Harold Hill Goldsmith - US grants

behavioral genetics; infant human (0-1 year); child psychology; social behavior; interpersonal relations; cognition; child behavior; personality tests; behavior test; questionnaires;

The growing subfield of infant and early childhood temperament holds great promise for conceptualizing the individual's contribution to social and cognitive development; however, the field is handicapped by insufficient basic psychometric research and inadequately standardized and validated measurement instruments. The goal of this research is to construct and validate a novel, theoretically based method for measuring temperament-related behavior: The Laboratory Temperament Assessment Battery (LAB-TAB). Building on extensive pilot work supported by the Foundation for Child Development, LAB-TAB will yield scores for activity, fear, anger, pleasure, and interest. Each of these dimensions will be objectively scored from standardized laboratory procedures. Embedded within the construction of LAB-TAB are three validity studies that examine developmental continuity, cross-method covergence, and relations between facial expressions and overt behavioral responses. The health relatedness of the research derives from the proposition that early temperament is implicated in the etiology of various childhood behavioral problems. Successful implementation of LAB-TAB should improve understanding of factors within the child that either contribute to vulnerability or protect the child from stressful environmental influences.

The growing subfield of infant and early childhood temperament holds great promise for conceptualizing the individual's contribution to social and cognitive development; however, the field is handicapped by insufficient basic psychometric research and inadequately standardized and validated measurement instruments. The goal of this research is to validate a novel, theoretically based method for measuring temperament- related behavior: The Laboratory Temperament Assessment Battery (LAB- TAB). LAB-TAB yields scores for activity, fear, anger, pleasure, and interest from objectively scored standardized laboratory measures. The assessment procedure will be extended to younger infants. Six validity studies examine developmental continuity, cross-method convergence, and relations between facial expressions and overt behavioral responses. Other validity studies demonstrate the relevance of temperament to various facets of social development. Issues addressed include prenatal efforts to socialize infant temperament, the role of temperament in emotional communication, and the role of temperament in instigating behavior. Both cross-sectional and longitudinal approaches are used. The health relatedness of the research derives from the proposition that early temperament is implicated in the etiology of various childhood behavioral problems. Successful implementation of LAB-TAB should improve understanding of factors within the child that either contribute to vulnerability or protect the child from stressful environmental influences.

behavioral /social science research tag; disease /disorder etiology; disease /disorder proneness /risk; personal log /diary; twin /multiplet

conduct disorder; depression; anxiety; behavioral genetics; mental health epidemiology; disease /disorder proneness /risk; attention deficit disorder; twin /multiplet; behavioral /social science research tag; human subject; child (0-11); clinical research;

DESCRIPTION (provided by applicant): This application seeks five years of support to conduct the first population-based twin study of autism spectrum disorder (ASD) with cases ascertained using current day diagnostic criteria. Inferences about the degree of genetic influence on autism depend crucially on the differential concordance of monozygotic (MZ) vs. dizygotic (DZ) cotwins. The results of twin studies affect the plausibility of various linkage approaches. Changing diagnostic practices lead to differences in base rates and in twin proband identification and thus require new studies. In addition, population-based studies of twins are needed to investigate claims that twins are over-represented among ASD cases. Building on extensive data that establish the project's feasibility, we shall collect a sample of virtually all twins aged 2-16 years in the state of Wisconsin, first by screening and case-finding, then by performing full diagnostic and behavioral assessments. We project a final sample of >120 pairs of twins, one or both with ASD; about 80% of the cases should be idiopathic. Given the goal to quantify genetic contributions to ASD, we will also assess the Broader Autism Phenotype in family members. We will characterize co occurring but non-diagnostic behavioral problems (anxiety, motor dyspraxia, sensory sensitivities, sleep problems, and aggressive or self-injurious behavior) as well as other medical conditions. Family functioning will be assessed in the interest of understanding the effects of ASD, and responses to treatment will be monitored in the interest of future translational research. A longitudinal follow-up will allow confirmation of early diagnoses and a measure of the course of ASD. A neuroimaging study, including eye tracking and electrodermal measures, will be conducted on the subsample of twins over 8 years of age, with particular attention paid to the discordant MZ pairs.

The Behavioral Assessment/Clinical Diagnosis Core will be responsible for ensuring that a common set of age appropriate, self-report and behavioral measures are used in all four projects that employ human subjects. The aims of Project 4, Study A, and Project 5 are highly complementary; thus, they employ the same protocol for the home visits done at the early adolescent age period. The Core describes this multi-source, multi-method protocol in some detail. Areas of emphasis include Child Emotional Reactivity and Regulation (temperament); Child Mental Health; Child Attributional Styles (and other social cognitive measures; Child Cognitive Functioning (field tests); Family Characteristics; Peer Characteristics; Parental Mental Health; and Major Life Events and Daily Hassles. With our consultant, Dr. Dahl, the Core will conduct assessments of pubertal timing and also coordinate assessments (e.g., of basal and reactive cortisol in the home) with the Biological Core. In addition to this early adolescent protocol, the Core will process questionnaires and ensure high-quality coding of behavior from videotapes for younger children (7-8 years old) who participate in two twin studies described in Project 4. These assessments generate extensive videotaped records that must be objectively coded. This core will also conduct diagnostic interviews by licensed clinicians on select groups of participants, thus confirming diagnoses made in the field and benefiting Projects 1, 3, 4, and 5. Finally, with our consultant Dr. Kraemer, the Core will publish methodological papers on two topics: (1) Clarifyiing the relationship between categorical field diagnoses of child psychopathology with the DISC and prior and concurrent dimensional symptom scores from the Health and Behavior Questionnaire using Receiver Operating Characteristic (ROC) approaches. Many developmental factors will be incorporated into these analyses. (2) Examining the psychometric quality of the batteries of videotaped measures of emotion reactivity and regulation (temperament), using item analytic and structural modeling approaches. These latter measures capture key risk factors for internalizing behavioral problems.

This project comprises two longitudinal twin studies that integrate the study of affective style, affective symptomatology, and affect-related physiology in children and adolescents. In Study A, the twins have already been followed longitudinally with a variety of measures, including detailed videotaped observations. An additional follow-up at age 11-12 years will allow developmental characterization of affective style and frank anxiety/depression. The genetic bases of improvement; chronic course; onset of comorbid symptoms, and other developmental variables will be pursued, as will the link between behavior and some of the neuroscience variables examined by other Center projects. Study A will also seek to identify toddler age risk factors (e.g., shy/inhibited temperament, obsessive features and repetitive movements, auditory and tactile sensitivities, and difficulties in down-regulating negative affect) that might be associated with later internalizing behavioral patterns. Study A shares an assessment protocol with Project 5 (Essex/Klein). To examine the impact of non-genetic factors (and other issues), genetically identical (MZ) cotwins from Study A who are discordant for chronic anxiety, as well as controls, will participate in structural neuroimaging studies. Core C will perform whole brain tensor-based morphometry, which should be more sensitive than most prior methods in determining whether regions of the hippocampus, prefrontal cortex, and amygdala are structurally altered in affected individuals and in their non-affected cotwins. Study B examines the association of individual differences in emotional reactivity and regulation with several psychophysiological measures (EEG, fear-potentiated startle, sympathetic and parasympathetic cardiac measures) as well as basal and reactive cortisol, all within a behavior-genetic framework. One role of Project 4's twin methodology in the broader Center is to help resolve the issue of causal direction in studies of experience and context in affective development. Another role is to determine whether physiological substrates of fearfulness/anxiety actually have a genetic basis, and whether common genetic variance accounts for affect-physiology associations.

DESCRIPTION (provided by applicant): Using the resources of an epidemiologically defined, longitudinal twin study, we examine developmental course and biopsychosocial risks for childhood psychopathology. Building on existing screening at ages 2 and 7 years, we characterize risk factors at ages 2, 7, and 12 relevant to the development of internalizing (anxiety and depression), externalizing (oppositional and conduct disorder), and ADHD. Most of our at-risk cases qualify for a DSM-IV diagnosis, yet we include individuals with sub-threshold symptoms and a large control group. Specific aims include characterization of risk factors, analysis of genetic and environmental effects, and improved measurement and classification of childhood disorders. "Child-based" risk factors include earlier symptoms, temperament and stress reactivity, basal and reactive cortisol, testosterone and DHEA, cognitive abilities and attributional styles, and cognitive-affective processing skills. Family and other psychosocial risk factors include parental diagnosis and family history of psychopathology, twin-twin and twin-parent social interaction styles, multiple facets of family stress, and negative parenting. The research methods that we employ include structured diagnostic interviews with caregivers and children, medical records, observer ratings, child self-report and parent-report questionnaires, videotaped home-based behavioral batteries, and computer-based testing (mostly reaction time tasks). The study's significance lies in understanding how known risk factors interact and/or mediate each other's effects on child psychopathology in a genetically informative, longitudinal design. Twin methodology allows us to parse phenotypic variance and covariance among measures into genetic and environmental components, and the components are studied developmentally. The results should also enhance our understanding of comorbidity, heterogeneity within disorders, and the association of disorders with traits. The project's public health relevance lies in its identification of risk factors for common childhood disorders and its investigation of how they interact in the context of genetic and environmental factors. The knowledge gained should inform efforts toward early detection, improved interventions, and better classification of childhood disorders.

0-11 years old; 12-20 years old; Active Follow-up; Adolescence; Adolescent; Adolescent Youth; Aeroseb-HC; Affective; Age; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biometrics; Biometry; Biometry and Biostatistics; Biostatistics; Birth; Birth Records; Bone callus; Bony Callus; Callus; Categories; Cetacort; Child; Child Youth; Childhood; Children (0-21); Class; Classification; Clinical; Cognitive; Comorbidity; Cort-Dome; Cortef; Cortenema; Cortisol; Cortispray; Cortril; DSM-IV; DSM4; Data; Depressed mood; Depression; Dermacort; Diagnosis; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders, 4th edition; Diagnostic and Statistical Manual of Mental Disorders-IV; Dimensions; Eldecort; Family; Foundations; Functional Magnetic Resonance Imaging; Gene Family; Gene variant; Generalized Growth; Genetic; Genetic Diversity; Genetic Variation; Gestation; Growth; Heritability; Heterogeneity; Human, Child; Hydrocortisone; Hydrocortone; Hytone; Image; Individual; Interview; Laboratories; Linear Regressions; MR Imaging; MR Tomography; MRI; MRI, Functional; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Mental Depression; Methods; Modeling; Mothers; Multivariate Analyses; Multivariate Analysis; NMR Imaging; NMR Tomography; Nervous; Neuroendocrine; Neuroendocrine System; Neurosecretory Systems; Nuclear Magnetic Resonance Imaging; Nutracort; Parturition; Pattern; Performance; Phenotype; Pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-, (11beta)-; Pregnancy; Principal Investigator; Problem behavior; Process; Proctocort; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; Psychopathology; Qualifying; Reaction Time; Records, Birth; Regressions, Linear; Response RT; Response Time; Risk Factors; SUBGP; Sampling; Sampling Studies; Specific qualifier value; Specified; Stress; Structure; Subgroup; Systematics; Telephone Interviews; Temperament; Testing; Therapeutic Hydrocortisone; Tissue Growth; Trier Social Stress Test; Twin Multiple Birth; Twin Studies; Twins; Variation (Genetics); Zeugmatography; abnormal psychology; adolescence (12-20); allelic variant; base; behavioral problem; childhood anxiety; children; depressed; disease classification; disease/disorder classification; disorder classification; fMRI; follow-up; hypothalamic pituitary axis; imaging; improved; juvenile; juvenile human; neural; neuroimaging; nosology; ontogeny; pediatric; programs; psychomotor reaction time; relating to nervous system; sadness; sex; statistics/biometry; teenage; youngster

The Clinical Diagnosis/Behavioral Assessment Core (Core C) will be responsible for ensuring that a common set of age appropriate, interview, behavioral, and diagnostic measures are used in all projects that employ human subjects. The aims of Projects 2 and 3 are highly complementary; thus, they employ similar protocols for the laboratory visits done in the late adolescent age period. As a central activity, the core will conduct structured diagnostic interviews by licensed clinicians on select groups of participants, thus following up on diagnoses made earlier in these longitudinal studies and benefiting Projects 2, 3, 4, and 5. These K-SADS interviews will allow results to be assimilated to the literature on anxiety disorders as defined by DSM-IV. The presence or absence of clinical diagnoses will prominently figure into addressing scientific aims on Projects 2, 3, 4, and 5. Core C will pay for diagnostic interviews and manage the resulting data. Projects 2 and 3 will screen their entire samples for behavioral problems in late adolescence, with the MacArthur Health and Behavior Questionnaire (HBQ) as the main screening instrument. The projects will conduct this screening, but Core C will manage the resulting data in a uniform manner and facilitate analyses across projects. The Trier Social Stress Test (TSST) figures prominently in both Project 2 and 3, and relates conceptually to all projects. Core 2 will facilitate uniform administration of the TSST and conduct behavioral coding of videotapes taken during the TSST. The development and implementation of a coding scheme for affect and behavior during the TSST will be an innovative contribution of Core C. Finally, with our consultant Dr. Kraemer on Project 2, the Core will publish methodological papers on two topics: (1) Clarifying the relationship between categorical field diagnoses of child psychopathology and prior and concurrent dimensional symptom scores from the HBQ and other measures using Receiver Operating Characteristic (ROC) curve approaches. Many developmental factors will be incorporated into these analyses. (2) Examining the psychometric quality of instruments used in the assessment protocols. These latter measures capture key risk factors for adolescent anxiety.

Project 3 incorporates two distinct studies, each of which capitalizes on extensive longitudinal, affective behavioral phenotyping during infancy or early childhood to study early adult outcomes based on neuroimaging (Study 1) or induced pluripotent stem cells. Study 1's monozygotic (MZ) twin difference design allows us to distinguish whether observed differences in later brain structure and function are associated with environmental influences versus familial influences on early anxious temperament. The comparison of MZ cotwins, with their age-matched, grossly similar brain morphology, allows detection of more subtle MRI effects in humans than any competing non-experimental design. Study 2 is a pilot study that is coordinated with the nonhuman primate stem cell work in Project 1. We examine whether young adults who are slow in amygdala recovery to negative affect elicitation and chronically anxious differ from those selected to be rapid in amygdala recovery and non-anxious differ in gene expression and cellular electrophysiology of GABAergic neurons that are derived from induced pluripotent stem cells.

DESCRIPTION (provided by applicant): This application proposes a two-part approach to understanding developmental aspects of the RDoC positive and negative valence systems. The project focuses on objective behavioral assessment and multimodal neuroimaging. Study 1 takes advantage of 1404 children (702 twin pairs) previously objectively assessed as 7 year-olds on positive and negative affect with a battery of videotaped behavioral measures that map onto RDoC dimensions. These children had also been assessed as toddlers and were later assessed at mean age 14 years, which allows for longitudinal tests of construct validity of the RDoC systems as applied to children. Study 1 includes completion of the age 14 data collection. Study 2 proposes to follow-up, at mean age 18 years, 640 of these participants (320 same-sex twin pairs) with comprehensive neuroimaging and concurrent psychophysiological and neuropsychological measures that assess selected RDoC constructs from the positive and negative valence systems. We will determine whether standing on the childhood RDoC measures (from Study 1) predicts adolescent neuroimaging measures of reactivity and recovery of positive and negative affect (from Study 2). We will test predictions concerning correlates of standing on RDoC constructs using structural and functional connectivity and dynamic features (reactivity and recovery) of responses to affective stimuli in an automatic emotion regulation task. We use the twin design to discern whether individual differences are genetically conditioned and whether the covariance across time (stability of RDoC) and the covariance between behavioral and neural measures (neural underpinnings of RDoC) have genetic bases. We investigate environmental bases of RDoC constructs by predicting monozygotic intrapair differences in neuroimaging parameters from earlier intrapair behavioral RDoC differences and from earlier measures of adversity and stress.