Prenatal maternal depressive symptoms are associated with neonatal left amygdala microstructure in a sex-dependent way.

Exposures to prenatal maternal depressive symptoms (PMDS) may lead to neurodevelopmental changes in the offspring in a sex-dependent way. Although a connection between PMDS and infant brain development has been established by earlier studies, the relationship between PMDS exposures measured at various prenatal stages and microstructural alterations in fundamental subcortical structures such as the amygdala remains unknown. In this study, we investigated the associations between PMDS measured during gestational weeks 14, 24 and 34 and infant amygdala microstructural properties using diffusion tensor imaging. We explored amygdala mean diffusivity (MD) alterations in response to PMDS in infants aged 11 to 54 days from birth. PMDS had no significant main effect on the amygdala MD metrics. However, there was a significant interaction effect for PMDS and infant sex in the left amygdala MD. Compared with girls, boys exposed to greater PMDS during gestational week 14 showed significantly higher left amygdala MD. These results indicate that PMDS are linked to infants' amygdala microstructure in boys. These associations may be relevant to later neuropsychiatric outcomes in the offspring. Further research is required to better understand the mechanisms underlying these associations and to develop effective interventions to counteract any potential adverse consequences.

Association of cumulative prenatal adversity with infant subcortical structure volumes and child problem behavior and its moderation by a coexpression polygenic risk score of the serotonin system.

Prenatal adversity has been linked to later psychopathology. Yet, research on cumulative prenatal adversity, as well as its interaction with offspring genotype, on brain and behavioral development is scarce. With this study, we aimed to address this gap. In Finnish mother-infant dyads, we investigated the association of a cumulative prenatal adversity sum score (PRE-AS) with (a) child emotional and behavioral problems assessed with the Strengths and Difficulties Questionnaire at 4 and 5 years (N = 1568, 45.3% female), (b) infant amygdalar and hippocampal volumes (subsample N = 122), and (c) its moderation by a hippocampal-specific coexpression polygenic risk score based on the serotonin transporter (SLC6A4) gene. We found that higher PRE-AS was linked to greater child emotional and behavioral problems at both time points, with partly stronger associations in boys than in girls. Higher PRE-AS was associated with larger bilateral infant amygdalar volumes in girls compared to boys, while no associations were found for hippocampal volumes. Further, hyperactivity/inattention in 4-year-old girls was related to both genotype and PRE-AS, the latter partially mediated by right amygdalar volumes as preliminary evidence suggests. Our study is the first to demonstrate a dose-dependent sexually dimorphic relationship between cumulative prenatal adversity and infant amygdalar volumes.

Allometry in the corpus callosum in neonates: Sexual dimorphism.

The corpus callosum (CC) is the largest fiber tract in the human brain, allowing interhemispheric communication by connecting homologous areas of the two cerebral hemispheres. In adults, CC size shows a robust allometric relationship with brain size, with larger brains having larger callosa, but smaller brains having larger callosa relative to brain size. Such an allometric relationship has been shown in both males and females, with no significant difference between the sexes. But there is some evidence that there are alterations in these allometric relationships during development. However, it is currently not known whether there is sexual dimorphism in these allometric relationships from birth, or if it only develops later. We study this in neonate data. Our results indicate that there are already sex differences in these allometric relationships in neonates: male neonates show the adult-like allometric relationship between CC size and brain size; however female neonates show a significantly more positive allometry between CC size and brain size than either male neonates or female adults. The underlying cause of this sexual dimorphism is unclear; but the existence of this sexual dimorphism in neonates suggests that sex-differences in lateralization have prenatal origins.

Larger bilateral amygdalar volumes are associated with affective loss experiences.

Affective loss (AL) (i.e., bereavement, relationship breakup) is a stressful life event leading to a heightened risk of developing a psychiatric disorder, for example, depression and anxiety disorder. These disorders have been associated with altered subcortical brain volumes. Little is known though, how AL in healthy subjects is linked to subcortical volumes. In a study with 196 healthy young adults, we probed the association between AL across the individual entire life span, assessed via the List of Threatening Experiences Questionnaire, and magnetic resonance imaging brain gray matter volumes (a priori selected: bilateral amygdalae, hippocampi, thalami; exploratory analyses: nuclei accumbens, caudate, putamina), segmented by use of volBrain. AL was defined as death of a first-degree relative/spouse, close relative/friend, and breakup of a marriage or steady relationship. AL was associated with larger bilateral amygdalar volumes and, after taking into account the total number of ALs, with smaller right hippocampal volumes, both irrespective of sex. Exploratory analyses of striatal volumes yielded an association of AL with larger right nucleus accumbens volumes in men, and increased caudate volumes after the loss of a first-degree relative irrespective of sex. Our data suggest that AL engenders alterations in limbic structures that likely involve processes of chronic stress and amygdala- and hippocampus-dependent fear conditioning, and resemble those observed in general anxiety disorder, childhood maltreatment, and major depressive disorder. Our exploratory findings of striatal volume alterations hint at a modulation of reward processing by AL.

Sex-specific association between infant caudate volumes and a polygenic risk score for major depressive disorder.

Polygenic risk scores for major depressive disorder (PRS-MDD) have been identified in large genome-wide association studies, and recent findings suggest that PRS-MDD might interact with environmental risk factors to shape human limbic brain development as early as in the prenatal period. Striatal structures are crucially involved in depression; however, the association of PRS-MDD with infant striatal volumes is yet unknown. In this study, 105 Finnish mother-infant dyads (44 female, 11-54 days old) were investigated to reveal how infant PRS-MDD is associated with infant dorsal striatal volumes (caudate, putamen) and whether PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant striatal volumes. A robust sex-specific main effect of PRS-MDD on bilateral infant caudate volumes was observed. PRS-MDD were more positively associated with caudate volumes in boys compared to girls. No significant interaction effects of genotype PRS-MDD with the environmental risk factor "prenatal maternal depressive symptoms" (genotype-by-environment interaction) nor significant interaction effects of genotype with prenatal maternal depressive symptoms and sex (genotype-by-environment-by-sex interaction) were found for infant dorsal striatal volumes. Our study showed that a higher PRS-MDD irrespective of prenatal exposure to maternal depressive symptoms is associated with smaller bilateral caudate volumes, an indicator of greater susceptibility to major depressive disorder, in female compared to male infants. This sex-specific polygenic effect might lay the ground for the higher prevalence of depression in women compared to men.

Intergroup empathy: Enhanced neural resonance for ingroup facial emotion in a shared neural production-perception network.

INTRODUCTION: Empathic behavior and related neural processing are strongly modified by group membership. Shared neural circuits for the production and perception of facial emotional expressions represent mirror neuron mechanisms which play a pivotal role for empathy. In this study, we investigate the influence of group membership on mirror neuron mechanisms for emotional facial expressions. METHODS: In a functional magnetic resonance imaging task, 178 healthy subjects perceived emotional and neutral facial expressions of artificial ingroup and outgroup members, displayed as 5 s video clips, and produced these facial expressions themselves. Before scanning, artificial group membership was manipulated ad-hoc through a minimal group paradigm. RESULTS: Shared neural activity for emotional facial expression production and perception was revealed in a large network with right-hemispheric preponderance encompassing motor mirror neuron regions, i.e., inferior frontal gyrus, supplementary motor area and middle temporal gyrus, in addition to limbic regions, i.e., amygdala, hippocampus, para-hippocampus, and insula. Within this network there was greater neural activation for ingroup compared to outgroup members in temporal poles, amygdalae, the left insula, the left inferior frontal gyrus, and the inferior and middle temporal gyrus, the right hippocampus and parahippocampus. DISCUSSION: We validate and extend knowledge on brain regions with mirror neuron properties. Most crucially, we provide evidence for the influence of group membership on regions within the mirror neuron system, indicating more neural resonance (mirroring) for ingroup facial emotional expressions.

Polygenic risk for neuroticism is associated with externalizing symptoms in 2-year-old boys.

Recent advances in genome-wide association studies have enabled the estimation of genetic risk of complex traits, including neuroticism, with polygenic risk scores (PRS). Neuroticism PRS has been associated with psychiatric disorders and symptoms in adults, but studies in children are scarce. We studied whether neuroticism PRS, and its subscales, worry PRS and depressive affect PRS, were associated with externalizing and internalizing symptoms in 2-year-olds. We also examined parental neuroticism PRSs' association with children's externalizing and internalizing symptoms and whether parental depressive symptoms mediated the effect. Participants from two Finnish birth cohorts, CHILD-SLEEP and FinnBrain Birth Cohort Study, who had DNA and data on Brief Infant-Toddler Social and Emotional Assessment (BITSEA) available were included in the study (N = 806 and N = 987, respectively). PRSs were calculated based on GWAS data from UK Biobank. Child's neuroticism PRS, and its subscale worry PRS, were positively associated with externalizing symptoms in 2-year-old boys, but not in girls. Mother's depressive symptoms mediated the association between maternal neuroticism PRS and externalizing and internalizing symptoms in boys, but not in girls. Our results suggest that neuroticism PRS, and its subscale worry PRS, are associated with externalizing symptoms in already as young as 2-year-old boys, and, that subclinical symptoms of maternal depression that are based on genetic disposition, have an effect on boy's internalizing and externalizing symptoms. As we did not find any associations in girls, our study supports the suggestion that girls and boys may differ in how genetic and environmental factors contribute to their development.

Auditory Mismatch Responses to Emotional Stimuli in 3-Year-Olds in Relation to Prenatal Maternal Depression Symptoms.

Maternal depression symptoms are common in pregnant women and can have negative effects on offspring's emotional development. This study investigated the association between prenatal maternal depression symptoms (assessed with the Edinburgh Postnatal Depression Scale at 24 weeks of gestation) and auditory perception of emotional stimuli in 3-year-olds (n = 58) from the FinnBrain Birth Cohort Study. Using electroencephalography (EEG), we examined mismatch responses for happy, sad, and angry sounds presented among neutral stimuli. A positive association between maternal depression symptoms and the emotional mismatch responses in an early time window (80-120 ms) was found, indicating that brain responses of children of mothers with depressive symptoms were weaker to happy sounds, though the results did not survive Bonferroni correction. There were no clear associations in the sad and angry emotional categories. Our results tentatively support that the 3-year-old children of mothers with depression symptoms may be less sensitive to automatically detect happy sounds compared to children whose mothers do not display symptoms of depression.

Emotion specific neural activation for the production and perception of facial expressions.

The distinction between different facial emotions is crucial for interpersonal communication. Shared neural circuits for facial emotion production and perception are considered to facilitate the ability to understand other's emotional state via mirror neuron mechanisms. Little is known about how diverse emotions differentially activate the Mirror Neuron System (MNS) during facial expression processing. In a functional magnetic resonance imaging (fMRI) task, 178 healthy subjects perceived and produced emotional (happy vs angry) and non-emotional (lip-protrusion vs no movement) facial expressions. Dynamic facial expressions were displayed as 5 sec video clips. We identified three overlapping networks of neural activation for happy, angry, and non-emotional (lip-protrusion) facial expression production and perception. Importantly, this overlap was largely due to the common motor component of facial expressions. However, for happy facial expressions, we found specific MNS activation in the right temporal pole. For angry facial expressions we found such activation in the left inferior frontal gyrus, pars orbitalis, and the cerebellum (lobules VII and VIII). We extend knowledge on mirror neuron mechanisms as our results provide evidence for emotion specific shared neural activation for the production and perception of facial emotions. This emotion specific representation of other's emotion in one's own neural production system might facilitate understanding of other's mental or emotional states.

Newborn amygdalar volumes are associated with maternal prenatal psychological distress in a sex-dependent way.

Maternal psychological distress during pregnancy (PPD)1 has been associated with changes in offspring amygdalar and hippocampal volumes. Studies on child amygdalae suggest that sex moderates the vulnerability of fetal brains to prenatal stress. However, this has not yet been observed in these structures in newborns. Newborn studies are crucial, as they minimize the confounding influence of postnatal life. We investigated the effects of maternal prenatal psychological symptoms on newborn amygdalar and hippocampal volumes and their interactions with newborn sex in 123 newborns aged 2-5 weeks (69 males, 54 females). Based on earlier studies, we anticipated small, but statistically significant effects of PPD on the volumes of these structures. Maternal psychological distress was measured at gestational weeks (GW)2 14, 24 and 34 using Symptom Checklist-90 (SCL-90, anxiety scale)3 and Edinburgh Postnatal Depression Scale (EPDS)4 questionnaires. Newborn sex was found to moderate the relationship between maternal distress symptoms at GW 24 and the volumes of left and right amygdala. This relationship was negative and significant only in males. No significant main effect or sex-based moderation was found for hippocampal volumes. This newborn study provides evidence for a sex-dependent influence of maternal psychiatric symptoms on amygdalar structural development. This association may be relevant to later psychopathology.

Maternal Pregnancy-Related Anxiety Is Associated With Sexually Dimorphic Alterations in Amygdala Volume in 4-Year-Old Children.

Prenatal stress is associated with child behavioral outcomes increasing susceptibility for psychiatric disorders in later life. Altered fetal brain development might partly mediate this association, as some studies suggest. With this study, we investigated the relation between prenatal stress, child's brain structure and behavioral problems. The association between self-reported maternal pregnancy-related anxiety (PRAQ-R2 questionnaire, second and third trimester) and brain gray matter volume was probed in 27 4-year-old children (13 female). Voxel based morphometry was applied with an age-matched template in SPM for the whole-brain analyses, and amygdala volume was assessed with manual segmentation. Possible pre- and postnatal confounders, such as maternal depression and anxiety among others, were controlled for. Child behavioral problems were assessed with the Strength and Difficulties Questionnaire by maternal report. We found a significant interaction effect of pregnancy-related anxiety and child's sex on child's amygdala volume, i.e., higher pregnancy-related anxiety in the second trimester was related to significantly greater left relative amygdala volume in girls compared to boys. Further exploratory analyses yielded that both maternal pregnancy-related anxiety and child's amygdala volume are related to child emotional and behavioral difficulties: While higher pregnancy-related anxiety was associated with more emotional symptoms, peer relationship problems and overall child difficulties, greater left amygdala volume was related to less of these child difficulties and might partly mediate sex-specific associations between pregnancy-related anxiety and child behavioral difficulties. Our data suggest that maternal prenatal distress leads to sexually dimorphic structural changes in the offspring's limbic system and that these changes are also linked to behavioral difficulties. Our results provide further support for the notion that prenatal stress impacts child development.