Lauren M. Ellman - US grants

DESCRIPTION (provided by applicant): The proposed project aims to investigate how maternal stress during pregnancy, maternal inflammation during pregnancy and fetal hypoxia (lack of oxygen to the fetus) influence the risk of symptoms of depression during adolescence in offspring. A secondary aim is to map trajectories of how these prenatal risk factors result in a cascade of events, leading to altered developmental trajectories in emotional, cognitive, and behavioral outcomes during childhood and subsequent depression during adolescence. The proposed project is based on a large birth cohort study, the Child Health and Development Study (CHDS), that followed women prospectively throughout their pregnancies from 1959-1966 and acquired detailed information on the mothers' experiences, health-risk behaviors, and medical complications during pregnancy and delivery. This information included maternal responses to open-ended questions about concerns or worries within the past year and feelings about the pregnancy. Multiple sera samples were collected from mothers throughout their pregnancies and archived at -20oC. Offspring were administered cognitive, behavioral, and psychological assessments at ages 5, 9, and 15. The present study will include 750 mothers and their offspring who have complete data at each time point. Serological analyses will be conducted on archived prenatal sera from the first and second trimesters of pregnancy in order to measure biomarkers of maternal stress during pregnancy (i.e. cortisol), maternal levels of inflammatory proteins, termed cytokines, (the soluble receptors for IL-1¿ and TNF-¿ and the cytokines IL-8 and IL-6), and markers of fetal hypoxia (VEGF). Further, prospectively collected labor and delivery information will be used for additional measures of fetal hypoxia. In addition, the present study will qualitatively code stress-related themes from narratives acquired in response to the aforementioned open- ended questions and geocode neighborhood-level contextual factors for each subject. The specific aims are as follows: 1) to investigate the contributions of fetal exposure to maternal stress and stress hormones to risk of depression in adolescent offspring, 2) to investigate whether there are intermediate childhood emotional and behavioral phenotypes, as well as altered cognitive trajectories between fetal exposure to maternal stress during pregnancy and subsequent depression in adolescence, and 3) to investigate whether fetal exposure to elevated levels of maternal stress adds to or interacts with other pre- and perinatal complications to increase risk for neurodevelopmental sequelae and adolescent psychopathology. The proposed study is uniquely positioned to answer key questions about how prenatal risk factors operate within the neurodevelopmental course of depression. The present study has the potential to influence the development of early intervention and prevention strategies, as well as to identify early risk markers for subsequent difficulties in adolescence. PUBLIC HEALTH RELEVANCE: The proposed project aims to investigate how maternal psychosocial and neuroendocrine indicators of stress during pregnancy, maternal inflammation during pregnancy and fetal hypoxia (lack of oxygen) contribute to the neurodevelopmental course of depression in adolescent offspring.

Project Summary/Abstract The proposed study aims to develop a brief, valid screening questionnaire to identify individuals at risk for psychosis in non-clinical populations across 3 large, community catchment areas with diverse populations. This is a needed study, as the current screening tools for at-risk psychotic populations have only been validated in clinical and/or treatment seeking samples, which likely do not generalize outside of these specialized settings. The proposed project will administer 3 well-known psychosis risk screeners, as well as additional symptom-based (e.g., depression, anxiety, etc.) and risk-factor based questionnaires (e.g., cannabis and other substance use, a family history of major mental disorders, trauma history) to 6,000 adolescents/young adults in local communities across 3 demographically diverse sites (Philadelphia, Baltimore, and the greater Chicago areas). Based on established cut-off scores from the 3 psychosis screeners, 1,560 subjects deemed as questionnaire higher risk (n=780; QHR) and questionnaire lower risk (n=780; QLR) for psychosis (estimated sample sizes based on pilot data) will be invited to complete semi- structured interviews to determine clinical high risk (CHR) for psychosis status based on the Structured Interview for Psychosis-Risk Syndromes (SIPS) and to assess current/past major mental disorders based on the Structured Clinical Interview for DSM-5 (SCID-5). Based on preliminary data and conservative estimates, we anticipate that 117 of the QHR group will be considered CHR for psychosis. The specific aims are as follows: 1) to determine norms and prevalence rates of attenuated positive psychotic symptoms across 3 diverse, community catchment areas and 2) to develop a questionnaire screener, using both symptom-based and risk factor-based questionnaires, that is validated against the SIPS to identify those at CHR for psychosis in the community. This is the first study in the U.S. to determine the rate of subthreshold psychotic symptoms across diverse non-help seeking samples, which is essential for investigations using dimensional approaches to psychotic disorders. Further, the proposed study will develop an essential screening tool that will identify which individuals have the greatest need for follow-up with structured interviews in CHR studies or clinical settings to determine psychosis-risk status. This tool is will be quite valuable given findings that those who develop psychotic disorders often do not seek treatment until after the onset of the disorder, and that duration of untreated psychosis is associated with more serious clinical outcomes. The proposed study has the potential for major contributions to the early detection and prevention of psychotic disorders.

Abstract of the Study ?Community psychosis risk screening: An instrument development study? The ongoing, funded parent study aims to develop a brief, valid screening questionnaire to identify individuals at risk for psychosis in non-clinical populations across 3 large, community catchment areas with diverse populations. This is a needed study, as the current screening tools for at-risk psychotic populations have been validated only in clinical and/or treatment seeking samples, which are not likely to generalize beyond these specialized settings. This project is administering 3 well-known psychosis risk screeners, as well as symptom- based (e.g., depression, anxiety, etc.) and risk-factor based questionnaires (e.g., cannabis and other substance use, a family history of major mental disorders, trauma history) to 12,000 adolescents/young adults in local communities across 3 demographically diverse sites (the greater Philadelphia, Baltimore, and Chicago areas, including neighboring rural/suburban areas). Based on established cut-off scores from the 3 psychosis screeners, 2,000 subjects deemed as questionnaire higher risk (QHR; n=1,000) and questionnaire lower risk (QLR; n=1,000) for psychosis (estimated sample sizes based on pilot data and anticipated loss to follow up) will be invited to complete semi-structured interviews to determine clinical high risk (CHR) for psychosis status based on the Structured Interview for Psychosis-Risk Syndromes (SIPS) and to assess current/past major mental disorders based on the Structured Clinical Interview for DSM-5 (SCID-5). The SIPS psychosis-risk persistence syndromes and the DSM-5 attenuated positive syndrome (both assessed with the SIPS 5.6) also will be collected and will be examined in supplementary analyses. Based on preliminary data and conservative estimates, we anticipate that 186 of the QHR group will be considered CHR for psychosis. The specific aims are as follows: 1) to determine norms and prevalence rates of attenuated positive psychotic symptoms across 3 diverse, community catchment areas and 2) to develop a screening questionnaire, inclusive of both symptom-based and risk factor-based questions, that is validated against the SIPS to identify those at CHR for psychosis in the community. This is the first study in the U.S. to determine the rate of subthreshold psychotic symptoms across diverse non-help seeking samples, which is essential for any investigation that uses dimensional approaches to psychotic disorders. Further, this study will develop an essential screening tool that will identify which individuals have the greatest need of follow-up with structured interviews in CHR studies or clinical settings to determine psychosis-risk status. This tool is will be valuable given findings that those who develop psychotic disorders often do not seek treatment until after the onset of the disorder, and that duration of untreated psychosis is associated with more serious clinical outcomes. The funded study has the potential for major contributions to the early detection and prevention of psychotic disorders.The proposed diversity supplement will fit within this award by providing essential training and time for a predoctoral student, Arielle Ered, to develop her program of investigating neural and psychosocial risk factors for psychosis.

Project Summary/Abstract This is a resubmission of an application that aims to investigate how maternal inflammation during pregnancy influences clinical, neurocognitive, and neural characteristics in adult offspring during the late middle-age period. Accumulating evidence suggests that maternal inflammation and infection during pregnancy increase risk for schizophrenia and depression in offspring, as well as for more severe outcomes among schizophrenia cases. However, no studies have determined whether difficulties persist into later periods of development, and the ability to draw inferences from existing studies has been limited by a variety of factors, such as selecting participants based on mental disorder status of offspring. Due to these limitations, previous studies have been unable to control variability in the level of exposure to inflammation within groups, control for potential confounding factors, and include outcomes that may be more directly linked to inflammation than psychiatric diagnoses. The proposed project aims to randomly select participants from a birth cohort with previously analyzed cytokine data to determine whether variability in fetal exposure to inflammation is related to specific neural and symptomatic outcomes that occur across disorders, which could provide findings pertinent to a range of neurodevelopmental sequelae. The proposed study is based on a very unique cohort, the Child Health and Development Study (CHDS), with biosamples collected during pregnancy, continual follow-up of offspring through adolescence, and assessment of a multitude of potential pre- and postnatal covariates. Specifically, 20,000 women were followed throughout their pregnancies from 1959-1966; a subset of offspring were given a range of assessments at multiple points from birth to adolescence. Previous findings from our group indicated consistent links between 2nd trimester inflammation and infection to increased risk of offspring depression, as well as childhood difficulties (e.g., internalization). The proposed project will collect detailed clinical (questionnaires, semi-structured interviews, and laboratory tasks), neurocognitive, and brain (multi- modal MRI) indices for offspring exposed to varying levels of inflammation in utero. The specific aims are as follows: to investigate whether fetal exposure to higher levels of inflammation increases risk for 1) specific symptom dimensions among offspring (e.g., psychotic symptoms, reward functioning, depression), and/or for 2) specific neurocognitive and neurological outcomes among offspring (assessed using multi-modal brain imaging and neuropsychological testing), and 3) to determine whether links between fetal exposure to inflammation and childhood/adolescent outcomes persist into middle-age. The proposed study is uniquely positioned to answer key questions about how maternal inflammation during pregnancy contributes to neurocognitive, brain, and clinical disturbances in offspring at various periods of development, has the potential to influence the development of intervention and prevention strategies, and could help clarify the role of inflammation in neurodevelopment and in a variety of mental disorders.

Project Summary/Abstract Research suggests that early identification of individuals at clinical high risk (CHR) for psychosis may be able to improve illness course. Studies suggest that early identification of CHR using specialized interviews with help-seeking individuals (with attenuated psychosis symptoms) is a useful approach. This work has two major limitations: 1) interview methods have limited specificity as only 20% of CHR individuals convert to psychosis, and 2) the expertise needed to make CHR diagnosis is only accessible in a few academic centers. We propose to develop a new psychosis symptom domain sensitive (PSDS) battery, prioritizing tasks that show correlations with the symptoms that define psychosis and are tied to the neurobiological systems and computational mechanisms implicated in these symptoms. To promote accessibility, we utilize behavioral tasks that could be administered over the internet; this will set the stage for later research testing widespread screening that would identify those most in need of in-depth assessment. To reach that goal we first need determine which tasks are effective for predicting illness course and how this strategy compares to published prediction methods. We propose to recruit 500 CHR participants, 500 help-seeking individuals, and 500 healthy controls across 5 sites with the following Aims: Aim 1A) To develop a psychosis risk calculator through the application of machine learning (ML) methods to the measures from the PSDS battery. In determine an exploratory ML analysis, we will the added value of combining the PSDS with self-report measures and historical predicators; Aim 1B) We will evaluate group differences on the risk calculator score and hypothesize that the risk calculator score of the CHR group will differ from help-seeking and healthy controls. We further hypothesize that the risk calculator score of the CHR converters will differ significantly from groups of CHR nonconverters, help-seeking and healthy controls. The inclusion of a help-seeking group is critical for translating the risk-calculator into clinical practice, where the goal is to differentiate those at greatest risk for psychosis from those with other forms of psychopathology; Aim 1C): Evaluate how baseline PSDS performance relates to symptomatic outcome 2 years later examining: 1) symptomatic worsening treated as a continuous variable, and 2) conversion to psychosis. We hypothesize that the PSDS calculator: 1) will predict symptom course and, 2) that the differences observed between converters and nonconverters will be larger on the PSDS calculator than on the NAPLS calculator. Aim 2) Use ML methods, as above, to develop calculators that predict: 2A) social, and, 2B) role function deterioration, both observed over two years. Because negative symptoms are strongly linked t o functional outcome than positive symptoms, we predict that negative symptom tasks will be the strongest predictor of functional decline in both domains.This project will provide a next-generation CHR battery, tied to illness mechanisms and powered by cutting-edge computational methods that can be used to facilitate the earliest possible detection of psychosis risk.