Karen Grewen

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Perinatal depression affects more than 400,000 mother-child dyads in the US every year and is associated with numerous adverse maternal and child developmental outcomes. Prior research implicates the dysregulation of oxytocin (OT) and hypothalamic-pituitary-adrenal (HPA) axis functioning in mothers and children as potential mechanisms mediating or moderating the transmission of risk associated with maternal depression. Objective: The Mood, Mother and Child (MMC) Study will examine psychobiological sources of risk and resilience within mother-child dyads affected by maternal depression. This manuscript describes (1) the study rationale and aims; (2) the research design and procedures and how they were altered in response to the Covid-19 pandemic, and (3) the data analysis plan to test study hypotheses. Methods: This is a prospective longitudinal study with an embedded randomized control trial that examines (1) correlations between postpartum depression and anxiety symptoms (PDAS), maternal and child OT and HPA axis functioning, and child developmental outcomes; and (2) the causal relationship between causal relationships between exogenous OT and HPA reactivity. This study is funded by the National Institute of Child Health and Human Development with Institutional Review Board approval. Results: Recruitment and data collection have commenced, and the expected results will be available in 2024. Analyses are presented for testing the proposed hypotheses. Conclusions: The unique combination of prospective longitudinal research design with an embedded RCT will allow the MMC Study to apply a developmental lens to the study of maternal depression and anxiety symptoms from birth through middle childhood and the psychobiological mechanisms promoting risk and resiliency for both mother and child outcomes. This will be the first study that simultaneously evaluates (1) the role of oxytocin using multiple methodologies, (2) the causal relationships between exogenous OT and HPA axis functioning among mothers at differing levels of depression and anxiety symptoms, and (3) the multiple mediating and moderating roles of parenting behaviors and maternal and child psychobiological characteristics. The goals of these aims is to provide insights into the psychobiological effects of OT in women and to inform future clinical trials to treat perinatal mood disorders Clinical Trial: This studyis registered with Clinical Trials.gov (NCT03593473).

BACKGROUND Perinatal depression affects >400,000 mother-child dyads in the United States every year and is associated with numerous adverse maternal and child developmental outcomes. Previous research implicates the dysregulation of oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis functioning in mothers and children as potential mechanisms mediating or moderating the transmission of risk associated with maternal depression. OBJECTIVE The Mood, Mother and Child study will examine the psychobiological sources of risk and resilience within mother-child dyads affected by maternal depression. This manuscript describes (1) the study rationale and aims, (2) the research design and procedures and how they were altered in response to the COVID-19 pandemic, and (3) the data analysis plan to test the study hypotheses. METHODS This is a prospective longitudinal study with an embedded randomized controlled trial that examines (1) correlations among postpartum depression and anxiety symptoms, maternal and child oxytocin and HPA axis functioning, and child developmental outcomes and (2) the causal relationship between exogenous oxytocin and HPA reactivity. This study is funded by the National Institute of Child Health and Human Development with institutional review board approval. RESULTS Recruitment and data collection have commenced, and the expected results will be available in 2024. Analyses are presented for testing the proposed hypotheses. CONCLUSIONS The unique combination of a prospective longitudinal research design with an embedded randomized controlled trial will allow the Mood, Mother and Child study to apply a developmental lens to the study of maternal depression and anxiety symptoms from birth to middle childhood and the psychobiological mechanisms promoting risk and resiliency for both mother and child outcomes. This will be the first study that simultaneously evaluates (1) the role of oxytocin using multiple methodologies, (2) the causal relationships between exogenous oxytocin and HPA axis functioning among mothers with differing levels of depression and anxiety symptoms, and (3) the multiple mediating and moderating roles of parenting behaviors and maternal and child psychobiological characteristics. The goals of these aims are to provide insights into the psychobiological effects of oxytocin in women and inform future clinical trials to treat perinatal mood disorders. CLINICALTRIAL ClinicalTrials.gov NCT03593473; https://classic.clinicaltrials.gov/ct2/show/NCT03593473 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/51132

Altered functional connectivity has been reported in infants with prenatal exposure to opioids, which significantly interrupts and influences endogenous neurotransmitter/receptor signaling during fetal programming. Better birth outcomes and long-term developmental outcomes are associated with medication for opioid use disorder (MOUD) during pregnancy, but the neural mechanisms underlying these benefits are largely unknown. We aimed to characterize effects of prenatal opioid/other drug exposure (PODE) and the neural basis for the reported beneficial effects of MOUD by examining neonatal brain functional organization. A cohort of 109 human newborns, 42 PODE, 39 with prenatal exposure to drugs excluding opioids (PDE), 28 drug-free controls (males and females) underwent resting-state fMRI at 2 weeks of age. To examine neural effects of MOUD, PODE infants were separated into subgroups based on whether mothers received MOUD (n= 31) or no treatment (n= 11). A novel heatmap analysis was designed to characterize PODE-associated functional connectivity alterations and MOUD-related effects, and permutation testing identified regions of interest with significant effects. PODE neonates showed alterations beyond those associated with PDE, particularly in reward-related frontal-sensory connectivity. MOUD was associated with a significant reduction of PODE-related alterations in key regions of endogenous opioid pathways including limbic and frontal connections. However, significant residual effects in limbic and subcortical circuitry were observed. These findings confirm altered brain functional organization associated with PODE. Importantly, widespread normalization effects associated with MOUD reveal, for the first time, the potential brain basis of the beneficial effects of MOUD on the developing brain and underscore the importance of this treatment intervention for better developmental outcomes.SIGNIFICANCE STATEMENTThis is the first study to reveal the potential neural mechanisms underlying the beneficial effects on the neonate brain associated with MOUD during pregnancy. We identified both normalization and residual effects of MOUD on brain functional architecture by directly comparing neonates prenatally exposed to opioids with MOUD and those exposed to opioids but without MOUD. Our findings confirm altered brain functional organization associated with prenatal opioid exposure and demonstrate that although significant residual effects remain in reward circuitry, MOUD confers significant normalization effects on functional connectivity of regions associated with socioemotional development and reward processing. Together, our results highlight the importance of MOUD intervention for better neurodevelopmental outcomes.

Although stress is a strong risk factor for poor health, especially for women, it remains unclear how stress affects the key neurohormones cortisol and oxytocin, which influence stress-related risk and resilience. Whereas cortisol mediates energy mobilization during stress, oxytocin has anti-inflammatory, anxiolytic, and analgesic effects that support social connection and survival across the lifespan. However, how these neurohormones interrelate and are associated with cognitive control of emotional information during stress remains unclear. To address these issues, we recruited 37 college-aged women (M_age = 19.19, SD = 1.58) and randomly assigned each to a one-hour experimental session consisting of either an acute stress (emotionally stressful video) or control (non-stressful video) condition in a cross-sectional manner across the semester. Salivary cortisol and oxytocin samples were collected at baseline and after the video, at which point participants also completed measures assessing affect and an emotional Stroop task. As hypothesized, the emotional stressor induced negative emotions that were associated with significant elevations in cortisol and faster Stroop reaction times. Moreover, higher baseline oxytocin predicted greater positive affect after the stressor and also better cognitive accuracy on the Stroop. Analyses examining the naturalistic stress effects revealed that basal oxytocin levels rose steeply three weeks before the semester’s end, followed by rising cortisol levels one week later, with both neurohormones remaining elevated through the very stressful final exam period. Considered together, these data suggest that women’s collective experiences of stress may be potentially buffered by a synchronous oxytocin surge that enhances cognitive accuracy and reduces stress “when the going gets tough”.

Prenatal drug exposure (PDE) is known to affect fetal brain development with documented long‐term consequences. Most studies of PDE effects on the brain are based on animal models. In this study, based on a large sample of 133 human neonates and leveraging a novel linear mixed‐effect model designed for intersubject variability analyses, we studied the effects of six prenatally exposed drugs (i.e., nicotine, alcohol, selective serotonin reuptake inhibitor, marijuana, cocaine, and opioids) on neonatal whole‐brain functional organization and compared them with five other critical nondrug variables (i.e., gestational age at birth/scan, sex, birth weight, and maternal depression). The behavioral implications were also examined. Magnitude‐wise, through summing across individual drug effects, our results highlighted ~5% of whole‐brain functional connections (FCs) affected by PDE, which was highly comparable with the combined effects of the five nond rug variables. Spatially, the detected PDE effects featured drug‐specific patterns with a common bias in higher‐order brain regions/networks. Regarding brain–behavioral relationships, the detected connections showing significant drug effects also demonstrated significant correlations with 3‐month behavioral outcomes. Further mediation analyses supported a mediation role of the detected brain FCs between PDE status and cognitive/language outcomes. Our findings of widespread, and spatially biased PDE effect patterns coupled with significant behavioral implications may hopefully stimulate more human‐based studies into effects of PDE on long‐term developmental outcomes.

Prenatal nicotine exposure (PNE) from maternal cigarette smoking is linked to developmental deficits, including impaired auditory processing, language, generalized intelligence, attention, and sleep. Fetal brain undergoes massive growth, organization, and connectivity during gestation, making it particularly vulnerable to neurotoxic insult. Nicotine binds to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity, and function of developing neural circuitry and neurotransmitter systems. Thus, PNE may have long-term impact on neurobehavioral development. The purpose of this study was to compare the auditory K-complex, an event-related potential reflective of auditory gating, sleep preservation and memory consolidation during sleep, in infants with and without PNE and to relate these neural correlates to neurobehavioral development. We compared brain responses to an auditory paired-click paradigm in 3- to 5-month-old infants during Stage 2 sleep, when the K-complex is best observed. We measured component amplitude and delta activity during the K-complex. Infants with PNE demonstrated significantly smaller amplitude of the N550 component and reduced delta-band power within elicited K-complexes compared to nonexposed infants and also were less likely to orient with a head turn to a novel auditory stimulus (bell ring) when awake. PNE may impair auditory sensory gating, which may contribute to disrupted sleep and to reduced auditory discrimination and learning, attention re-orienting, and/or arousal during wakefulness reported in other studies. Links between PNE and reduced K-complex amplitude and delta power may represent altered cholinergic and GABAergic synaptic programming and possibly reflect early neural bases for PNE-linked disruptions in sleep quality and auditory processing. These may pose significant disadvantage for language acquisition, attention, and social interaction necessary for academic and social success.