Seth David Pollak, Ph.D. - US grants

DESCRIPTION (provided by applicant): More than 1.5 million children were victims of substantiated child maltreatment in the United States last year. One concern is that while we have identified a heightened rate of behavioral disorders associated with such traumatic experience in these children, the mechanisms linking these children's emotional experiences with the later development of psychopathology remain largely unknown. Understanding the processes by which experience alters developing regulatory systems may provide insights into the development of psychopathology. The proposed research will characterize cognitive electrophysiological differences in children's processing of emotion that are not observable from overt behavioral responses alone. I propose to determine if and how child maltreatment affects children's perceptual processing of emotional information by: (1) Measuring maltreated children's sensitivity to auditory affective cues. Event-related potentials (ERPS) will record information processing as children listen to effectively charged words, presented dichotically. 2) Isolating the effects of emotion on maltreated children's attentional processes, ERPs will be used to determine the effect of emotional cues on children's attentional control and on attentional resource allocation in response to facial displays of emotion and emotional sounds. (3) Determining whether maltreatment affects children's perceptual organization of emotional information. Children will make perceptual categorization judgments of facial expressions of affect that have been digitally blended with other emotions. (4) Assessing differences in affective chronometry among maltreated children. Since transmission of emotion occurs very quickly, most tasks that require behavioral responses may not be sensitive to temporal aspects of information processing. This experiment will measure maltreated children's responses to dynamically unfolding perceptual information about facial expressions without reliance on reaction time measures. Taken together, these studies will extend knowledge about the development of psychopathology in maltreated children by focusing upon specific perceptual and cognitive processes through which aberrant experience affects subsequent affective functioning. In addition, studying the effects of maltreatment in this manner will shed light on the mechanisms contributing to the developmental organization of emotion systems. Because dysregulation of affect is common to so many forms of child psychopathology, insights generated with regard to the neuro-behavioral processes associated with maltreated children's behavior may help explicate pathways of both adaptive and maladaptive development.

[unreadable] DESCRIPTION (provided by applicant): This application is a supplement to MH61285 ("Emotion Processing: Risk for Psychopathology"). The aim of the MH61285 is to extend knowledge about both child maltreatment and normal emotional development by focusing upon the mechanisms through which trauma affects children's subsequent affective functioning. This supplemental project will augment and expand the program of research currently supported by the base project by (a) examining stress-regulatory biobehavioral processes, (b) assessing maltreated children's stress regulation in three ecologically-valid social contexts, and (c) determining the developmental effects of early versus chronic trauma. Specifically, we propose to: Characterize the diurnal rhythm of neuroendocrine and immune markers of stress in maltreated children; Determine whether hypo- or hyperarousal of the stress system is differentially related to the development of psychopathology in maltreated children; Investigate whether diurnal rhythms among maltreated children are differentially altered based upon social contexts. [unreadable] [unreadable] By building upon the existing infrastructure established by an existing R01, this project has high potential for generating new knowledge in a field in which very little is currently known, and does so using innovative methods at relatively low cost. Our general aim is to shed new light on the ways in which early traumatic experience may continue to compromise biobehavioral development, while also highlighting processes that are likely candidates for intervention/remediation. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application is the first competitive renewal of a project designed to understand the effects of abuse on children's brain-behavioral development. Studies of non-human animals have shown that adverse parental care shapes the development of the neural systems that underlie risk for mental health problems. Our work during the initial project period successfully highlighted the importance of perceptual and attentional processes as mechanisms underlying the emotional difficulties of maltreated children. This next phase of research will clarify the biological basis of these links, examine risk and protective factors, and identify the factors that place children at risk for particular forms of mental illness. The proposed work is designed to motivate development of clinical intervention trials during a subsequent project period. This application proposes to harness behavioral, cognitive neuro-physiological, anatomical, genetic, and neuro-endocrine measures to clarify the developmental mechanisms linking early stress in childhood with the emergence of mental health problems in adolescence. We will: (1) Determine the stability of the link between early stress experience and emotion processing measures across children's development;(2) Identify how specific aspects of emotion processing are associated with different forms of mental illness;(3) Specify the biological mechanisms which serve as links between children's early emotional experiences, regulation of emotion in childhood, and emergence of mental illness. Measurements will employ biological approaches including cognitive psycho-physiological, brain imaging, genetic and neuro-endocrine methods. In sum, this application proposes a continuing program of research that will examine altered emotional regulatory processes associated with child abuse and that will link these measures to mental health outcomes. This project has potential to synthesize key areas necessary to advance prevention and treatment of mental health problems in children and adults. Those include understanding the neurobiology of the brain's regulation of emotion and response to chronic social stress, the sensitivity of the human brain to contextual or environmental influences, and the ways in which the environment creates long-term effects on human behavior. Each of these foci holds tremendous promise for advancement of knowledge and application to improvement of public health.

The Clinical Translational Core (CTC) promotes the use of, provides access to, and supports state-of- the art technologies and resources to facilitate translation of research findings into the clinical settings of diagnosis and patient care. Our newly configured Core has expanded to incorporate new technologies and resources in the areas of population health, biomedical research, and biomanufacturing, and serves as a focal point for cost-effective and innovative translational research. The CTC has grown in significant ways to support the increase in interest among our investigators in topics ranging from epidemiology and population health through novel therapeutics and clinical trials. Our collection of registries was dramatically enhanced by the formalized relationship with the Personalized Medicine Research Project (PMRP) of the Marshfield Clinic. We now also provide substantial resources for therapeutics development through Waisman Biomanufacturing, which supports translational investigators by assisting in preparing drug development plans, developing cGMP compliant manufacturing and Quality Control test methods, and providing cGMP manufacturing and testing services for pre-clinical animal studies and early-stage human clinical trials. We propose three specific aims for the next project period. Aim 1 is to facilitate recruitment of human participants and access to data/specimens for behavioral, biobehavioral, and biomedical research and clinical trials. Registry coordinators, both in Madison and in Marshfield, will facilitate identification and access to unique individuals or populations relevant to studies on IDD. The Madison cohorts include the individuals and families seen in our clinics and the children in our pre-school (one-third of whom have a disability), as well as several distinct registries such as the IDD registry, the fragile X syndrome registry, the infant-toddler registry, and the K-12 registry (the last two especially useful for recruitment of controls). The Marshfield PMRP cohort includes 20,000 people who have consented to share their electronic health records, DNA, and other biosamples for research, and to be re-contacted for future data collections. Aim 2 is to provide specialized clinical assessments of participants. Core staff will include a clinically certified psychologist and speech-language therapist, who provide standardized psychological and other assessments to supplement the more specialized types of testing needed by the individual projects. Aim 3 is to provide technologies and consultative services to support development of new behavioral methods and custom applications. The Core provides eye-tracking equipment and behavioral testing suites equipped for remote observation, and the staff have particular expertise in database construction and software development. Aim 4 is to promote advancement of therapeutics for IDD populations. The Core provides advanced biomanufacturing capability for viruses, plasmids, proteins, and cellular therapeutics, through the Waisman Biomanufacturing facility. Through the interactions with the clinics and access to the registries the Core also fosters participation in several types of therapeutic research.

Project Summary/Abstract These experiments will further understanding about how and why child abuse leads to a broad range of mental and physical health problems. Although millions of children experience various forms of child abuse each year in the US, little is understood about how this experience influences brain-behavioral development. The General Aim of this research is to determine how environmental experience shapes neural circuitry in ways that lead to child mental health problems, and determine how these systems can be targeted to provide treatments for affected individuals. Here, we will test aspects of learning that might underlie problems in abused children. Once we identify a mechanism, we will advance our basic science to a pre-clinical space by determining if these mechanisms are responsive to laboratory manipulations. The Specific Aims are: (1) To specify the mechanisms affected by child abuse that lead to developmental changes in systems needed to effectively learn to communicate, interpret, and regulate emotion in the context of social interactions; (2) To determine which of these processes are most amenable to change through experimental manipulation. The proposed experiments combine neuroimaging, behavioral, and computational approaches to examine precise and novel questions about how experiences of child abuse are transformed into disruptions of the brain networks underlying emotional pathologies. This project: (1) Examines developmental change in children ages 8-14 years, covering critical pubertal transitions when many mental health problems emerge, (2) Probes discrete developmental mechanisms that can be targeted for intervention, (3) Is amply powered to properly test the hypotheses, (4) Characterizes aspects of relevant brain-behavior relationships are related to both RDoC dimensional constructs and DSM diagnoses, and (5) Employs sophisticated computational rigor to truly interrogate the critical questions under examination. Because child abuse is a powerful determinant of many subsequent mental health problems, the data generated from this project has profound implications for conceptualizing novel and more precise treatments for vulnerable children. It will do so by determining effects of chronic stress exposure on human neural circuitry early in development, when the brain may be particularly sensitive to environmental influences. The project moves away from description of risk groups to defining and specifying mechanistic ways in which the environment creates long-term effects on brain and behavior. These foci hold tremendous promise for advancement of knowledge and application to improvement of public health.