volume of grey matter (GM) in depression-related cortical regions, will be associated with faster epigenetic clock in a community-based sample of young adults. Participants included 88 young adults (53% men; 23-24 years of age) from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) who participated in its neuroimaging follow-up and provided saliva samples for epigenetic analysis. Epigenetic age was calculated according to Horvath (Horvath, 2013). Women had slower epigenetic clock than men (Cohen's d = 0.48). In women (but not men), slower epigenetic clock was associated with less symptoms of anxiety. In the brain, women (but not men) with slower epigenetic clock had greater GM volume in the cerebral cortex (brain size-corrected; R2 = 0.07). Lobe-specific analyses showed that in women (but not men), slower epigenetic clock was associated with greater GM volume in frontal lobe (R2 = 0.16), and that GM volume in frontal lobe mediated the relationship between the speed of epigenetic clock and anxiety trait (ab = 0.15, SE = 0.15, 95% CI [0.007; 0.369]). These findings were not replicated, however, in a community-based sample of adolescents (n = 129; 49% men; 12-19 years of age), possibly due to the different method of tissue collection (blood vs. saliva) or additional sources of variability in the cohort of adolescents (puberty stages, socioeconomic status, prenatal exposure to maternal smoking during pregnancy).

Prenatal Stress, Mood, and Gray Matter Volume in Young Adulthood.

This study aimed to determine whether prenatal stress, measured by the number of stressful life events during the first 20 weeks of pregnancy, might relate to mood dysregulation and altered brain structure in young adulthood. Participants included 93 young adults from a community-based birth cohort from the Czech Republic. Information on prenatal stress exposure was collected from their mothers in 1990-1992. Magnetic resonance imaging (MRI) and mood-related data were collected from the young adults in 2015. MRI analyses focused on overall gray matter (GM) volume and GM volume of cortical regions previously associated with major depression. Higher prenatal stress predicted more mood dysregulation, lower overall GM volume, and lower GM volume in mid-dorsolateral frontal cortex, anterior cingulate cortex, and precuneus in young adulthood. We observed no prenatal stress by sex interactions for any of the relations. We conclude that prenatal stress is an important risk factor that relates to worse mood states and altered brain structure in young adulthood irrespective of sex. Our results point to the importance and long-lasting effects of prenatal programming and suggest that offspring of mothers who went through substantial stress during pregnancy might benefit from early intervention that would reduce the odds of mental illness in later life.

Developmental origins of depression-related white matter properties: Findings from a prenatal birth cohort.

Depression is the leading cause of years lost due to disability worldwide. Still, the mechanisms underlying its development are not well understood. This study aimed to evaluate white-matter properties associated with depressive symptomatology in young adulthood and their developmental origins. Diffusion tensor imaging and assessment of depressive symptomatology were conducted in 128 young adults (47% male, age 23-24) from a prenatal birth cohort (European Longitudinal Study of Pregnancy and Childhood). For a subset of these individuals, the database included information on prenatal stress (n = 93) and depressive symptoms during adolescence (assessed repeatedly at age 15 and 19). Depressive symptoms in young adulthood were associated with lower fractional anisotropy in the left and right cingulum and higher fractional anisotropy in the right corticospinal tract and superior longitudinal fasciculus. Further analyses revealed that prenatal stress and depressive symptomatology during adolescence were independent predictors of altered white-matter properties in the cingulum in young adulthood. We conclude that typically developing young adults with more depressive symptoms already exhibit tract-specific alterations in white-matter properties and that prenatal stress and depressive symptomatology during adolescence might contribute to their development.

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

OBJECTIVE: Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. METHOD: Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). RESULTS: The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. CONCLUSIONS: The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care.