BACKGROUND: Maternal perinatal mental health is essential for optimal brain development and mental health of the offspring. We evaluated whether maternal depression during the perinatal period and early life of the offspring might be selectively associated with altered brain function during emotion regulation and whether those may further correlate with physiological responses and the typical use of emotion regulation strategies. METHODS: Participants included 163 young adults (49% female, 28-30 years) from the ELSPAC prenatal birth cohort who took part in its neuroimaging follow-up and had complete mental health data from the perinatal period and early life. Maternal depressive symptoms were measured mid-pregnancy, 2 weeks, 6 months, and 18 months after birth. Regulation of negative affect was studied using functional magnetic resonance imaging, concurrent skin conductance response (SCR) and heart rate variability (HRV), and assessment of typical emotion regulation strategy. RESULTS: Maternal depression 2 weeks after birth interacted with sex and showed a relationship with greater brain response during emotion regulation in a right frontal cluster in women. Moreover, this brain response mediated the relationship between greater maternal depression 2 weeks after birth and greater suppression of emotions in young adult women (ab = 0.11, SE = 0.05, 95% CI [0.016; 0.226]). The altered brain response during emotion regulation and the typical emotion regulation strategy were also as sociated with SCR and HRV. CONCLUSIONS: These findings suggest that maternal depression 2 weeks after birth predisposes female offspring to maladaptive emotion regulation skills and particularly to emotion suppression in young adulthood.

• Keywords
• emotion regulation, fMRI, heart rate variability, maternal perinatal depression, prenatal birth cohort, skin conductance,
• MeSH
• Depression * physiopathology   MeSH
• Adult MeSH
• Emotional Regulation * physiology   MeSH
• Galvanic Skin Response physiology   MeSH
• Birth Cohort MeSH
• Pregnancy Complications * physiopathology   psychology   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Mothers * psychology   MeSH
• Young Adult MeSH
• Brain * physiopathology   diagnostic imaging   MeSH
• Heart Rate physiology   MeSH
• Pregnancy MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

• Keywords
• Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences,
• MeSH
• Bipolar Disorder genetics   MeSH
• Genome-Wide Association Study MeSH
• Depressive Disorder, Major * genetics   MeSH
• Endothelial Cells MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Sex Characteristics * MeSH
• Psychotic Disorders * genetics   MeSH
• Receptors, Vascular Endothelial Growth Factor MeSH
• Schizophrenia genetics   MeSH
• Sulfurtransferases MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• MOCOS protein, human MeSH Browser
• Receptors, Vascular Endothelial Growth Factor MeSH
• Sulfurtransferases MeSH

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.

• Keywords
• functional brain imaging, prenatal immune programming, prenatal stress, sex, stress circuitry,
• MeSH
• Cytokines blood   MeSH
• Adult MeSH
• Hypothalamus diagnostic imaging   MeSH
• Connectome * MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Stress, Psychological diagnostic imaging   MeSH
• Sex Factors MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects diagnostic imaging   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cytokines MeSH

Cardiac autonomic dysregulation has been implicated in the comorbidity of major psychiatric disorders and cardiovascular disease, potentially through dysregulation of physiological responses to negative stressful stimuli (here, shortened to stress response). Further, sex differences in these comorbidities are substantial. Here, we tested the hypothesis that mood- and sex-dependent alterations in brain circuitry implicated in the regulation of the stress response are associated with reduced peripheral parasympathetic activity during negative emotional arousal. Fifty subjects (28 females) including healthy controls and individuals with major depression, bipolar psychosis and schizophrenia were evaluated. Functional magnetic resonance imaging and physiology (cardiac pulse) data were acquired during a mild visual stress reactivity challenge. Associations between changes in activity and functional connectivity of the stress response circuitry and variations in cardiovagal activity [normalized high frequency power of heart rate variability (HFn)] were evaluated using GLM analyses, including interactions with depressed mood and sex across disorders. Our results revealed that in women with high depressed mood, lower cardiovagal activity in response to negative affective stimuli was associated with greater activation of hypothalamus and right amygdala and reduced connectivity between hypothalamus and right orbitofrontal cortex, amygdala, and hippocampus. No significant associations were observed in women with low levels of depressed mood or men. Our results revealed mood- and sex-dependent interactions in the central regulation of cardiac autonomic activity in response to negative affective stimuli. These findings provide a potential pathophysiological mechanism for previously observed sex differences in the comorbidity of major depression and cardiovascular disease.

• MeSH
• Amygdala MeSH
• Depressive Disorder, Major * MeSH
• Hippocampus MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Brain diagnostic imaging   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

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.

• MeSH
• Algorithms MeSH
• Depression physiopathology   MeSH
• Adult MeSH
• Stress, Physiological * MeSH
• Hippocampus pathology   MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Magnetic Resonance Imaging MeSH
• Young Adult MeSH
• Infant, Newborn MeSH
• Organ Size MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Maladaptive responses to negative affective stimuli are pervasive, including clinically ill and healthy people, and men and women respond differently at neural and hormonal levels. Inspired by the Research Domain Criteria initiative, we used a transdiagnostic approach to investigate the impact of sex and dysphoric mood on neural-hormonal responses to negative affective stimuli. METHODS: Participants included 99 individuals with major depressive disorder, psychosis and healthy controls. Functional magnetic resonance imaging (fMRI) was complemented with real-time acquisition of hypothalamo-pituitary-adrenal (HPA) and -gonadal (HPG) hormones. fMRI data were analyzed in SPM8 and task-related connectivity was assessed using generalized psychophysiological interaction. RESULTS: Across all participants, elevated cortisol response predicted lower brain activity in orbitofrontal cortex and hypothalamus-amygdala connectivity. In those with worse dysphoric mood, elevated cortisol response predicted lower activity in hypothalamus and hippocampus. In women, elevated cortisol response was associated with lower activity in medial prefrontal cortex and low hypothalamo-hippocampal connectivity. In women with high dysphoric mood, elevated cortisol response was associated with low hypothalamo-hippocampal connectivity. There were no interactions with diagnosis or medication. LIMITATIONS: There was limited power to correct for multiple comparisons across total number of ROIs and connectivity targets; cortisol responses were relatively low. CONCLUSIONS: We conclude that the pathophysiology in neural-hormonal responses to negative affective stimuli is shared across healthy and clinical populations and varies as a function of sex and dysphoric mood. Our findings may contribute to the development of hormonal adjunctive therapeutics that are sex-dependent, underscoring the importance of one's sex to precision medicine.

• Keywords
• Cortisol response, Dysphoric mood, FMRI, Negative affect, RDoC, Sex differences,
• MeSH
• Affect physiology   MeSH
• Amygdala physiopathology   MeSH
• Depressive Disorder, Major diagnostic imaging   physiopathology   psychology   MeSH
• Adult MeSH
• Hippocampus physiopathology   MeSH
• Hydrocortisone physiology   MeSH
• Hypothalamus physiopathology   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Young Adult MeSH
• Prefrontal Cortex physiopathology   MeSH
• Psychotic Disorders diagnostic imaging   physiopathology   psychology   MeSH
• Sex Factors * MeSH
• Pituitary-Adrenal System physiology   MeSH
• Hypothalamo-Hypophyseal System physiology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hydrocortisone MeSH