Large-scale magnetic resonance (MR) studies of the human brain offer unique opportunities for identifying genetic and environmental factors shaping the human brain. Here, we describe a dataset collected in the context of a multi-centre study of the adolescent brain, namely the IMAGEN Study. We focus on one of the functional paradigms included in the project to probe the brain network underlying processing of ambiguous and angry faces. Using functional MR (fMRI) data collected in 1,110 adolescents, we constructed probabilistic maps of the neural network engaged consistently while viewing the ambiguous or angry faces; 21 brain regions responding to faces with high probability were identified. We were also able to address several methodological issues, including the minimal sample size yielding a stable location of a test region, namely the fusiform face area (FFA), as well as the effect of acquisition site (eight sites) and scanner (four manufacturers) on the location and magnitude of the fMRI response to faces in the FFA. Finally, we provided a comparison between male and female adolescents in terms of the effect sizes of sex differences in brain response to the ambiguous and angry faces in the 21 regions of interest. Overall, we found a stronger neural response to the ambiguous faces in several cortical regions, including the fusiform face area, in female (vs. male) adolescents, and a slightly stronger response to the angry faces in the amygdala of male (vs. female) adolescents.

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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.

Both behavioral and neuroimaging evidence support a female advantage in the perception of human faces. Here we explored the possibility that this relationship may be partially mediated by female sex hormones by investigating the relationship between the brain's response to faces and the use of oral contraceptives, as well as the phase of the menstrual cycle. First, functional magnetic resonance images were acquired in 20 young women [10 freely cycling and 10 taking oral contraception (OC)] during two phases of their cycle: mid-cycle and menstruation. We found stronger neural responses to faces in the right fusiform face area (FFA) in women taking oral contraceptives (vs freely cycling women) and during mid-cycle (vs menstruation) in both groups. Mean blood oxygenation level-dependent response in both left and right FFA increased as function of the duration of OC use. Next, this relationship between the use of OC and FFA response was replicated in an independent sample of 110 adolescent girls. Finally in a parallel behavioral study carried out in another sample of women, we found no evidence of differences in the pattern of eye movements while viewing faces between freely cycling women vs those taking oral contraceptives. The imaging findings might indicate enhanced processing of social cues in women taking OC and women during mid-cycle.

Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging (fMRI) study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n=99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited BOLD responses in the following circuitry: periaqueductal gray [PAG], hypothalamus [HYPO], amygdala [AMYG], hippocampus [HIPP], orbitofrontal cortex [OFC], medial prefrontal cortex [mPFC], and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO - R OFC, R AMYG - R OFC, and R AMYG - R HIPP. Overall, our findings demonstrated sex-dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex-dependent lens in determining these biosignatures.

Maternal depression during pregnancy is associated with elevated risk of anxiety and depression in offspring, but the mechanisms are incompletely understood. Here we conducted a neuroimaging follow-up of a prenatal birth cohort from the European Longitudinal Study of Pregnancy and Childhood (n = 131; 53% women, age 23–24) to test whether deviations from age-normative structural brain development in young adulthood may partially underlie this link. Structural brain age was calculated based on previously published neuroanatomical age prediction models using cortical thickness maps from healthy controls aged 6–89. Brain age gap was computed as the difference between chronological and structural brain age. Participants also completed self-report measures of anxiety and mood dysregulation. Further, mothers of a subset of participants (n = 103, 54% women) answered a self-report questionnaire in 1990–1992 about depressive symptoms during pregnancy. Higher exposure to maternal depressive symptoms in utero showed a linear relationship with elevated brain age gap, which showed a quadratic relationship with anxiety and mood dysregulation in the young adult offspring. Our findings suggest that exposure to maternal depressive symptoms in utero may be associated with accelerated brain maturation and that deviations from age-normative structural brain development in either direction predict more anxiety and dysregulated mood in young adulthood.

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring’s risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

The main objective of this study was to investigate the impact of prenatal and early postnatal stress on hippocampal volume in young adulthood. In sharp contrast to numerous results in animal models, our data from a neuroimaging follow-up (n = 131) of a community-based birth cohort from the Czech Republic (European Longitudinal Study of Pregnancy and Childhood) showed that in typically developing young adults, hippocampal volume was not associated with birth weight, stressful life events during the prenatal or early postnatal period, or dysregulated mood and wellbeing in the mother during the early postnatal period. Interestingly, mother’s anxiety/co-dependence during the first weeks after birth did show long-lasting effects on the hippocampal volume in young adult offspring irrespective of sex. Further analyses revealed that these effects were subfield-specific; present in CA1, CA2/3, CA4, GC-DG, subiculum, molecular layer, and HATA, hippocampal subfields identified by translational research as most stress- and glucocorticoid-sensitive, but not in the remaining subfields. Our findings provide evidence that the type of early stress is critical when studying its effects on the human brain.