Preconception maternal posttraumatic stress and child negative affectivity: Prospectively evaluating the intergenerational impact of trauma.

The developmental origins of psychopathology begin before birth and perhaps even prior to conception. Understanding the intergenerational transmission of psychopathological risk is critical to identify sensitive windows for prevention and early intervention. Prior research demonstrates that maternal trauma history, typically assessed retrospectively, has adverse consequences for child socioemotional development. However, very few prospective studies of preconception trauma exist, and the role of preconception symptoms of posttraumatic stress disorder (PTSD) remains unknown. The current study prospectively evaluates whether maternal preconception PTSD symptoms predict early childhood negative affectivity, a key dimension of temperament and predictor of later psychopathology. One hundred and eighteen women were recruited following a birth and prior to conception of the study child and were followed until the study child was 3-5 years old. Higher maternal PTSD symptoms prior to conception predicted greater child negative affectivity, adjusting for concurrent maternal depressive symptoms and sociodemographic covariates. In exploratory analyses, we found that neither maternal prenatal nor postpartum depressive symptoms or perceived stress mediated this association. These findings add to a limited prospective literature, highlighting the importance of assessing the mental health of women prior to conception and providing interventions that can disrupt the intergenerational sequelae of trauma.

Infant negative affectivity and patterns of affect-biased attention.

Biased attention toward affective cues often cooccurs with the emergence and maintenance of internalizing disorders. However, few studies have assessed whether affect-biased attention in infancy relates to early indicators of psychopathological risk, such as negative affectivity. The current study evaluates whether negative affectivity relates to affect-biased attention in 6-month-old infants. Affect-biased attention was assessed via a free-viewing eye-tracking task in which infants were presented with a series of face pairs (comprised of a happy, angry, or sad face and a neutral face). Attention was quantified with metrics of both attention orienting and attention holding. Overall, infants showed no differences in attention orienting (i.e., speed of looking) or attention holding (i.e., duration of looking) toward emotional faces in comparison to the neutral face pairs. Negative affectivity, assessed via parent report, did not relate to attention orienting but was associated with biased attention toward positive, happy faces and away from threat-cueing, angry faces in comparison to the neutral faces they were paired with. These findings suggest that negative affectivity is associated with differences in attention holding, but not initial orienting toward emotional faces; biases which have important implications for the trajectory of socioemotional development.

Maternal caregiving ameliorates the consequences of prenatal maternal psychological distress on child development.

Children exposed to prenatal maternal psychological distress are at elevated risk for a range of adverse outcomes; however, it remains poorly understood whether postnatal influences can ameliorate impairments related to prenatal distress. The current study evaluated if sensitivematernal care during the first postnatal year could mitigate child cognitive and emotional impairments associated with prenatal psychological distress. Prenatal maternal psychological distress was assessed via self-reports of anxiety, depression, and perceived stress for 136 mothers at five prenatal and four postpartum time points. Quality of maternal care (sensitivity to nondistress, positive regard, and intrusiveness reverse-scored) were assessed during a mother-child play interaction at 6 and 12 months. Child cognitive function and negative emotionality were assessed at 2 years, using The Bayley Scales and the Early Childhood Behavior Questionnaire. Elevated prenatal distress was associated with poorer child cognitive function and elevated negative emotionality. Children exposed to elevated prenatal maternal distress did not, however, display these outcomes if they received high-quality caregiving. Specifically, maternal care moderated the relation between prenatal psychological distress and child cognitive function and negative emotionality. This association remained after consideration of postnatal maternal psychological distress and relevant covariates. Sensitive maternal care was associated with altered offspring developmental trajectories, supporting child resilience following prenatal distress exposure.

Maternal Depressive Symptoms Predict General Liability in Child Psychopathology.

Objective: The current study examines how maternal depressive symptoms relate to child psychopathology when structured via the latent bifactor model of psychopathology, a new organizational structure of psychopathological symptoms consisting of a general common psychopathology factor (p-factor) and internalizing- and externalizing-specific risk.Method: Maternal report of depressive symptoms (Beck Depression Inventory - II) and child psychopathological symptoms (Child Behavior Checklist and Children's Behavior Questionnaire) were provided by 554 mother-child pairs. Children in the sample were 7.7 years old on average (SD = 1.35, range = 5-11 years), and were 49.8% female, 46% Latinx, and 67% White, 6% Black, 5% Asian/Pacific Islander, and 21% multiracial.Results: Maternal depressive symptoms were positively associated with the child p-factor but not with the internalizing- or externalizing-specific factors. We did not find evidence of sex/gender or race/ethnicity moderation when using latent factors of psychopathology. Consistent with past research, maternal depressive symptoms were positively associated with internalizing and externalizing composite scores on the Child Behavior Checklist.Conclusions: Findings suggest that maternal depressive symptoms are associated with transdiagnostic risk for broad child psychopathology (p-factor). Whereas the traditional Achenbach-style approach of psychopathological assessment suggests that maternal depressive symptoms are associated with both child internalizing and externalizing problems, the latent bifactor model suggests that these associations may be accounted for by risk pathways related to the p-factor rather than internalizing or externalizing specific risk. We discuss clinical and research implications of using a latent bifactor structure of psychopathology to understand how maternal depression may impact children's mental health.

Does Prenatal Maternal Distress Contribute to Sex Differences in Child Psychopathology?

PURPOSE OF REVIEW: Prenatal maternal psychological distress is an established risk factor for the development of psychopathology in offspring. The purpose of this review is to evaluate whether sex differences in fetal responses to maternal distress contribute to sex differences in subsequent psychopathology. RECENT FINDINGS: Male and female fetuses respond differently to stress signals. We review recent evidence that demonstrates a sex-specific pattern of association between prenatal maternal distress and pathways associated with risk for psychopathology including offspring hypothalamic pituitary adrenocortical (HPA) axis regulation, brain development, and negative emotionality. Prenatal maternal distress exerts sex-specific consequences on the fetus. These differences may contribute to the well-established sex differences in psychopathology and in particular to greater female vulnerability to develop internalizing problems.

An experimental test of the fetal programming hypothesis: Can we reduce child ontogenetic vulnerability to psychopathology by decreasing maternal depression?

Maternal depression is one of the most common prenatal complications, and prenatal maternal depression predicts many child psychopathologies. Here, we apply the fetal programming hypothesis as an organizational framework to address the possibility that fetal exposure to maternal depressive symptoms during pregnancy affects fetal development of vulnerabilities and risk mechanisms, which enhance risk for subsequent psychopathology. We consider four candidate pathways through which maternal prenatal depression may affect the propensity of offspring to develop later psychopathology across the life span: brain development, physiological stress regulation (hypothalamic-pituitary-adrenocortical axis), negative emotionality, and cognitive (effortful) control. The majority of past research has been correlational, so potential causal conclusions have been limited. We describe an ongoing experimental test of the fetal programming influence of prenatal maternal depressive symptoms using a randomized controlled trial design. In this randomized controlled trial, interpersonal psychotherapy is compared to enhanced usual care among distressed pregnant women to evaluate whether reducing prenatal maternal depressive symptoms has a salutary impact on child ontogenetic vulnerabilities and thereby reduces offspring's risk for emergence of later psychopathology.

Maternal depression and cortisol in pregnancy predict offspring emotional reactivity in the preschool period.

Prenatal exposures to higher levels of maternal cortisol and depression have been linked to a variety of adverse physiological, neurological, and behavioral outcomes, such as dysregulated cortisol production, structural and functional differences in limbic areas of the brain, and greater negative emotionality. This study investigated prospective associations between maternal prepartum depression/cortisol levels and offspring emotional reactivity in 163 mother-child pairs. Women were assessed repeatedly during pregnancy, and later participated in a laboratory visit with their preschool-aged children. Mothers self-reported on depressive symptomatology during pregnancy and provided saliva samples for cortisol assay. Offspring emotional reactivity was assessed through multiple measures, including caregiver reports, cortisol response following a stressor, and laboratory observations of behavior. The findings suggest potential prenatal timing effects, with depression and maternal cortisol measured in the first and second trimesters being more strongly associated with child emotional reactivity. Sex was found to moderate associations between maternal prepartum depression/cortisol and child emotional reactivity, with the general pattern reflecting positive associations in girls, and negative associations in boys.

Venezuelan Equine Encephalitis Virus Induces Apoptosis through the Unfolded Protein Response Activation of EGR1.

UNLABELLED: Venezuelan equine encephalitis virus (VEEV) is a previously weaponized arthropod-borne virus responsible for causing acute and fatal encephalitis in animal and human hosts. The increased circulation and spread in the Americas of VEEV and other encephalitic arboviruses, such as eastern equine encephalitis virus and West Nile virus, underscore the need for research aimed at characterizing the pathogenesis of viral encephalomyelitis for the development of novel medical countermeasures. The host-pathogen dynamics of VEEV Trinidad donkey-infected human astrocytoma U87MG cells were determined by carrying out RNA sequencing (RNA-Seq) of poly(A) and mRNAs. To identify the critical alterations that take place in the host transcriptome following VEEV infection, samples were collected at 4, 8, and 16 h postinfection and RNA-Seq data were acquired using an Ion Torrent PGM platform. Differential expression of interferon response, stress response factors, and components of the unfolded protein response (UPR) was observed. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm of the UPR was activated, as the expression of both activating transcription factor 4 (ATF4) and CHOP (DDIT3), critical regulators of the pathway, was altered after infection. Expression of the transcription factor early growth response 1 (EGR1) was induced in a PERK-dependent manner. EGR1(-/-) mouse embryonic fibroblasts (MEFs) demonstrated lower susceptibility to VEEV-induced cell death than isogenic wild-type MEFs, indicating that EGR1 modulates proapoptotic pathways following VEEV infection. The influence of EGR1 is of great importance, as neuronal damage can lead to long-term sequelae in individuals who have survived VEEV infection. IMPORTANCE: Alphaviruses represent a group of clinically relevant viruses transmitted by mosquitoes to humans. In severe cases, viral spread targets neuronal tissue, resulting in significant and life-threatening inflammation dependent on a combination of virus-host interactions. Currently there are no therapeutics for infections cause by encephalitic alphaviruses due to an incomplete understanding of their molecular pathogenesis. Venezuelan equine encephalitis virus (VEEV) is an alphavirus that is prevalent in the Americas and that is capable of infecting horses and humans. Here we utilized next-generation RNA sequencing to identify differential alterations in VEEV-infected astrocytes. Our results indicated that the abundance of transcripts associated with the interferon and the unfolded protein response pathways was altered following infection and demonstrated that early growth response 1 (EGR1) contributed to VEEV-induced cell death.

Temporal dynamics of neurobehavioral hormone sensitivity in a scaled-down experimental model of early pregnancy and parturition.

The hormonal changes of pregnancy and parturition can trigger robust changes in affective state, particularly among patients with a history of postpartum depression. However, more work is needed to elucidate the temporal dynamics of symptom emergence. The current study explored how quickly hormone-sensitive (HS+) individuals can be differentiated from hormone-insensitive (HS-) controls in the context of a tightly controlled experimental hormone manipulation, and which symptoms demonstrate the most rapid, consistent, and largest response during this protocol. Participants were female, non-pregnant, and euthymic, with a history of DSM-5 major depressive episode with peripartum onset (n = 15) or parous healthy controls with no psychiatric history (n = 15). Perinatal hormonal changes were simulated by inducing hypogonadism, adding back estradiol (E2) and progesterone (P4) to reach first-trimester levels for 8 weeks, and then subsequently withdrawing both hormones. Those reporting a 30% or greater increase during addback or withdrawal on select subscales of the Inventory of Depression and Anxiety Symptoms (IDAS) were identified as HS+. Participants provided daily ratings of symptoms throughout the study via the Daily Record of Severity of Problems. Results indicated that HS+ participants could be differentiated from HS- participants early in the hormone protocol, with many symptoms showing significantly greater change from baseline within the first week of addback. Notably, the most rapid symptom increases were observed for Anger/Irritability, Mood Swings, Overwhelm, Lethargy, Increased Appetite, Joint and Muscle Pain, and Breast Tenderness, reaching 50% of peak group contrast within the first week of hormone addback. The largest group effects were observed for Anger/Irritability, followed by Fatigue and Anxiety, and the most consistent group effects were observed for Anger/Irritability, Interpersonal Conflict, Overwhelm, and Hopelessness. Findings support the role of reproductive hormones in the onset of perinatal affective disorders. The rapid emergence of anger and irritability in HS+ participants suggests that these symptoms may be early indicators of perinatal hormone sensitivity.

Maternal anxiety during pregnancy predicts infant attention to affective faces.

BACKGROUND: Prenatal maternal anxiety is a known influence on offspring development. General anxiety and pregnancy-related anxiety (a distinct type of anxiety encompassing fears associated with pregnancy) are associated with offspring socioemotional development, with potential consequences for later emotional and behavioral problems. This study examines whether maternal pregnancy-related and general anxiety relate to infant attention to affective faces, a process which plays an integral role in early socioemotional development. METHODS: Participants included 86 mothers and their 6-month-old infants (56.3 % female). Mothers completed measures of pregnancy-related and general anxiety three times through gestation. Infants' attention to affective faces was assessed with an eye-tracking task during which a series of face pairs were presented (happy, angry, or sad face paired with a neutral face). Overall attention measures included attention-holding (total looking time) and attention-orienting (latency to faces); affect-biased attention measures included proportion of total looking time to emotional faces and latency difference score. RESULTS: Higher maternal pregnancy-related anxiety across gestation predicted decreased infant attention-holding to affective faces [F(1,80) = 7.232, p = .009, partial η2 = 0.083]. No differences were found in infant attention-orienting or affect-biased attention. LIMITATIONS: Reliance on a correlational study design precludes the ability to make causal inferences. CONCLUSIONS: Maternal pregnancy-related anxiety is an important predictor of child outcomes. We provide novel evidence that pregnancy-related anxiety predicts infant attention to emotional faces, behaviors which have important implications for socioemotional development. Providers may consider pregnancy-related anxiety as a target for screening and treatment that may benefit both pregnant individual and offspring.

Across ages and places: Unpredictability of maternal sensory signals and child internalizing behaviors.

BACKGROUND: Patterns of sensory inputs early in life play an integral role in shaping the maturation of neural circuits, including those implicated in emotion and cognition. In both experimental animal models and observational human research, unpredictable sensory signals have been linked to aberrant developmental outcomes, including poor memory and effortful control. These findings suggest that sensitivity to unpredictable sensory signals is conserved across species and sculpts the developing brain. The current study provides a novel investigation of unpredictable maternal sensory signals in early life and child internalizing behaviors. We tested these associations in three independent cohorts to probe the generalizability of associations across continents and cultures. METHOD: The three prospective longitudinal cohorts were based in Orange, USA (n = 163, 47.2 % female, Mage = 1 year); Turku, Finland (n = 239, 44.8 % female, Mage = 5 years); and Irvine, USA (n = 129, 43.4 % female, Mage = 9.6 years). Unpredictability of maternal sensory signals was quantified during free-play interactions. Child internalizing behaviors were measured via parent report (Orange & Turku) and child self-report (Irvine). RESULTS: Early life exposure to unpredictable maternal sensory signals was associated with greater child fearfulness/anxiety in all three cohorts, above and beyond maternal sensitivity and sociodemographic factors. The association between unpredictable maternal sensory signals and child sadness/depression was relatively weaker and did not reach traditional thresholds for statistical significance. LIMITATIONS: The correlational design limits our ability to make causal inferences. CONCLUSIONS: Findings across the three diverse cohorts suggest that unpredictable maternal signals early in life shape the development of internalizing behaviors, particularly fearfulness and anxiety.

Hormone sensitivity predicts the beneficial effects of transdermal estradiol on reward-seeking behaviors in perimenopausal women: A randomized controlled trial.

Depression is highly prevalent during the menopause transition (perimenopause), and often presents with anxious and anhedonic features. This increased vulnerability for mood symptoms is likely driven in part by the dramatic hormonal changes that are characteristic of the menopause transition, as prior research has linked fluctuations in estradiol (E2) to emergence of depressed mood in at risk perimenopausal women. Transdermal estradiol (TE2) has been shown to reduce the severity of depression in clinically symptomatic women, particularly in those with recent stressful life events. This research extends prior work by examining the relation between E2 and reward seeking behaviors, a precise behavioral indicator of depression. Specifically, the current study utilizes a randomized, double blind, placebo-controlled design to investigate whether mood sensitivity to E2 flux ("hormone sensitivity") predicts the beneficial effects of TE2 interventions on reward seeking behaviors in perimenopausal women, and whether recent stressful life events moderate any observed associations. METHOD: Participants were 66 women who met standardized criteria for being early or late perimenopausal based on bleeding patterns. Participants were recruited from a community sample; therefore, mood symptoms varied across the continuum and the majority of participants did not meet diagnostic criteria for a depressive or anxiety disorder at the time of enrollment. Hormone sensitivity was quantified over an 8-week baseline period, using within-subjects correlations between repeated weekly measures of E2 serum concentrations and weekly anxiety (State Trait Anxiety Inventory) and anhedonia ratings (Snaith-Hamilton Pleasure Scale). Women were then randomized to receive 8 weeks of TE2 (0.1 mg) or transdermal placebo, and reward-seeking behaviors were assessed using the Effort-Expenditure for Rewards Task (EEfRT). RESULTS: Participants who were randomized to receive transdermal estradiol and who demonstrated greater anxiety sensitivity to E2 fluctuations at baseline, demonstrated more reward seeking behaviors on the EEfRT task. Notably, the strength of the association between E2-anxiety sensitivity and post-randomization EEfRT for TE2 participants increased when women experienced more recent stressful life events and rated those events as more stressful. E2-anhedonia sensitivity was not associated with reward-seeking behaviors. CONCLUSION: Perimenopausal women who are more sensitive to E2 fluctuations and experienced more recent life stress may experience a greater benefit of TE2 as evidenced by an increase in reward seeking behaviors.

Can Placental Corticotropin-Releasing Hormone Inform Timing of Antenatal Corticosteroid Administration?

Context: Antenatal corticosteroids are commonly administered to pregnant women at risk for delivering between 23 and 34 gestational weeks; they provide crucial benefits to fetal lung maturation and reduce risk for neonatal morbidity and mortality. Corticosteroids are maximally efficacious for lung maturation when administered within 2 to 7 days of delivery. Accurately identifying the timing of preterm delivery is thus critical to ensure that antenatal corticosteroids are administered within a week of delivery and to avoid unnecessary administration to women who will deliver at term. A plausible biomarker for predicting time of delivery is placental corticotropin-releasing hormone (pCRH). Objective: To assess whether pCRH concentrations predict time to delivery and specifically which women will deliver within a week of treatment. Design: pCRH concentrations were evaluated before administration of the corticosteroid betamethasone, and timing of delivery was recorded. Participants: A total of 121 women with singleton pregnancies who were prescribed betamethasone. Results: Elevated pCRH concentrations were associated with a shorter time from treatment to delivery. Receiver-operating characteristic curves revealed that pCRH may improve the precision of predicting preterm delivery. Conclusions: In the current sample, pCRH concentrations predicted the likelihood of delivering within 1 week of corticosteroid treatment. Current findings suggest that pCRH may be a diagnostic indicator of impending preterm delivery. Increasing the precision in predicting time to delivery could inform when to administer antenatal corticosteroids, thus maximizing benefits and reducing the likelihood of exposing fetuses who will be delivered at term.

Exposure to traumatic events in childhood predicts cortisol production among high risk pregnant women.

Childhood exposure to traumatic events has a profound and disruptive impact on mental and physical health, including stress physiology. In the current study, we evaluate 90 pregnant women at risk for preterm delivery and assess the association between history of exposure to traumatic events and hair cortisol concentrations, an integrated measure of cortisol production. Exposure to more traumatic events in childhood and in adulthood independently predicted elevated hair cortisol concentrations in pregnancy. Notably, the impact of childhood exposure to traumatic events remained after accounting for more proximal traumatic events in adulthood. Further, there was a significant interaction between childhood and adult exposures. Traumatic experiences in adulthood were more strongly associated with hair cortisol concentrations among mothers with a history of greater childhood trauma. Findings suggest that not only do proximal adult exposures impact HPA-axis functioning during pregnancy, but that childhood traumatic experiences have persisting consequences for HPA-axis functioning during pregnancy. Maternal HPA-axis dysregulation in pregnancy has consequences for both maternal health and for fetal development. Therefore, we consider prenatal maternal HPA-axis functioning as a potential biological pathway underlying intergenerational consequences of childhood trauma.