Children prenatally exposed to maternal anxiety devote more attentional resources to neutral pictures.

Maternal anxiety during pregnancy can negatively affect fetal neurodevelopment, predisposing the offspring to a higher risk of behavioral and emotional problems later in life. The current study investigates the association between maternal anxiety during pregnancy and child affective picture processing using event-related brain potentials (ERPs). Mothers reported anxiety during the second trimester using the anxiety subscale of the Symptom Checklist (SCL-90). At age 4 years, child affective picture processing (N = 86) was measured by recording ERPs during viewing of neutral, pleasant, and unpleasant pictures selected from the International Affective Pictures System. The late positive potential (LPP)-an ERP component reflecting individual differences in affective processing-was used as child outcome. The expected positive association between maternal anxiety and LPP amplitude for unpleasant pictures was not found. Nevertheless, we found a positive association between maternal anxiety during pregnancy and LPP amplitudes for neutral pictures in the middle and late time window at anterior locations (all p < .05). These associations remained significant after adjusting for maternal postnatal anxiety and gestational age at birth and after FDR correction for multiple comparisons. Our study provides neurophysiological evidence that children prenatally exposed to higher maternal anxiety devote more attentional resources to neutral pictures, but not to unpleasant pictures. Possibly, these children show enhanced vigilance for threat when viewing neutral pictures. Although useful in dangerous environments, this enhanced vigilance may predispose children prenatally exposed to higher maternal anxiety to developing behavioral and/or emotional problems later in life. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=kEzYi6IS2HA.

Prenatal stress and the developing brain: Risks for neurodevelopmental disorders.

The prenatal period is increasingly considered as a crucial target for the primary prevention of neurodevelopmental and psychiatric disorders. Understanding their pathophysiological mechanisms remains a great challenge. Our review reveals new insights from prenatal brain development research, involving (epi)genetic research, neuroscience, recent imaging techniques, physical modeling, and computational simulation studies. Studies examining the effect of prenatal exposure to maternal distress on offspring brain development, using brain imaging techniques, reveal effects at birth and up into adulthood. Structural and functional changes are observed in several brain regions including the prefrontal, parietal, and temporal lobes, as well as the cerebellum, hippocampus, and amygdala. Furthermore, alterations are seen in functional connectivity of amygdalar-thalamus networks and in intrinsic brain networks, including default mode and attentional networks. The observed changes underlie offspring behavioral, cognitive, emotional development, and susceptibility to neurodevelopmental and psychiatric disorders. It is concluded that used brain measures have not yet been validated with regard to sensitivity, specificity, accuracy, or robustness in predicting neurodevelopmental and psychiatric disorders. Therefore, more prospective long-term longitudinal follow-up studies starting early in pregnancy should be carried out, in order to examine brain developmental measures as mediators in mediating the link between prenatal stress and offspring behavioral, cognitive, and emotional problems and susceptibility for disorders.

Psychological distress and cognitive coping in pregnant women diagnosed with cancer and their partners.

OBJECTIVE: A cancer diagnosis during pregnancy may be considered as an emotional challenge for pregnant women and their partners. We aimed to identify women and partners at risk for high levels of distress based on their coping profile. METHODS: Sixty-one pregnant women diagnosed with cancer and their partners filled out the Cognitive Emotion Regulation Questionnaire (CERQ) and the newly constructed Cancer and Pregnancy Questionnaire (CPQ). K-means cluster analysis was performed on the CERQ scales. Scores on the CPQ were compared between the women and their partners and between the CERQ-clusters. RESULTS: Comparison of women and partners on the CPQ did not reveal significant differences on distress about the child's health, the cancer disease, and the pregnancy or on information satisfaction (P = .16, P = .44, P = .50, and P = .47, respectively). However, women were more inclined to maintain the pregnancy than their partners (P = .011). Three clusters were retrieved based on the CERQ scales, characterized by positive coping, internalizing coping, and blaming. Women and partners using internalizing strategies had significantly higher scores on concerns about the child's health (P = .039), the disease and treatment (P < .001), and the pregnancy and delivery (P = .009) compared with positive and blaming strategies. No cluster differences were found for information satisfaction (P = .71) and tendency to maintain the pregnancy (P = .35). CONCLUSION: Women and partners using internalizing coping strategies deal with the highest levels of distress and may benefit from additional psychosocial support.

Maternal long-chain polyunsaturated fatty acid status during early pregnancy and children's risk of problem behavior at age 5-6 years.

OBJECTIVE: To prospectively investigate the association between maternal long-chain polyunsaturated fatty acid (LCPUFA) status and ratio during pregnancy and children's risk of problem behavior at 5 years of age. STUDY DESIGN: Maternal LCPUFA status in plasma phospholipids during pregnancy (M = 13.3, SD = 3 weeks) was available for 4336 women. Children's behavior was rated by their mother (n = 2502) and teacher (n = 2061). RESULTS: When using multivariate logistic regression analyses, we found that greater concentrations of omega-3 fatty acid docosahexaenoic acid (OR 0.75; 95% CI 0.56-0.99; P = .05) decreased children's risk for emotional symptoms. Although lower eicosapentaenoic acid and a greater omega-6:omega-3 LCPUFA (ie, arachidonic acid/[docosahexaenoic acid + eicosapentaenoic acid]) tended to increase the risk for emotional symptoms and the risk of hyperactivity/inattention problems for the omega-6:omega-3 LCPUFA, the results were nonsignificant (P = .07). No evidence was found for mediation by preterm birth and being small for gestational age. The child's sex and infant feeding pattern did not modify the associations. CONCLUSION: Our results suggest long-term developmental programming influences of maternal LCPUFA status during pregnancy and stress the importance of an adequate and balanced supply of fatty acids in pregnant women for optimal fetal brain development and subsequent long-term behavioral outcomes.

Current perspectives on perinatal mental health and neurobehavioral development: focus on regulation, coregulation and self-regulation.

PURPOSE OF REVIEW: Perinatal mental health research provides an important perspective on neurobehavioral development. Here, we aim to review the association of maternal perinatal health with offspring neurodevelopment, providing an update on (self-)regulation problems, hypothesized mechanistic pathways, progress and challenges, and implications for mental health. RECENT FINDINGS: (1) Meta-analyses confirm that maternal perinatal mental distress is associated with (self-)regulation problems which constitute cognitive, behavioral, and affective social-emotional problems, while exposure to positive parental mental health has a positive impact. However, effect sizes are small. (2) Hypothesized mechanistic pathways underlying this association are complex. Interactive and compensatory mechanisms across developmental time are neglected topics. (3) Progress has been made in multiexposure studies. However, challenges remain and these are shared by clinical, translational and public health sciences. (4) From a mental healthcare perspective, a multidisciplinary and system level approach employing developmentally-sensitive measures and timely treatment of (self-)regulation and coregulation problems in a dyadic caregiver-child and family level approach seems needed. The existing evidence-base is sparse. SUMMARY: During the perinatal period, addressing vulnerable contexts and building resilient systems may promote neurobehavioral development. A pluralistic approach to research, taking a multidisciplinary approach to theoretical models and empirical investigation needs to be fostered.

Maternal perceived stress and green spaces during pregnancy are associated with adult offspring gene (NR3C1 and IGF2/H19) methylation patterns in adulthood: A pilot study.

BACKGROUND: Changes in NR3C1 and IGF2/H19 methylation patterns have been associated with behavioural and psychiatric outcomes. Maternal mental state has been associated with offspring NR3C1 promotor and IGF2/H19 imprinting control region (ICR) methylation patterns. However, there is a lack of prospective studies with long-term follow-up. METHODS: 52 mother-offspring pairs were studied from 12 to 22 weeks of pregnancy and offspring was followed-up until 28-29 years-of-age. During pregnancy, mothers filled in a Life Event Scale and a Daily Hassles Scale measuring perceived stress; i.e., appraisal or subjectively experienced severity of impact of important life events and of daily hassles in several life domains during pregnancy, respectively. Green space was quantified around the residence, using high-resolution (1 m2) map data. Saliva and blood samples were obtained from the adult offspring. Absolute DNA methylation levels were determined in blood and saliva on four NR3C1 amplicons, and one IGF2/H19 ICR amplicon using a bisulfite PCR and sequencing method. Linear mixed effect models were used to test the associations between perceived stress and green spaces during pregnancy, and adult offspring methylation patterns. RESULTS: We found associations between maternal perceived stress during pregnancy and methylation patterns on two out of the four NR3C1 amplicons, measured in blood, from offspring in adulthood, but not with IGF2/H19 methylation. For an interquartile-range (IQR) increase in maternal perceived life event or daily hassles stress scores, absolute methylation levels on several NR3C1 CpG sites were significantly changed (-1.62 % to +5.89 %, p<0.05). Maternal perceived stress scores were not associated with IGF2/H19 methylation, neither in blood nor in saliva. Maternal exposure to green spaces surrounding the residence during the pregnancy was associated with IGF2/H19 ICR methylation (-0.80 % to -1.04 %, p<0.05) in saliva, but not with NR3C1 promotor methylation. CONCLUSION: We observed significant long-term effects of maternal perceived stress during pregnancy on the methylation patterns of the NR3C1 promotor in offspring well into adulthood. This may imply that maternal psychological distress during pregnancy may influence the regulation of the HPA-axis well into adulthood. Additionally, maternal proximity to green spaces was associated with IGF2/H19 ICR methylation patterns, which is a novel finding.

Psychosocial stress during pregnancy is related to adverse birth outcomes: results from a large multi-ethnic community-based birth cohort.

BACKGROUND: Prevalence rates of psychosocial stress during pregnancy are substantial. Evidence for associations between psychosocial stress and birth outcomes is inconsistent. This study aims to identify and characterize different clusters of pregnant women, each with a distinct pattern of psychosocial stress, and investigate whether birth outcomes differ between these clusters. METHODS: Latent class analysis was performed on data of 7740 pregnant women (Amsterdam Born Children and their Development study). Included constructs were depressive symptoms, state anxiety, job strain, pregnancy-related anxiety and parenting stress. RESULTS: Five clusters of women with distinct patterns of psychosocial stress were objectively identified. Babies born from women in the cluster characterized as 'high depression and high anxiety, moderate job strain' (12%) had a lower birth weight, and those in the 'high depression and high anxiety, not employed' cluster (15%) had an increased risk of pre-term birth. CONCLUSIONS: Babies from pregnant women reporting both high levels of anxiety and depressive symptoms are at highest risk for adverse birth outcomes.

Maternal anxiety during pregnancy is associated with weaker prefrontal functional connectivity in adult offspring.

BACKGROUND: The connectome, constituting a unique fingerprint of a person's brain, may be influenced by its prenatal environment, potentially affecting later-life resilience and mental health. METHODS: We conducted a prospective resting-state functional Magnetic Resonance Imaging study in 28-year-old offspring (N = 49) of mothers whose anxiety was monitored during pregnancy. Two offspring anxiety subgroups were defined: "High anxiety" (n = 13) group versus "low-to-medium anxiety" (n = 36) group, based on maternal self-reported state anxiety at 12-22 weeks of gestation. To predict resting-state functional connectivity of 32 by 32 ROIs, maternal state anxiety during pregnancy was included as a predictor in general linear models for both ROI-to-ROI and graph theoretical metrics. Sex, birth weight and postnatal anxiety were included as covariates. RESULTS: Higher maternal anxiety was associated with weaker functional connectivity of medial prefrontal cortex with left inferior frontal gyrus (t = 3.45, pFDR < 0.05). Moreover, network-based statistics (NBS) confirmed our finding and revealed an additional association of weaker connectivity between left lateral prefontal cortex with left somatosensory motor gyrus in the offspring. While our results showed a general pattern of lower functional connectivity in adults prenatally exposed to maternal anxiety, we did not observe significant differences in global brain networks between groups. CONCLUSIONS: Weaker (medial) prefrontal cortex functional connectivity in the high anxiety adult offspring group suggests a long-term negative impact of prenatal exposure to high maternal anxiety, extending into adulthood. To prevent mental health problems at population level, universal primary prevention strategies should aim at lowering maternal anxiety during pregnancy.

Developmental programming of early brain and behaviour development and mental health: a conceptual framework.

The Developmental Origins of Health and Disease (DOHaD) hypothesis studies the short- and long-term consequences of the conditions of the developmental environment for phenotypic variations in health and disease. Central to this hypothesis is the idea of interdependence of developmental influences, genes, and environment. Developmental programming effects are mediated by alterations in fundamental life functions, and the most enduring effects seem to occur if the main regulatory instances of the organ - the (epi)genome and the brain - are affected. Some new insights in the role of chromatin, in cellular development and differentiation, and neural plasticity from the field of epigenetics are introduced, followed by a section on epigenetics and brain development. It is proposed to extend the DOHaD hypothesis into the 'Developmental Origins of Behaviour, Health, and Disease' (DOBHaD) concept. Pregnancy and the early postnatal period are times of both great opportunity and considerable risk, and their influence can extend over a lifetime. The DOBHaD hypothesis opens fundamental new perspectives on preventing diseases and disorders.

Helping Families of Infants With Persistent Crying and Sleep Problems in a Day-Clinic.

Excessive crying and sleep problems affect up to 30% of infants and often coexist. Although usually benign and self-limiting, persistent crying, and sleep problems exceeding 6 months of age need attention as they may impair the mental health of the infant and its family. The source and the impact of these persistent regulatory problems is often not restricted to the infant, but extends to the parents and the parent-infant relationship. Clinical practice needs interdisciplinary and multi-method interventions focusing beyond regulatory problems of the infant but also on parental self-regulation and parent's co-regulatory responses toward the infant. Treating clinicians may encounter limitations of home-visits, outpatient, and pediatric residential settings when working with families in distress. We describe an infant mental health day-clinic treatment, drawing attention to this viable future direction. It offers a therapeutic climate based on forming a triangle of co-regulation between clinician, parent and infant to first help the parent and the infant settle down. This stress reduction restores parent-infant connectedness and parental learning and reflecting capacity. Clinicians then use established therapeutic modalities to support parental self- and co-regulatory skills which is important for the development of self-regulation in the infant. Experience with this treatment program suggests that a day-clinic setting facilitates interdisciplinary and integrative multi-method intervention, infant and parental stress reduction and integration of parental self- and co-regulatory skills in daily family life, improving overall outcomes. This perspective warrants further investigation.

Epigenetic Modifications Associated with Maternal Anxiety during Pregnancy and Children's Behavioral Measures.

Epigenetic changes are associated with altered behavior and neuropsychiatric disorders and they modify the trajectory of aging. Maternal anxiety during pregnancy is a common environmental challenge for the fetus, causing changes in DNA methylation. Here, we determined the mediating role of DNA methylation and the moderating role of offspring sex on the association between maternal anxiety and children's behavioral measures. In 83 mother-child dyads, maternal anxiety was assessed in each trimester of pregnancy when the child was four years of age. Children's behavioral measures and children's buccal DNA methylation levels (NR3C1, IGF2/H19 ICR, and LINE1) were examined. Higher maternal anxiety during the third trimester was associated with more methylation levels of the NR3C1. Moderating effects of sex on the association between maternal anxiety and methylation were found for IGF2/H19 and LINE1 CpGs. Mediation analysis showed that methylation of NR3C1 could buffer the effects of maternal anxiety on children's behavioral measures, but this effect did not remain significant after controlling for covariates. In conclusion, our data support an association between maternal anxiety during pregnancy and DNA methylation. The results also underscore the importance of sex differences and timing effects. However, DNA methylation as underlying mechanism of the effect of maternal anxiety during pregnancy on offspring's behavioral measures was not supported.

Removal of BCG artifacts from EEG recordings inside the MR scanner: a comparison of methodological and validation-related aspects.

Multimodal approaches are of growing interest in the study of neural processes. To this end much attention has been paid to the integration of electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) data because of their complementary properties. However, the simultaneous acquisition of both types of data causes serious artifacts in the EEG, with amplitudes that may be much larger than those of EEG signals themselves. The most challenging of these artifacts is the ballistocardiogram (BCG) artifact, caused by pulse-related electrode movements inside the magnetic field. Despite numerous efforts to find a suitable approach to remove this artifact, still a considerable discrepancy exists between current EEG-fMRI studies. This paper attempts to clarify several methodological issues regarding the different approaches with an extensive validation based on event-related potentials (ERPs). More specifically, Optimal Basis Set (OBS) and Independent Component Analysis (ICA) based methods were investigated. Their validation was not only performed with measures known from previous studies on the average ERPs, but most attention was focused on task-related measures, including their use on trial-to-trial information. These more detailed validation criteria enabled us to find a clearer distinction between the most widely used cleaning methods. Both OBS and ICA proved to be able to yield equally good results. However, ICA methods needed more parameter tuning, thereby making OBS more robust and easy to use. Moreover, applying OBS prior to ICA can optimize the data quality even more, but caution is recommended since the effect of the additional ICA step may be strongly subject-dependent.

Antenatal maternal anxiety modulates the BOLD response in 20-year-old men during endogenous cognitive control.

Evidence is building for an association between the level of anxiety experienced by a mother during pregnancy and offspring cognition and structural and functional brain correlates. The current study uses fMRI to examine the association between prenatal exposure to maternal anxiety and brain activity associated with endogenous versus exogenous cognitive control in 20-year-old males. Endogenous cognitive control refers to the ability to generate control over decisions, strategies, conflicting information and so on, from within oneself without external signals, while exogenous control is triggered by external signals. In line with previous results of this long-term follow-up study we found that 20-year-olds of mothers reporting high levels of anxiety during weeks 12-22 of pregnancy exhibited a different pattern of decision making in a Gambling paradigm requiring endogenous cognitive control, compared to adults of mothers reporting low to average levels of anxiety. Moreover, the blood oxygenation level dependent (BOLD) response in a number of prefrontal cortical areas was modulated by the level of antenatal maternal anxiety. In particular, a number of right lateralized clusters including inferior frontal junction, that were modulated in the adults of mothers reporting low to average levels of anxiety during pregnancy by a task manipulation of cognitive control, were not modulated by this manipulation in the adults of mothers reporting high levels of anxiety during pregnancy. These differences in brain functional correlates provide a neurobiological underpinning for the hypothesis of an association between exposure to maternal anxiety in the prenatal life period and a deficit in endogenous cognitive control in early adulthood.

The late positive potential (LPP): A neural marker of internalizing problems in early childhood.

BACKGROUND: One potentially relevant neurophysiological marker of internalizing problems (anxiety/depressive symptoms) is the late positive potential (LPP), as it is related to processing of emotional stimuli. For the first time, to our knowledge, we investigated the value of the LPP as a neurophysiological marker for internalizing problems and specific anxiety and depressive symptoms, at preschool age. METHOD: At age 4 years, children (N = 84) passively viewed a series of neutral, pleasant, and unpleasant pictures selected from the International Affective Pictures System. Affective picture processing was measured via the LPP (EEG recorded) and mothers reported on child behavior via the Child Behavior Checklist 1 ½ - 5 (internalizing, DSM-anxiety, DSM-affective/depression subscales). Difference scores between the neutral and affective pictures (i.e., neutral-pleasant and neutral-unpleasant) were computed for posterior, central and anterior brain locations for early (300-700 ms), middle (700-1200 ms) and late (1200-2000 ms) time windows. RESULTS: Greater LPP difference scores for pleasant images in the anterior recording site, in the middle time window, were associated with greater internalizing behaviors. Greater DSM-anxiety symptoms were associated with greater LPP difference scores for unpleasant and pleasant images. After correcting for multiple testing, only the association between greater DSM-affective/depression symptoms and greater LPP difference scores for unpleasant images in the anterior recording site (early time window) remained significant. DISCUSSION: Our study has identified a potential neural marker of preschool internalizing problems. Children with larger LPPs to unpleasant images may be at greater risk of internalizing problems, potentially due to an increased emotional reactivity.

Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy.

Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are: aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system.

Effects of maternal stress and nutrient restriction during gestation on offspring neuroanatomy in humans.

Cognitive and mental health are major determinants of quality of life, allowing integration into society at all ages. Human epidemiological and animal studies indicate that in addition to genetic factors and lifestyle, prenatal environmental influences may program neuropsychiatric disorders in later life. While several human studies have examined the effects of prenatal stress and nutrient restriction on brain function and mental health in later life, potentially mediating effects of prenatal stress and nutrient restriction on offspring neuroanatomy in humans have been studied only in recent years. Based on neuroimaging and anatomical data, we comprehensively review the studies in this emerging field. We relate prenatal environmental influences to neuroanatomical abnormalities in the offspring, measured in utero and throughout life. We also assess the relationship between neuroanatomical abnormalities and cognitive and mental disorders. Timing- and gender-specific effects are considered, if reported. Our review provides evidence for adverse effects of an unfavorable prenatal environment on structural brain development that may contribute to the risk for cognitive, behavioral and mental health problems throughout life.

Comment on 'Prenatal maternal anxiety and children's brain structure and function: A systematic review of neuroimaging studies' (Adamson et al., J Affect Disord 2018, 241, 117-126).

In the review article by Adamson, Letourneau and Lebel (J Affect Disord 2018, 241, 117-126) the article of Mennes, Van den Bergh, Lagae & Stiers (Clin Neurophysiolol 2009, 120, 116-1122) was rated as "weak, due to lack of information provided regarding the sample population of mothers". However, Mennes et al. (2009) had referred to previous articles describing data and results of earlier waves. Unfortunately, this went unnoticed, most probably because of the use of an automatic extraction method and/or inaccurate verification of the data extraction tool. Moreover, Adamson et al. (2018) omit in Table 1 and in several sections of the text, crucial information that was provided in Mennes et al. (2009), pertaining to measurement of maternal state and trait anxiety, measurement of maternal anxiety at three times during pregnancy and the use of postnatal maternal trait anxiety as a control variable. In this letter we have clarified why the manuscript of Mennes et al. (2009) was not fully appreciated and kindly ask the authors of the review paper to add a corrigendum in which the remarks are considered.

Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood.

Depressive symptomatology can proceed from altered hypothalamic-pituitary-adrenocortex (HPA)-axis function. Some authors stress the role that early life stress (ELS) may play in the pathophysiology of depressive symptoms. However, the involvement of the HPA-axis in linking prenatal ELS with depressive symptoms has not been tested in a prospective-longitudinal study extending until after puberty in humans. Therefore, we examined whether antenatal maternal anxiety is associated with disturbances in HPA-axis regulation and whether the HPA-axis dysregulation mediates the association between antenatal maternal anxiety and depressive symptoms in post-pubertal adolescents. As part of a prospective-longitudinal study, we investigated maternal anxiety at 12-22, 23-32, and 32-40 weeks of pregnancy (wp) with the State Trait Anxiety Inventory (STAI). In the 14-15-year-old offspring (n=58) HPA-axis function was measured through establishing a saliva cortisol day-time profile. Depressive symptoms were measured with the Children's Depression symptoms Inventory (CDI). Results of regression analyses showed that antenatal exposure to maternal anxiety at 12-22 wp was in both sexes associated with a high, flattened cortisol day-time profile (P=0.0463) which, in female adolescents only, was associated with depressive symptoms (P=0.0077). All effects remained after controlling for maternal smoking, birth weight, obstetrical optimality, maternal postnatal anxiety and puberty phase. Our prospective study demonstrates, for the first time, the involvement of the HPA-axis in the link between antenatal maternal anxiety/prenatal ELS and depressive symptoms for post-pubertal female adolescents.