Christina S. Meade, Ph.D. - US grants

DESCRIPTION (provided by applicant): Neurobehavioral and fMRI Research in HIV Infection and Cocaine Dependence Dr. Christina Meade's long-term goal is to establish an independent and productive program of patient-oriented research dedicated to understanding the impact of drug abuse on behavioral and clinical outcomes in persons living with or at risk for HIV/AIDS. This application presents integrated training and research plans focused on HIV neurobehavioral dysfunction. The guiding hypothesis is that co-occurring HIV infection and cocaine dependence is associated with greater neurocognitive impairment and behavioral risk compared to each disease independently. As the fields of HIV/AIDS and drug abuse evolve, transdisciplinary research has the potential to accelerate advances in the prevention and treatment of these neuropsychiatric diseases. Therefore, Dr. Meade, a licensed clinical psychologist with a strong behavioral science background in HIV/AIDS and drug abuse, aims to develop expertise in cognitive neuroscience. Specifically, she seeks advanced training in: (1) neuroAIDS and neurocognitive assessment;(2) functional magnetic resonance imaging (fMRI);(3) brain circuitry relevant to addiction and neuroAIDS;and (4) longitudinal data analysis with repeated measures and latent variables. The training plan includes didactic coursework and workshops, one- on-one mentorship, participation in working groups and seminars, and attendance at national and international conferences. Consistent with the transdisciplinary nature of the proposed research, a mentorship team with distinct but complementary areas of expertise has been assembled: Drs. Scott Huettel (fMRI and executive function), Kevin Robertson (neuroAIDS and neuropsychology), Joseph McClernon (addiction and neuroimaging), Kathleen Sikkema (behavioral aspects of HIV), Rick Hoyle (statistics and methodology), and Roger Weiss (drug addiction). Duke University provides a rich environment in which Dr. Meade's career development goals can be readily accomplished, including access to state-of-the-art neuroimaging facilities, clinical units supportive of patient-oriented research, graduate-level courses in fMRI, statistics, and neurobiology, and several directly relevant interdisciplinary research centers and institutes. The research plan has been carefully designed to parallel the training plan;for each training goal there is a corresponding research directive that will allow Dr. Meade to implement newly developed skills. Both HIV infection and stimulant abuse affect neurocognitive functioning, yet few studies have empirically examined the effects of co- occurring HIV infection and stimulant abuse on neurobehavioral outcomes. This is an important research topic due to the high prevalence of co-occurring HIV infection and stimulant abuse, and the high rates of risky and impulsive behavior in this population. The research plan has 2 studies with the following specific aims: (1) identify patterns of neurocognitive impairment in HIV infection and cocaine dependence, and test whether these are associated with risky decision making and behavioral risk;and (2) examine brain activation patterns associated with attention and decision making as a function of HIV disease progression and co-occurring versus independent HIV infection and cocaine dependence. A sample of 160 patients will be recruited for a 3- group comparison study of persons with co-occurring HIV infection and cocaine dependence, HIV infection only, and cocaine dependence only. Participants will complete a battery of neurocognitive and behavioral measures;results will be analyzed using latent variable techniques. A subset (25 from each group, 75 total) will participate in an fMRI experiment that examines brain activity during attention and decision tasks;within and between group analyses will be conducted. This integration of behavioral and cognitive neuroscience techniques is novel and innovative, and results may help shed light on the mechanisms underlying neuropsychiatric disorders characterized by risk taking and impulsivity. This line of research has the potential to improve techniques for early identification of neurocognitive impairment and guide the development of transformative treatment approaches to improve behavioral and clinical outcomes in this population. Moreover, as a clinician, Dr. Meade will be uniquely poised to translate these findings into clinical practice. In sum, the proposed K23 award will provide the advanced training and mentored research necessary for Dr. Meade to become a nationally recognized expert in the neuropsychiatry of drug abuse and HIV/AIDS and to conduct transdisciplinary research in this evolving field. PUBLIC HEALTH RELEVANCE: Over 1 million Americans are living with HIV/AIDS, with approximately 56,000 new infections each year in the United States. Stimulant abuse, primarily cocaine and methamphetamine, is common among HIV-infected adults and is associated with continued sexual risk taking, poor treatment adherence, and other risky behaviors. A better understanding of the underlying mechanisms associated with neurobehavioral dysfunction in HIV-infected drug abusers may guide the development of innovative prevention and treatment approaches.

DESCRIPTION (provided by applicant): Scope of Work Problem: South Africa, particularly the Western Cape, has experienced a dramatic rise in methamphetamine use over the past decade and also has the largest number of HIV-infected individuals (5.3 million) of any country in the world. It is feared that methamphetamine use may further fuel this HIV epidemic because of its association with risky sexual behaviors. Despite widespread concern about methamphetamine, there has been limited research examining the intersection of the methamphetamine and HIV epidemics in South Africa. Aims: The primary purpose of this exploratory study is to characterize the patterns and severity of drug use among methamphetamine users in Cape Town, and to identify the multiple levels of influence on HIV sexual risk behavior in this population (Aims 1 and 2). We will apply Ecological Systems Theory, which views behavior as reciprocally influenced by factors from the individual, social, environmental, and community levels, as an organizing framework for this research. A secondary purpose is to test the feasibility of using respondent driven sampling (RDS) to recruit methamphetamine users for future HIV prevention studies (Aim 3). Method: Following a phase of formative research to inform the recruitment strategy and pilot test the assessment battery, we will use a chain referral approach to enroll a convenience sample of 160 male and female methamphetamine users from a township in Cape Town for a multi-method study. All participants will complete a quantitative survey that assesses patterns of methamphetamine use and history of substance abuse treatment; rates of sexual risk behavior and use of HIV-related services; and correlates of sexual risk behavior at multiple levels of influence. A sub-sample of 30 participants will be selected for in-depth qualitative interviews to explore patterns of methamphetamine use, progression from casual use to addiction, and the social context of drug use; how methamphetamine use contributes to sexual risk behavior; and barriers and facilitators to drug cessation and treatment, safer sex practices, and HIV testing. Finally, we will test the feasibility of using RDS to enroll methamphetamine users in Cape Town into future HIV prevention research by conducting formative research to determine the suitability and acceptability of this recruitment method and to calibrate the method for this population, and by analyzing the chain referral data to determine whether RDS requirements are met. Significance: This timely proposal, among the first to target methamphetamine users in South Africa, will advance the field of HIV prevention by examining how methamphetamine use may contribute to HIV sexual risk behavior in a sample of non-injecting and primarily heterosexual drug users. The goal of the proposed research is to identify key factors that will inform the development of integrative prevention interventions to reduce methamphetamine use and sexual risk behaviors in the population.

DESCRIPTION (provided by applicant): Individuals addicted to stimulant drugs like cocaine are at high risk for engaging in sexual behaviors that contribute to the acquisition of HIV and, once infected, to the forward transmission of HIV to others. HIV-related decision making, like most real-world decisions, involves the valuation of potential gains and losses in the context of uncertain outcomes. Cocaine dependence and HIV infection can each disrupt brain circuits that regulate executive functions involved in decision making. We postulate that these neural changes affect the processing of reward evaluation and outcome uncertainty and contribute to sexual risk behavior. Our preliminary work suggests that cocaine dependence increases loss aversion (i.e., overweighting of potential losses relative to potential gains), and that HIV infecton is associated with greater risk taking propensity among persons with cocaine dependence. Moreover, loss aversion is positively correlated with sexual risk behavior, suggesting that basic decision making processes may be predictive of more complex real-world behavior. The proposed research builds upon our prior work by combining functional neuroimaging, behavioral risk assessment, and computational modeling to: (1) isolate the effects of cocaine dependence and HIV infection on decision making processes, specifically loss aversion and ambiguity tolerance, and (2) examine the relationship between these decision making processes and sexual risk behavior. Using a case-control design, we will examine behavioral choice and brain activity during monetary gambles that vary independently on the value of gains and losses and the certainty of outcomes. The sample will include 80 adults who differ on cocaine and HIV status, comprising four distinct groups (20/group). Our multidisciplinary team, with expertise in clinical psychology, cognitive neuroscience, behavioral neuroeconomics, and MR physics, has extensive experience conducting patient-oriented research on HIV risk behavior in persons with drug dependence and is uniquely poised to successfully implement this innovative and clinically important project. Results of this R21 proposal will provide unique insights into the mechanisms underlying HIV-related decision making, providing support for a subsequent R01 application to further investigate how HIV disease progression may affect neural processes that contribute to risky decision making among cocaine users. This research has strong potential for translation to clinical practice, informing the development of novel interventions to more effectively reduce risk behavior by directly targeting underlying neurocognitive deficits, with the ultimate goal of reducing HIV- related morbidity and mortality in persons with drug use disorders.

Project Summary Marijuana is the most common drug of abuse among HIV-infected persons in the United States. Of the 1.2 million Americans living with HIV/AIDS, over half experience neurocognitive impairment, including deficits in executive control. Previous research has documented that marijuana and HIV independently disrupt functioning in the fronto-parietal executive control network of the brain, and white matter damage is an integral part of HIV-associated neuropathology. However, the interactions of marijuana and HIV on brain functioning and structure have not been well characterized. In this Imaging - Science Track Award for Research Transition (I/START) grant, we propose to combine multi-modal magnetic resonance imaging (MRI) and neuropsychological assessment to test whether marijuana use and HIV infection have synergistic effects on neurocognitive impairment, specifically in executive control functions, and how differences in brain function and structure relate to neurocognitive impairment. Using a case-control design, we will assess 60 adults across four study groups who differ on marijuana and HIV status (15/group). The specific aims are to examine white matter integrity using diffusion tensor imaging (DTI), functional connectivity using resting state functional MRI (RS-fMRI), and the relationship between neurocognitive impairment and these MRI data . Our multidisciplinary team, with expertise in clinical psychology, cognitive neuroscience, and MR physics, has extensive experience conducting patient-oriented research with HIV-infected drug users and is uniquely poised to successfully implement this innovative and clinically important project. The overarching goals of this research are to elucidate brain regions affected by marijuana and HIV that contribute to observed neurocognitive impairments in HIV-infected marijuana users. Results of this I/START grant will provide support for a subsequent R01 application to further investigate the role of marijuana in predicting neurocognitive decline in patients with early, middle, and advanced stages of HIV disease and test how frequency and chronicity of marijuana use moderate outcomes. This research has strong potential for translation to clinical practice (e.g., use of medical marijuana to treat HIV-related symptoms and integration of substance abuse treatment into HIV care) and will inform the development of neural biomarkers for early identification of neurocognitive decline in drug users, with the ultimate goal of reducing HIV-related morbidity and mortality in the many HIV-infected persons who abuse drugs.

? DESCRIPTION: Individuals addicted to illicit stimulants like cocaine play an important role in the continued transmission of HIV due to high rates of sexual risk behavior and, among those already infected, poor adherence to antiretroviral therapy. The field of neuroAIDS has provided convincing evidence that persons with HIV infection and/or drug addiction are more likely to experience deficits in decision making that are potentially relevant to HIV risk behavior. However, case-control designs and laboratory-based measures of decision making have been limited in predicting HIV risk behaviors in the real world. The goal of this Avenir Award is to advance our understanding of the cognitive mechanisms through which drug addiction and HIV infection impact decision- making processes relevant to HIV risk behavior. Specifically, this proposal addresses the following limitations of the field: (1) modeling addiction as a static condition rather than a chronic, relapsing disorder, with studies utilizing strict eligibility that minimize generalizability to the population and analyses that do not adequately account for variability and fluctuations in drug use; (2) cognitive assessments in controlled laboratory settings intended to optimize performance; and (3) reliance on convenience sampling for a hard-to-reach population. The proposed Avenir project will: use respondent driven sampling to engage a heterogeneous cohort of cocaine users, both HIV-positive and HIV-negative, from the community; conduct trimonthly laboratory-based assessments of neurobehavioral functioning over 1 year to capture natural fluctuations in drug use, decision making, and HIV risk behavior; and use mobile health (mHealth) technology to assess cognitive functioning and risk behaviors in real-time in natural settings. During an initial period of formative work, including focus group with the target population, we will adapt three widely used decision making tasks and develop an app for mobile devices. We will then screen and enroll 200 participants into the neuroAIDS cohort. Between the 3- and 6- month follow-ups, cohort participants will use a smartphone to record daily drug use and HIV risk behavior and complete ecological momentary assessments of decision making, drug state (e.g., craving, intoxication) and context (e.g., setting, social situation). This Avenir project builds logically from my previous research on decision making and HIV risk, integrating multi-disciplinary techniques to advance our understanding of HIV-related decision making in drug users. Through the use of innovative approaches to improve the

Project Summary Even in the era of widespread combination antiretroviral therapy, over half of HIV-infected patients experience HIV-associated neurocognitive impairment (NCI). NCI is driven in part by persistent neuro- inflammation with activated monocytes and T cells playing pathogenic roles. Marijuana and cocaine, two of the mostly commonly abused drugs among HIV-infected persons, cause alterations in neural and cognitive functioning, and have significant immunomodulatory effects. While the effects of HIV infection and drug abuse on immune dysfunction and inflammation, brain structure/function, and NCI have been independently studied, the complex interactions between these biological systems are poorly characterized. Our preliminary work suggests that cocaine and marijuana use have discordant effects on NCI in persons with HIV, with differential impacts across domains of cognitive function. In addition, research has shown that stimulants like cocaine induce an activated immune state, whereas marijuana has anti-inflammatory effects. Building on the prior work of our multi-disciplinary team, with complementary expertise in neuroscience, drug addiction, HIV immunology, and computational biology, the proposed research uses a systems biology approach to investigate the effects of cocaine and marijuana on immune function, brain structure/function, and neurocognition in HIV-infected persons. We aim to: (1) identify the independent and joint effects of cocaine and marijuana use on MRI measures of cerebral volume, white matter integrity, and functional connectivity, and on behavioral measures of neurocognition; (2) quantify differences in peripheral and CNS immune function between marijuana and cocaine users; and (3) employ a systems biology approach to integrate immunology, neuroimaging, and behavioral data into a multi-level predictive model. Our guiding hypothesis is that cocaine induces an immune activated state that causes alterations in brain structure/function and cognitive impairment, while marijuana attenuates these effects through anti-inflammatory processes. The sample will include 150 adults with HIV infection who use cocaine only, marijuana only, cocaine and marijuana, or neither drug, comprising 4 distinct groups (~37/group). At study completion, we will have produced a comprehensive, multi-disciplinary dataset, and our systems biology approach will provide significant insights to generate novel hypotheses for future research on the complex biological intersection of HIV and substance use. This proposal addresses both a critical need to identify ?factors that impact differences in neurocognitive impairment in association with specific patterns of substance abuse? [RFA-DA-16-013] and multiple high priority topics for AIDS-designated funding, including investigation of HIV-associated comorbidities such as neurological complications and understanding the basic biology of immune dysfunction and HIV transmission [NOT-15-137]. This innovative project has strong potential to elucidate the complex biological mechanisms through which HIV infection and drug abuse impact NCI, and to identify appropriate targets for novel therapeutics and clinical interventions.

Project Summary Of the 1.2 million Americans living with HIV, over half experience neurocognitive impairments (NCI) that adversely affect daily living and are predictive of increased morbidity and mortality. HIV-infected individuals who are addicted to stimulant drugs like cocaine are at even higher risk for NCI, which contributes to impulsive decision making, and engage in high rates of risky behaviors that are associated with both poor clinical outcomes and HIV transmission to others. Delay discounting, a key aspect of impulsivity, describes the tendency to devalue a reward as the delay to its receipt increases. Individuals addicted to drugs tend to prefer smaller, immediate rewards over larger, delayed rewards. Excessive discounting is associated with a wide range of other health risk behaviors, including risky sex. The Competing Neurobehavioral Decision Systems model posits that excessive discounting results from greater relative strength of the impulsive system over the executive control system. Our own work suggests that HIV infection modulates the effect of cocaine on brain functioning in the executive control network during delay discounting. Prior research supports a robust association between excessive discounting and working memory impairment. As a core executive function that supports self-regulation, working memory is theoretically an intervention target for HIV risk reduction. Computerized working memory training has been shown to decrease delay discounting in stimulant users, but it has not yet been tested in HIV-infected drug users. The proposed R21 study will test the preliminary efficacy of a computerized cognitive training program to improve working memory and reduce delay discounting in HIV- infected cocaine users. Using a randomized trial design, we will assign 50 participants to either the experimental cognitive training condition or an attention-matched control condition. Participants will complete 16 sessions in 8 weeks, with assessments at baseline, post-training, and 1-month follow-up to evaluate intervention effects. We hypothesize that cognitive training will, relative to the control condition, lead to greater improvements in working memory and reductions in delay discounting. We will also examine change in HIV risk behaviors (cocaine use, risky sex, and medication adherence). Results will support an R01 application for a larger scale trial to rigorously test the impact of cognitive training on HIV-related behavioral and clinical outcomes. This innovative line of research has important translational implications for HIV clinical practice, including dissemination in resource-limited settings with few neuropsychology specialists. This proposal directly advances a high priority topic for AIDS-designated funding by testing a novel treatment for HIV- associated NCI in drug users. By focusing on a high-risk population that continues to drive HIV transmission, this research has strong potential to improve neurobehavioral functioning in HIV-infected persons, and ultimately to reduce the incidence of new HIV infections.

Project Summary Despite widespread use of antiretroviral therapy, nearly half of the 1.2 million Americans living with HIV experience neurocognitive impairments (NCI) that negatively impact daily functioning. HIV-associated NCI is estimated to be the most common form of midlife NCI worldwide. Drug abuse, a highly prevalent comorbidity in HIV+ persons, increases the risk of HIV-associated NCI. Unimodal MRI studies have shown that HIV and drug abuse are each linked with a distinct set of structural and functional alterations in the brain, but how they interact is not well understood. Conventional unimodal analyses are limited in their ability to characterize complex neuropsychiatric diseases because each modality provides an incomplete view of the brain. In contrast, we propose to use innovative fusion approaches that exploit the richness of multimodal data to discover covariations across multiple neuroimaging modalities and cognitive measures simultaneously. This proposal capitalizes on existing data from 3 completed NIDA-funded projects on the neurobehavioral effects of HIV and drug abuse. When combined, the dataset will consist of 217 unique cases (108 HIV+ and 109 HIV-) with in-depth substance use histories, multimodal brain images (i.e., structural, diffusion, and resting-state functional MRI), comprehensive neurocognitive batteries, and a wide range of other phenotypic data. The central hypothesis is that HIV-specific co-alterations in gray matter volume and white matter integrity shape neural functioning and in turn NCI, and that cocaine use worsens these alterations due to its long-term effects on neural circuitry. Using complementary multimodal analyses (supervised fusion and connectomics), we aim to: (1) identify neural biomarkers of HIV neurological disease and associated NCI; and (2) test cocaine as a moderator of HIV-specific co-alterations in brain structure and function and associated NCI. In addition, the project will develop new, advanced methods to improve MRI data quality for cross-study harmonization and to optimize the prediction of NCI based on multimodal indices. This amalgamated dataset provides an unprecedented opportunity to test new and clinically important hypotheses about the neural substrates of HIV- associated NCI in the context of drug abuse. The proposal responds directly to the need for research to ?characterize brain morphology or function that is aberrant as a consequence of chronic drug use? and ?[its role] in the evolving dynamics of HIV/AIDS pathogenesis, treatment, prevention, and service delivery? [PAR- 16-234]. This research also addresses high priority topics for AIDS-designated funding, including investigation of neurological complications [NOT-15-137]. Building upon a sound premise and robust preliminary data, this innovative project has strong potential to identify appropriate neural biomarkers of neuroHIV that may facilitate diagnosis and treatment monitoring in active drug users and serve as targets for clinical interventions to mitigate the burden caused by HIV-associated NCI.

Project Summary Despite widespread use of combination antiretroviral therapy (cART), nearly half of HIV+ Americans will experience HIV-related neurological comorbidities that negatively impact daily functioning and clinical outcomes. Alterations in brain structure and function are consistently linked to HIV-associated neurocognitive disorders (HAND), but the mechanisms through which HIV causes alterations in neural networks and associated cognitive function are not well characterized. Marijuana use, which is disproportionately prevalent among HIV+ persons, may increase the risk of HAND. Our preliminary work suggests that co-occurring marijuana use and HIV infection intensifies dysfunction in major neural networks, including white matter abnormalities and decoupling of functional activation patterns. Capitalizing on a strong foundation of neurobehavioral research on drug addiction and HIV/AIDS by our multidisciplinary team, the proposed research will apply connectomic analyses to achieve the following aims: (1) examine the independent and interactive effects of HIV and marijuana on structural and functional organization of the brain; (2) investigate the longitudinal relationship between network-level disruptions in brain organization and cognitive impairment; and (3) use machine deep learning algorithms to develop individualized prediction models for HAND diagnosis and severity based on multimodal graph features. Using a cross-lagged panel design, 200 adults stratified by HIV and marijuana status (4 groups) will have multimodal MRIs and cognitive testing at baseline and 1 year later. The central hypothesis is that marijuana use will exacerbate structural and functional disruptions in brain organization that underlie the expression and progression of HAND. Our proposal responds directly to RFA-18- 610, which highlights the need for studies on ?the underlying mechanisms whereby drugs of abuse and HIV infection interact to impair CNS functions mediated through altered neuronal networks.? This research uses a team science approach to address high priority topics for AIDS-designated funding, including neurological complications [NOT-15-137]. Building upon a sound premise and robust preliminary data, this innovative project has strong potential to identify appropriate neural biomarkers that may aid in the diagnosis and monitoring of HAND in persons with chronic substance use disorders and serve as targets for novel clinical interventions. In addition, our classification models are expected to provide a generalizable framework applicable to individual patients for tailoring of treatment approaches.

Marijuana, the mostly widely used illicit drug in the United States, is disproportionately prevalent in persons with HIV. Despite the promise of cannabinoids as a therapeutic agent for HIV disease, chronic marijuana use is also associated with potential neurobiological harms. Neurological complications of HIV disease remain a persistent clinical problem even in the age of combination antiretroviral therapy. Our prior work demonstrates that chronic marijuana use exacerbates HIV-associated cognitive deficits, even in patients with sustained HIV suppression, and is associated with complex brain abnormalities in persons with HIV. Additional preliminary data shows reduced levels of inflammatory cytokines in marijuana users compared to non users that correlate with cognitive function. Building on a strong foundation of neuroHIV and addiction research by our multidisciplinary team, this hypothesis-driven proposal will use an in vivo model to investigate the underlying pathophysiological mechanisms of HIV-associated brain dysfunction. Using this translational approach, we aim to: (1) investigate the independent and additive effects of HIV disease and chronic marijuana use on inflammatory processes linked to brain injury; (2) model the longitudinal relationship of chronic marijuana use to HIV-induced inflammation and its relationship to brain injury; and (3) determine the relationship of cannabinoid metabolites to inflammatory and neuronal markers. A prospective cohort of 140 adults stratified marijuana status will complete cutting-edge neuroimaging, immune and cytokine profiling, and neuropsychological testing three times over 2 years. Capitalizing on ultrahigh-resolution magnetic resonance imaging (MRI) capabilities at Duke, we will use multimodal, multi-parametric sequences to investigate neuroinflammatory and neurodegenerative processes. The baseline will include comparison groups of 80 HIV- negative adults. The central hypothesis is that marijuana use disrupts the central nervous system through both anti-inflammatory and neurotoxic pathways. Our proposal responds directly to RFA-DA-20-022, which calls for mechanistic studies to ?discern the impact of chronic and/or heavy use of cannabis on the interaction between endocannabinoid system function and HIV-induced inflammation? and ?its consequent effects on nervous system function.? This research uses a team science approach to address topics aligned with NIH HIV/AIDS research priorities, including a focus on persistent inflammation and HIV-relevant comorbid conditions [NOT- 20-018]. By considering both beneficial and adverse effects of marijuana available in the United States market, our proposal has strong translational potential to guide clinical recommendations for medical and recreational marijuana in persons with HIV. This timely and ecologically valid research is also expected to advance our understanding of the inflammatory mechanisms through which cannabinoids modulate neurological disorders and other comorbidities in persons with HIV.