1998 |
Curtin, John J. |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Alcohol, Emotion, and Event Related Potentials @ Florida State University
The proposed study will take the next step in an ongoing line of research designed to elucidate alcohol-cognition-emotion connections. Recent theorists and empirical data suggest that alcohol does not directly affect emotional responding. However, alcohol may exert an influence on emotion indirectly through its impact on cognitive processes. Specifically, alcohol may have a detrimental effect on the processing of peripheral or task irrelevant stimuli presented in the context of more central, task relevant cues. Thus, if these peripheral stimuli would ordinarily evoke distress, intoxicated individuals may experience deficient emotional responding. In the current study, the effect of alcohol on the emotional response to a cue signaling the impending onset of a potent stressor will be assessed both when the cue is presented in the periphery of a more central cognitive task, and when the threat cue is presented without competing central stimuli. State- of-the-art psychophysiological measures of emotion and cognition will provide both an index of fear responding to the stressor and a much needed simultaneous assessment of alcohol's selective impact on the processing of both the central and peripheral cues. It is predicted that intoxicated individuals will exhibit deficient feat responding to the stressor when it is presented in the periphery of a central cognitive task. Moreover, a concomitant reduction in the processing of the peripheral fear cue should be observed. No such alcohol-related reduction in the central tasks is expected.
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0.939 |
2002 — 2003 |
Curtin, John J. |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Alcohol Effects On Explicit Cue Vs. Contextual Fear @ University of Wisconsin Madison
DESCRIPTION (provided by applicant): Research on the effects of acute alcohol intoxication on negative affect has been dominated by the Stress Response Dampening perspective, which suggests that alcohol reduces negative affective response to aversive stimuli through direct pharmacological suppression of activity in the primary subcortical fear system. However, recent compelling demonstrations of differential effects of alcohol on fear response dependent upon the cognitive processing requirements of the fear-eliciting cue suggest a more complex mechanism. Current advances in animal models of the neural circuitry of fear indicate that fear cues are processed through multiple, parallel pathways from subcortical and cortical structures into the primary subcortical fear system, with different pathways responsible for processing different characteristics of the cues. Synthesis of these neuroscience findings with the recent observed dissociations in alcohol's effect on fear suggests that alcohol does not directly affect the primary subcortical defensive system but instead exerts its influence on fear through its deleterious effects on specific cortical structures and pathways required for cognitive appraisal of certain emotionally evocative stimuli. The current project will examine human fear conditioning in intoxicated and non-intoxicated individuals, indexed with fear potentiated startle (FPS), in two distinct cuing conditions. These conditions will involve either 1) Cues which require higher-order cognitive processing (e.g., memory for context) that is mediated by the hippocampus and affiliated brain structures (i.e., contextual fear conditioning); or 2) Simpler, explicit cues not requiring such complex processing (i.e., explicit-cue fear conditioning). Substantial neuroscience research exists to indicate that different neural pathways and cognitive systems/structures are required for the development of conditioned fear to these two different sets of cues. Therefore, dissociation in alcohol's effect on fear across these cuing conditions would indicate that this drug's effect on emotion is mediated by specific higher brain processes and pathways, rather than produced by the direct action on the primary fear system. In line with the hypothesis that alcohol affects emotional responsivity indirectly, through its impact on higher Drain regions including the hippocampus, the primary aim of this experiment is to determine whether ethanol ingestion selectively impairs acquisition and/or expression of contextual conditioning, but leaves explicit-cue conditioning intact in humans.
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1 |
2006 — 2010 |
Curtin, John J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cognitive Control Deficits in Alcoholism Risk @ University of Wisconsin-Madison
Acute alcohol intoxication frequently results in various forms of dysregulated responding including aggression, sexual and other risk taking, alterations in emotional response, and even apparent temporary loss of control over alcohol use itself. Many examples in which alcohol intoxication results in these dysregulated responses are characterized by conflict between strong, but inappropriate, response tendencies and incompatible alternative responses that are more adaptive yet weaker. Similarly, alcohol dependent users frequently experience conflict or ambivalence surrounding their alcohol use and preliminary evidence suggests that they may be impaired in the attention functions that are necessary to adaptively resolve conflict surrounding their alcohol use. In fact, many theorists have speculated that the same attention mechanisms that account for the acute effects of alcohol challenge may also be chronically impaired in individuals with substance use and other externalizing disorders. Moreover, impaired attention may represent a premorbid etiological risk mechanism which accounts for the increased risk for alcohol use disorders among individuals with a family history of alcoholism. The aim of this research is to confirm and clarify the nature of alcohol challenge and alcoholism family history effects on attention function and to examine the consequences of potential impairment for the regulation of behavior and emotion responding. Recent theory andbasic cognitive neuroscience research hassignificantly advanced andrefined , understanding about the attention processes and underlying neurobiological structures that are necessary for the adaptive regulation of behavior and emotional response during conflict. This basic research has identified discrete functions of the attention system including maintenance of an alert state, sensory orienting, and executive control function responsible for the control of cognitive operations. In particular, executive control attention (and sub-components;evaluative and regulative control) are crucial to overcome contextually maladaptive, strong and/or habitual responding. This theory and research provides the foundation for the proposed research on attention function in intoxicated and family history positive individuals. The five proposed experiments will use electro-physiological measures (e.g., event related brain potentials) and well-validated cognitive paradigms designed to systematically index discrete components of attention function. This will allow mediation tests to determine if predicted alcohol challenge and family history of alcoholism effects on behavior and emotion regulation are the result of impaired attention function.
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1 |
2010 — 2011 |
Curtin, John J. Newman, Joseph P [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Matching Cognitive Remediation to Cognitive Deficits in Substance-Abusing Inmates @ University of Wisconsin-Madison
DESCRIPTION (provided by applicant): People with psychopathy are at high risk for alcohol and drug abuse as well as diverse forms of antisocial behavior (Smith &Newman, 1990). Thus, addressing the risk factors associated with psychopathy may prove to be crucial for the successful treatment of substance abuse, especially in incarcerated samples. In this regard, there is a strong precedent for differentiating the risk factors associated with emotionally reactive or emotionally stable forms of psychopathy. Although both types are associated with significant substance abuse, the self-control problems of these two subtypes are associated with distinct cognitive-affective deficits. In the proposed research, we use recent progress in distinguishing and characterizing the psychobiological deficits associated with these subtypes to develop novel cognitive remediation protocols that match their respective skill deficits and evaluate whether these protocols result in greater change than those that do not address the putative deficits. Specifically, 128 incarcerated offenders diagnosed with emotionally reactive or emotionally stable forms of psychopathy will receive one of two computer-based interventions designed to develop core cognitive skills that have been linked to self-regulation deficits in either emotionally reactive or emotionally stable psychopathic offenders. One intervention (ACC) targets the affective cognitive control deficits associated with emotionally reactive offenders whereas the other intervention (ATC) targets the attention to context deficits associated with emotionally stable offenders. To evaluate the impact and specificity of the ACC and ATC in this initial investigation, we will use pre- and post-treatment behavioral and brain-related measures that have been found to distinguish emotionally reactive and emotionally stable psychopathic offenders in past research. We predict that a treatment designed to remediate the cognitive deficits of one experimental group will result in significantly greater change than a treatment designed to remediate the cognitive deficits of the other experimental group. The results of the study will (a) provide important baseline information concerning the magnitude of change that may be expected from a brief computer-based intervention in the absence of supporting cognitive-behavioral materials designed to enhance the generalization of such training to daily functioning and (b) shed light on the plausibility of demonstrating differential treatment responses in these two similarly antisocial, but etiologically distinct, subtypes. PUBLIC HEALTH RELEVANCE: To realize the potential of research advances in experimental psychopathology, it is necessary to improve the technology for translating these advances into meaningful therapeutic interventions. Toward this end, we (a) translate research on the distinct psychobiological mechanisms associated with emotionally-reactive and emotionally-stable criminal offenders into distinct computer-assisted interventions that train skills designed to overcome their deficits and reduce alcohol / drug abuse, (b) examine the extent to which these deficit-focused interventions modify brain-related responses associated with the disorders, and (c) test the hypothesis that deficit-matched treatments produce significantly greater post-treatment change.
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1 |
2012 — 2016 |
Curtin, John J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Clinical Relevance of Stress Neuroadaptation in Tobacco Dependence @ University of Wisconsin-Madison
DESCRIPTION (provided by applicant): Neuroscience research with animal models implicates neuroadaptation in the stress response as a critical mechanism in the etiology of addiction across multiple classes of drugs including nicotine. Repeated homeostatic adjustments in the brain's stress systems due to chronic drug administration eventually lead to persistent compensatory adaptations in the structures involved in emotional response and its regulation. Among smokers, these stress neuroadaptations result in deregulated negative affect when nicotine-deprived and provide the strong motivational press for further smoking that manifests as urge and increased risk for smoking cessation failure. Animal models have provided substantial evidence to support this stress neuroadaptation thesis in addiction However, programmatic laboratory research that examines the stress response in nicotine deprived and non- deprived smokers (relative to non-smokers) is necessary to confirm that our understanding of stress neuroadaptations from animal models translate to addiction etiology in smokers. Negative affect is the core motivational element of the human drug withdrawal syndrome across additive drugs including nicotine. Unfortunately, much of what we know about these motivationally critical affective processes in humans is based on a narrow range of measures collected in isolation. The examination of the characteristics and neurobiological substrates of negative affect has not kept pace with the rapid conceptual, methodological, and measurement advances in the affective sciences over the past decade. Moreover, complementary methods (e.g., laboratory task manipulations, clinical treatment interventions) and measurement approaches (e.g., psychophysiology, ecological momentary assessment) are rarely combined. The research in this application capitalizes on recent research with both animals and humans that has synthesized precise laboratory manipulations of stress with sensitive psycho physiological measurement of startle reflex potentiating to parse the affective response to stress into its constituent components. In particular, startle potentiating during uncertain (vs. certain) threats holds promise as a biomarker of stress neuroadaptation following chronic nicotine or other drug use. We propose to measure stress neuroadaptation in the laboratory via startle potentiating during uncertain threat in two validated cued threat tasks among nicotine deprived and non-deprived smokers and non-smokers. Smokers will be subsequently assigned to combo NRT or placebo during smoking cessation treatment and will report on episodic stressors, negative effect, smoking urge, and smoking via ecological momentary assessment procedures. Treatment outcome will be assessed at 2 weeks post-quit. The broad goals of this research are to identify etiologically relevant psycho physiological biomarkers of stress neuroadaptation that results from chronic smoking. We evaluate the impact of this stress neuroadaptation on smokers' real-world affect, urge and smoking during smoking cessation treatment. We also evaluate if NRT can attenuate the influence of this stress neuroadaptation on smoking cessation outcomes via its effects on withdrawal.
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1 |
2015 — 2019 |
Curtin, John J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dynamic, Real-Time Prediction of Alcohol Use Lapse Using Mhealth Technologies @ University of Wisconsin-Madison
? DESCRIPTION (provided by applicant): Available psychosocial and pharmacological treatments for alcohol use disorder are effective at establishing abstinence. However, the vast majority of patients relapse within a year and often within the first few months following treatment. Patients often fail to detect dynamic changes in their relapse risk. Furthermore, the majority of patients fail to adequately sustain use of skills developed during treatment and/or through continuing care. Well-established theoretical models indicate that alcohol and other drug use lapse risk is a dynamic, non-linear function of both distal, relatively static, patient characteristics and often moment-by- moment dynamic changes in proximal, precipitating risk factors. However, comprehensive, precise assessment of dynamic risk indicators in real-time has not been possible until very recently. Furthermore, innovative methods from predictive analytics have not been applied to the lapse risk prediction problem. The broad goals of this project are to develop, validate, preliminarily optimize, and deliver a dynamic, real-time lapse risk prediction model for forecasting alcohol use among abstinent alcoholics. To pursue these goals, we propose to follow 200 patients for three months during or following completion of standard of care treatment for alcohol use disorder. We will measure well-established distal, static relapse risk indicators on study intake. More importantly, we will use innovative mHealth technology to densely sample dynamic risk indicators including patient physiology, subjective experience, and behavior daily for three months using smartphones and wearable biometric sensors. Data obtained for these static and dynamic risk indicators will provide the foundation to accomplish the following Specific Aims: 1. Assess burden (feasibility, cost, and patient acceptability) to collect innovative, densely sampled risk indicators via smartphone and wearable sensors. 2. Use machine learning methods to develop, train, and validate a real-time quantitative lapse risk prediction signal based on static and dynamic risk indicators. 3. Use innovative Markov decision process models to optimize decisions about if, when, and how to provide additional treatment or support. 4. Integrate and deliver risk prediction and decision model within the Comprehensive Health Enhancement Support System for Addiction (A-CHESS) program. These project aims position A-CHESS to make relapse prevention and recovery support, information, and risk monitoring available to patients continuously. Compared to conventional continuing care, A-CHESS will provide personalized care and be available and implemented during moments of greatest need. Integrated real-time risk prediction holds substantial promise to encourage sustained recovery through adaptive use of these continuing care services.
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1 |
2015 — 2019 |
Curtin, John J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Rct Targeting Noradrenergic Stress Mechanisms in Alcoholism With Doxazosin @ University of Wisconsin-Madison
? DESCRIPTION (provided by applicant): Current pharmacotherapy or alcohol and drug addiction yields relatively low probability for attaining long- term recovery. The recent dramatic reduction in R&D by the pharmaceutical industry for novel medications to treat psychiatric conditions, particularly substance use disorders, provides a strong impetus to repurpose currently available compounds that may be effective treatment alternatives. Orally available, brain-penetrant ?1-noradrenergic (NE) receptor antagonists are widely used to treat hypertension. Additionally, ?1-NE antagonists are increasingly used to treat post-traumatic stress disorder (PTSD), consistent with the well- documented role of NE in mediating multiple behavioral and physiological processes in stress. Stress is a significant contributor to alcohol/drug relapse. Stress-related reinstatement is a well-validated animal model of addiction and ?1-NE antagonists reduce relapse in this animal model. NIAAA Director George Koob has made strong calls for translational research on stress-mechanisms in humans. This preclinical evidence in animals suggests the use of ?1-NE antagonists may be useful in relapse prevention including stress-related relapse. To test this hypothesis, we propose two complementary preclinical and clinical objectives in humans: 1. To translate the preclinical evidence from animal models to stress-induced relapse in humans via direct pharmacological antagonism of the NE system in abstinent alcoholics with doxazosin, an ?1-NE blocker. 2. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in abstinent alcoholics as a cost-effective first step to repurpose this ?1-NE antagonist for relapse prevention in addiction. Thes two objectives will be accomplished in a randomized controlled trial (RCT) of recently abstinent alcoholics, to examine the efficacy of 8 mg doxazosin (vs. placebo, between-subjects) on stress reactivity and clinical outcome measures (e.g., drinks/week, alcohol craving) during a 8 week treatment period. We assess doxazosin's impact on stress-related relapse mechanisms using a well-validated human model of stressor reactivity (NPU task) at baseline (pre-treatment), and after 4 weeks and 8 weeks of treatment. The NPU task has strong translational ties to both methods and measures from the preclinical literature in animals. This task has demonstrated reliable, robust effects of drug administration and drug deprivation in drug dependent users. As such, it serves as an attractive early surrogate endpoint post-treatment to assess treatment efficacy and examine stress mechanisms. Repurposing existing pharmaceutical agents has recently been promoted by NIH director, Francis Collins, as a research priority. Tom Insel and others have strongly advocated for the development and use of early surrogate endpoints in clinical research. This project aligns well with the NIMH RDoC focus on dimensions of observable behavior and neurobiological measures in psychopathology research. This project also anticipates changes at NIMH to capitalize on simultaneous examination of mechanism and outcome in RCTs.
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1 |
2019 — 2021 |
Curtin, John J. Shah, Dhavan (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Contextualized Daily Prediction of Lapse Risk in Opioid Use Disorder by Digital Phenotyping @ University of Wisconsin-Madison
PROJECT SUMMARY Opioid use disorder is increasingly widespread, leading to devastating consequences and costs for patients and their families, friends, and communities. Available treatments for opioid and other substance use disorders (SUD) are not successful at sustaining sobriety. The vast majority of people with SUD relapse within a year. Critically, they often fail to detect dynamic, day-by-day changes in their risk for relapse and do not adequately employ skills they developed or take advantage of support available through continuing care. The broad goals of this project are to develop and deliver a highly contextualized, lapse risk prediction models for forecasting day-by-day probability of opioid and other drug use lapse among people pursuing drug abstinence. This lapse risk prediction model will be delivered within the Addiction-Comprehensive Health Enhancement Support System (A-CHESS) mobile app, which has been established by RCT as a state-of-the-art mHealth system for providing continuing care services for alcohol and substance use disorders. To accomplish these broad goals, a diverse sample of 480 participants with opioid use disorder who are pursing abstinence will be recruited. These participants will be followed for 12 months of their recovery, with observations occurring as early as one week post-abstinence and as late as 18 months post-abstinence across participants in the sample. Well-established distal, static relapse risk signals (e.g., addiction severity, comorbid psychopathology) will be measured on intake. A range of more proximal, time-varying opioid (and other drug use) lapse risk signals will also be collected via participants? smartphones. These signals include self-report surveys every two months, daily ecological momentary assessments, daily video recovery ?check-ins?, voice phone call and text message logs, text message content, moment-by-moment location (via smartphone GPS and location services), physical activity (via smartphone sensors), and usage of the mobile A-CHESS Recovery Support app. The predictive power of these risk signals will be further increased by anchoring them within an inter-personal context of known people, locations, dates, and times that support or detract from participants? abstinence efforts. Machine learning methods will be used to train, validate, and test opioid (and other drug) lapse risk prediction models based on these contextualized static and dynamic risk signals. These lapse risk prediction models will provide participant specific, day-by-day probabilistic forecast of a lapse to opioid (or other drug) use among opioid abstinent individuals. These lapse risk prediction models will be formally added to the A-CHESS continuing care mobile app at the completion of the project for use in clinical care. These project goals position A-CHESS to make relapse prevention and recovery support, information, and risk monitoring available to patients continuously. Compared to conventional continuing care, A-CHESS will provide personalized care and be available and implemented during moments of greatest need. Integrated real-time risk prediction holds substantial promise to encourage sustained recovery through adaptive use of these continuing care services.
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