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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

Associations between maternal psychological distress and salivary cortisol during pregnancy: A mixed-models approach.

BACKGROUND: Maternal psychological distress during pregnancy is related to adverse child behavioral and emotional outcomes later in life, such as ADHD and anxiety/depression. The underlying mechanisms for this, however, are still largely unknown. The hypothalamic-pituitary-adrenal (HPA)-axis, with its most important effector hormone cortisol, has been proposed as a mechanism, but results have been inconsistent. The current study investigated the association between maternal psychological distress (i.e. anxiety and depressive symptoms) and maternal cortisol levels during pregnancy using a mixed models approach. METHOD: During three pregnancy trimesters, mothers (N = 170) collected four salivary samples for two consecutive days. Mothers reported symptoms of anxiety and depression three times during pregnancy (at 13.3 ±â€¯1.1, 20.2 ±â€¯1.5, and 33.8 ±â€¯1.5 weeks of pregnancy, respectively) using the anxiety subscale of the Symptom Checklist (SCL-90), the Spielberger State and Trait Anxiety Inventory (STAI), and the Edinburgh Postnatal Depression Scale (EPDS). Specific fears and worries during pregnancy were measured with the short version of the Pregnancy Related Anxiety Questionnaire (PRAQ-R). RESULTS: We found a significant effect of SCL-90 anxiety subscale on cortisol levels at awakening (p = .008), indicating that mothers with higher anxiety showed lower cortisol at awakening. Maternal psychological variables explained 10.5% of the variance at the person level in awakening cortisol level, but none in the overall diurnal cortisol model. CONCLUSION: More research is necessary to unravel the underlying mechanisms of the association between maternal psychological distress and cortisol and the search for mechanisms other than the HPA-axis should be continued and extended.

Exogenously triggered response inhibition in developmental stuttering.

PURPOSE: The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. METHOD: Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). RESULTS: Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. CONCLUSIONS: Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition.

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.

Potential benefits of mindfulness during pregnancy on maternal autonomic nervous system function and infant development.

Mindfulness is known to decrease psychological distress. Possible benefits in pregnancy have rarely been explored. Our aim was to examine the prospective association of mindfulness with autonomic nervous system function during pregnancy and with later infant social-emotional development. Pregnant women (N = 156) completed self-report mindfulness and emotional distress questionnaires, and had their autonomic function assessed in their first and third trimesters, including heart rate (HR), indices of heart rate variability (HRV), preejection period (PEP), and systolic (SBP) and diastolic blood pressure (DBP). The social-emotional development of 109 infants was assessed at 4 months of age. More mindful pregnant women had less prenatal and postnatal emotional distress (p < .001) and higher cardiac parasympathetic activity: root mean square of successive differences (RMSSD: p = .03) and high-frequency (HF) HRV (p = .02). Between the first and third trimesters, women's overall HR increased (p < .001), and HRV (RMSSD, HF HRV, and low-frequency (LF) HRV: p < .001) and PEP decreased (p < .001). In more mindful mothers, parasympathetic activity decreased less (RMSSD: p = .01; HF HRV: p = .03) and sympathetic activity (inversely related to PEP) increased less (PEP: p = .02) between trimesters. Their offspring displayed less negative social-emotional behavior (p = .03) compared to offspring of less mindful mothers. Mindfulness in pregnancy was associated with ANS changes likely to be adaptive and with better social-emotional offspring development. Interventions to increase mindfulness during pregnancy might improve maternal and offspring health, but randomized trials are needed to demonstrate this.

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.

Differences between human auditory event-related potentials (AERPs) measured at 2 and 4 months after birth.

Infant auditory event-related potentials (AERPs) show a series of marked changes during the first year of life. These AERP changes indicate important advances in early development. The current study examined AERP differences between 2- and 4-month-old infants. An auditory oddball paradigm was delivered to infants with a frequent repetitive tone and three rare auditory events. The three rare events included a shorter than the regular inter-stimulus interval (ISI-deviant), white noise segments, and environmental sounds. The results suggest that the N250 infantile AERP component emerges during this period in response to white noise but not to environmental sounds, possibly indicating a developmental step towards separating acoustic deviance from contextual novelty. The scalp distribution of the AERP response to both the white noise and the environmental sounds shifted towards frontal areas and AERP peak latencies were overall lower in infants at 4 than at 2 months of age. These observations indicate improvements in the speed of sound processing and maturation of the frontal attentional network in infants during this period.

Age-related microstructural differences quantified using myelin water imaging and advanced diffusion MRI.

Age-related microstructural differences have been detected using diffusion tensor imaging (DTI). Although DTI is sensitive to the effects of aging, it is not specific to any underlying biological mechanism, including demyelination. Combining multiexponential T2 relaxation (MET2) and multishell diffusion MRI (dMRI) techniques may elucidate such processes. Multishell dMRI and MET2 data were acquired from 59 healthy participants aged 17-70 years. Whole-brain and regional age-associated correlations of measures related to multiple dMRI models (DTI, diffusion kurtosis imaging [DKI], neurite orientation dispersion and density imaging [NODDI]) and myelin-sensitive MET2 metrics were assessed. DTI and NODDI revealed widespread increases in isotropic diffusivity with increasing age. In frontal white matter, fractional anisotropy linearly decreased with age, paralleled by increased "neurite" dispersion and no difference in myelin water fraction. DKI measures and neurite density correlated well with myelin water fraction and intracellular and extracellular water fraction. DTI estimates remain among the most sensitive markers for age-related alterations in white matter. NODDI, DKI, and MET2 indicate that the initial decrease in frontal fractional anisotropy may be due to increased axonal dispersion rather than demyelination.