Timothy J. Trull - US grants

Borderline personality disorder (BPD) is a sever personality disorder that develops in early adulthood, and is characterized by a lack of control of anger, intense and frequent mood changes, impulsive acts, disturbed interpersonal relationships, and life-threatening behaviors. BPD is relatively prevalent in both clinical and nonclinical populations. Despite the prevalence of this condition, we know very little about how BPD features develop. Although a number of etiological factors have been proposed, studies exploring the etiological relevance of these factors suffer from a number of methodological limitations including: assessing subjects only after they have developed BPD, failing to assess gender effects, and employing cross-sectional designs. This application proposes a two-year prospective multi-cohort study of 500 18 year-old subjects that manifest varying degrees of BPD features; both genders will be equally represented. All subjects will be incoming freshman at the University of Missouri-Columbia, and subjects will complete a number of inventories and interviews at study intake (Time 1) and two-year follow-up (Time 2) that target the following constructs: BPD and other personality disorder features; parental psychopathology; and abuse experiences in childhood. The proposed study has five major aims: (1) to assess the correspondence between alternative measures of BPD features (self-report and interview); (2) to assess the relationship between personality traits and BPD features and determine whether the relations remain significant after partialling out variance in BPD scores accounted for by gender, parental psychopathology childhood physical and sexual abuse, and Axis l pathology; (3) to assess the two-year stability of scores on BPD measures; (4) To evaluate several models of how BPD features develop over time that include personality trail childhood abuse experiences, and parental psychopathology as moderators or mediators; and (5) to assess the relationship between Time 1 BPD symptom scores and negative outcome across a number of domains functioning, and to evaluate the potential moderating influence of personality traits, childhood abuse, and parental psychopathology on the relationship between Time 1 BPD scores and outcome two years later. By addressing these five aims, factors influencing future BPD pathology will be identified, more comprehensive etiological mode for BPD will be empirically evaluated, the level of dysfunction exhibited by syndromal and subsyndromal subjects will be assessed, and the predictive validity of BPD scores will be determined.

[unreadable] DESCRIPTION (provided by applicant): This study will use methods, techniques, and findings from the fields of affect and emotion, behavioral assessment, and psychometrics to shed light on a core feature of BPD, affective instability. In this revised application, we propose to conduct an intensive study of affective instability using ecological momentary assessment (EMA) --- a real time assessment of behaviors, emotions, and cognitive variables via hand held computers. Study participants will include 75 BPD outpatients and 75 psychiatric controls (with Major Depressive Disorder) who will rate their mood states, behaviors, and life events six times per day for a 28 day period. We will address four major aims: (1) characterize the mood state patterns of BPD patients and contrast these patterns with those of patients of near-neighbor diagnoses (in this case major depression); (2) identify antecedents (life events) and consequents (substance use behaviors) of mood shifts; (3) determine whether BPD patients can accurately recall (via retrospective self-report instruments) their mood shifts and variables associated with these shifts; and (4) assess whether existing measures of affective instability, affective intensity, and personality are related to EMA measures of affective variability and mood shifts. This study will represent the most intensive, naturalistic study of affective instability, and it will address several theoretical questions regarding affective instability. Further, these results will have implications for treatment and for the assessment of affective instability. Funding for this study will allow us to provide multidisciplinary training to an advanced graduate student who plans to conduct research in this area in the future. Completion of this study will also enable us to conduct multiple studies aimed at elucidating the utility of EMA in the assessment of BPD and the utility of EMA in tracking treatment effects, as well as to take part in the development of a multidisciplinary center for the study of BPD and its features that will foster collaborations among scientists with expertise in psychometrics and measurement theory, psychobiology, social and affective neuroscience, and basic behavioral science. [unreadable] [unreadable]

This study extends currently ongoing research on both drinking and smoking (current Project 6) using ecological momentary assessment (EMA) to examine the use of alcohol with and without conjoint smoking to regulate emotions, and the effects of these regulation strategies on subsequent mood. We add a comparison group of Borderline Personality Disorder (BPD) patients. BPD exhibits high comorbidity with alcohol use disorders (AUDs) in both clinical and population-based samples. Cardinal symptoms of BPD, impulsivity and affective instability, are central constructs in theories of AUD etiology, so BPD represents a type of "model system" for studying the role of emotion regulation and disordered self-control in the genesis of AUD. We will collect EMA data from both random and event-based (e.g., drinking, smoking) assessments to address our aims. We will test the following hypotheses: (1) drinking episodes in BPD patients will be presaged by both positive and negative moods;drinking in non-affected controls (CON) will be presaged by positive but not negative moods;impulsivity will moderate these mood-substance use relations. (2) BPD patients'drinking episodes will be associated with heavier consumption (sex and body weight adjusted) than CON;group differences will be moderated by both affective instability and by impulsivity. Drinks consumed will be moderated by number of cigarettes in both groups. (3) Alcohol consumption's effect on mood will be characterized by both positive and negative reinforcement;smoking will attenuate the degree of reinforcement due to acute cross-tolerance effects in both groups. In BPD patients, underlying affective instability will attenuate the duration of alcohol-related, salutary effects on mood. (4) Negative post-drinking effects of alcohol on mood will be larger in BPD patients than controls because of additive effects of hedonic rebound effects of alcohol and negative affectivity in BPD patients;smoking will increase these effects in both groups. This study will provide important information about the role mood dysregulation plays in the etiology and maintenance of AUD, and how impulsivity and smoking may interact with mood dysregulation to lead to increased drinking. These results will have implications for both prevention and treatment of alcohol problems.

DESCRIPTION (provided by applicant): Excessive alcohol use has many negative health consequences, including higher risk of mortality. In addition, in 2006, the estimated economic cost of excessive drinking was $223.5 billion when the combined costs of lost productivity, health and health care, and crime are considered61. Despite unparalleled advances in technology over the last several decades, the clinical assessment of features and correlates of alcohol use disorders (and psychopathology more generally), still primarily relies on traditional paper-and-pencil questionnaires and face-to- face clinical interviews. However, these tried-and-true methods are limited in a number of ways, including total reliance on patients' retrospective self-report, the skill of the clinical interviewer, and the artificial setting of the assessment (te clinic consulting room). The present study proposes to use an innovative methodology, ambulatory assessment (AA) to describe and investigate alcohol use and dependence-related symptomatology (specifically, cue- reactivity/craving), and emotional dysregulation among psychiatric outpatients with disorders characterized by clinical significant emotional dysregulation problems (mood disorders, anxiety disorders, or borderline personality disorder) while in their natural environment. This real-world approach can shed light on the causes and correlates of alcohol dependence, and suggest improvements in treatment approaches.

DESCRIPTION (provided by applicant): The over-arching aim of this proposal is to identify an impairment in neural mechanisms involved in emotion regulation and examine its relationship to emotional distress symptoms in people's daily lives. Emotional distress symptoms are found in a range of disorders (e.g., major depression, borderline personality disorder, and anxiety disorders), in part explaining extremely high comorbidity across these disorders. These disorders can be very common (e.g., combined prevalence over 1/3 of US population), are associated with intense personal suffering, and are associated with great costs to society (e.g., depression one of the leading causes of disability; anxiety disorders double medical care costs). Emotion regulation involves attempts to influence the presence, type, experience, and expression of emotion and emotional distress psychopathology is often posited to reflect impaired emotion regulation. Converging human and animal research has identified top-down ventromedial prefrontal cortex (vmPFC) regulation of amygdala activation as a critical neural emotion regulation mechanism, with some evidence that deficits in this mechanism are related to emotional distress psychopathology. Unlike possibly all previous research that examined the functional consequences of impaired vmPFC-amygdala functional connectivity, this neural deficit will be identified with functional magnetic resonance imaging (fMRI) by using both resting state data as well two different emotion regulation task paradigms, one implicit and the other explicit. This will provide converging evidence across very different functional imaging contexts to assess the breadth of this neural deficit. However, the relationship between this neural emotion dysregulation deficit and its manifestation in people's daily lives is still unknown. Previous research suggests that key emotional distress symptoms and correlates are often inaccurately recalled. Ambulatory assessment (AA) is a powerful, innovative way to assess affective, behavioral, and physiological symptoms and correlates in real world environments reliably (e.g., with smart phones), while minimizing the inaccuracy of retrospective self-reports. The use of AA will allow accurate characterization of how impaired vmPFC-amygdala functional connectivity translates into people's daily life experiences, such as self-reported negative affect affective instability, and behavioral dysregulation. In addition, physiological assessment is a critical complement to self-reported affect in order to validly assess emotional states. The current study will use wireless and continuous physiological assessment to provide converging evidence to self-reported emotional distress symptoms. Furthermore, this study will examine the relationship between this neural emotion dysregulation endophenotype with the frequency and duration (i.e., emotional recovery time) of real world emotional distress episodes measured objectively with continuously recorded physiological activity. Understanding the specific relationship between this neural emotion dysregulation and emotional distress psychopathology will have important implications assessment and treatment.

? DESCRIPTION (provided by applicant): Excessive alcohol use has many negative health consequences, including higher risk of mortality. In addition, the estimated economic cost of excessive drinking is more than 1% of the gross national product in high- income and middle-income countries (Rehm et al., 2009). The over-arching goal of this application is to improve the definition and assessment of alcohol use disorder (AUD). Our proposal is consistent with the goals outlined in the most recent NIAAA Strategic Plan (2009-2014). Most broadly, our study will develop and validate optimal diagnostic criteria sets and algorithms (ODCSAs) for the diagnosis of AUD that we anticipate will perform substantially better than existing diagnostic criteria (i.e. DSM-5 and ICD-10). We will employ emerging methods and develop and apply new methods in statistics and classification science to existing large population-based epidemiological data sets (the National Epidemiological Survey of Alcoholism and Related Conditions, NESARC; the National Longitudinal Alcohol Epidemiologic Survey, NLAES; the National Survey on Drug Use and Health, NSDUH), a large multi-site sample enriched for high density of AUDs (the Collaborative Study on the Genetics of Alcoholism, COGA), a major, multi-site treatment outcome study (Combining Medications and Behavioral Interventions; COMBINE) and two smaller non-clinical and clinical data sets spanning a decade or more of participants lives in order to refine assessment methods, diagnostic criteria, and diagnostic algorithms for AUDs. Specifically, by employing state-of-the art techniques in data harmonization and computational statistics, we will identify those criteria sets and decision rules that will optimize the associaton with heaviness of alcohol consumption, both within and across data sets. These new ODCSAs will then be subjected to extensive evaluation of their structural validity and external validity. n addition, we will conduct extensive validation analyses of DSM-5, ICD-10, and draft ICD-11 criteria, because these are of interest in their own right, and because that will allow us to benchmark our new ODCSAs with the current standards. We believe the development of empirically-based diagnosis for AUD will improve research on the causes and correlates of AUD and should lead to improved diagnostic criteria for clinical practice. The methods developed for this application should have broad applicability for developing diagnostic criteria or assessment instruments for a range of clinically important constructs when there are no clear gold standards. The proposed research exploits increased availability of data sharing, new developments in data harmonization, and advances in computational science.

High levels of alcohol consumption clearly place individuals at great risk and present a significant health and economic burden to society. Emerging evidence indicates that many young adults engage in what can be called extreme drinking (i.e., drinking at levels likely to lead to BACs > .16). Despite recent attention to extreme drinking5,6, we know surprisingly little about this behavior beyond associations revealed by cross?sectional studies that rely exclusively on retrospective self?report. The proposed study is designed to provide some of the first comprehensive data about influences on the extreme drinking phenotype, and to compare these with those identified for the typical binge drinking phenotype. Whether there are unique causes and correlates of extreme drinking (compared to binge drinking) is an empirical question that has not been tested. There are challenges to investigating extreme drinking, including 1) overcoming the limitations of retrospective self?report, 2) adequately measuring personological and environmental influences, and 3) capturing the temporal associations of these diverse influences and their impact on extreme drinking occasions. The proposed project is designed to meet these challenges using a combination of laboratory, genetic, and ecological momentary assessment (EMA) methods. Our multi?method approach will combine laboratory alcohol administration, EMA, and real?time BAC assessment to capture the interplay between a broad range of potential influences on extreme drinking, extend our investigation outside the lab and into the natural drinking environment, and explore the temporal associations of influences on extreme drinking. We focus on four core constructs central to current theoretical models of addiction that are hypothesized to influence substance use through in?the?moment processes: reward sensitivity (RS), incentive salience (IS), impulsivity/loss of control (Imp), and negative affectivity (NA). We will recruit a sample of 400 young adults (ages 21?29), ascertained from a statewide DMV database, who have a recent legal action with a recorded BAC consistent with extreme drinking (? .12). Using a longitudinal burst design, we will follow participants over a 12?month period, with five self?report assessments and four, two?week EMA bursts. A baseline laboratory session will assess behavioral, trait, and electrophysiological markers of core study constructs. We aim to (1) Evaluate the validity and utility of real?time assessments for identifying extreme drinking and alcohol?related behavior. This aim could inform estimation methods for characterizing extreme drinking and guide refinement of definitions of problematic drinking profiles. (2) Characterize the structural influence of stable individual differences, transient intra?individual factors, and environmental variables on risky, binge, and extreme drinking occasions and alcohol?related negative consequences. This aim will reveal the incremental validity of state (EMA) and trait (lab; baseline questionnaires; polygenic risk scores [PRSs] when applicable) indices of core study constructs in predicting extreme drinking occasions within and between individuals; as well as test their interaction with specific contextual factors to predict extreme drinking behavior. (3) Identify multidimensional profiles associated with stable or highly variable binge and extreme drinking behavior. Our longitudinal burst design allows us to test hypotheses about the stability of drinking behavior over time.