Deborah Yurgelun-Todd - US grants

[unreadable] DESCRIPTION (provided by applicant): The overall aims of this revised proposal are to build on existing MRI/functional MRI capacity in South Africa and to apply newly implemented structural and functional imaging techniques to examine brain function in adolescents of the Western Cape region of South Africa who are heavy users of methamphetamine alone or in combination with cannabis. Over the past several years we have initiated a research collaboration between the Brain Imaging Center (BIC) at McLean Hospital, Harvard Medical School and the Brain Imaging Group (BIG) at the University of Stellenbosch made possible through a NIDA sponsored supplementary grant award. The proposed R21 is designed to consolidate and extend this collaboration by training collaborative South African partners in MR methodology and the application of MR techniques while simultaneously collecting data on the effects of methamphetamine and cannabis use. Functional magnetic resonance imaging capacity, recently installed in South Africa, will be expanded by a) providing workshops and tutorials on fundamental concepts underlying MR methods; b) describing strategies for optimization of structural and functional imaging protocols in order to maximize image quality and facilitate optimal co- registration of functional to structural data at the individual level; c) reviewing approaches for development and validation of neurocognitive activation paradigms for use with fMRI; d) training of South African investigators in image processing and analysis of morphometric and functional imaging data to develop independent image analysis capacity using SPM and brain voyager software and; e) evaluating hardware and software needs for implementing MR spectroscopy. These fMRI techniques will be applied to test the hypothesis that frontal dysfunction, as measured by reduced BOLD signal in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) will be present in adolescents, aged 13-17, of the Western Cape region of South Africa, who are heavy users of methamphetamine alone (n=10) or in combination with cannabis (n=10), relative to matched non-using controls (n=10). An R01 application will then be prepared based on the data acquired during the R21 period. [unreadable] [unreadable] [unreadable]

The overall aim of our proposed study is to examine the effects of marijuana on the development of frontal lobe systems and their function in marijuana-smoking adolescents and healthy non-using adolescents by applying a complementary set of magnetic resonance (MR) techniques and neuropsychological assessments. Our previous investigations have identified age-related differences in cognition, morphometry and functional magnetic resonance imaging (fMRI) in healthy adolescents. Furthermore, we have found an association between early onset of marijuana use and poorer neuropsychological performance, as well as abnormal cortical activation in the anterior cingulate and dorsal lateral prefrontal cortex on measures of motor and memory function shortly after cessation of marijuana use in adults. We therefore propose to examine the effects of age of onset of marijuana use in two adolescent cohorts: 1) a 14 year old cohort who report a minimum of 100 episodes of using marijuana;and 2) an 18 year old cohort who report the same amount of marijuana usage, but who did not begin smoking until after their 16thbirthday. Both groups will be compared to age matched non- smoking adolescents. Although significant evidence has accumulated indicating an association between marijuana use and altered frontal-executive function, it has been difficult to study and document functional human brain changes associated with marijuana, particularly during adolescence. In this proposal, we will take advantage of the high spatial resolution and increased signal to noise offered by complementary high field MR techniques to investigate chemical and functional effects of marijuana use in frontal brain regions that are known to undergo maturational refinements during adolescence. Specifically, this study will incorporate focal functional MR BOLD techniques using cognitive and affective challenge paradigms at 3 Tesla, and single voxel GABA spectroscopy of the cingulate at 4 Tesla, with neuropsychological measures of executive function, in order to address the question of whether developing frontal brain regions are more vulnerable to illicit drug use when there is an early versus late onset of marijuana use. We believe these complimentary measures of brain function will provide new insights into the neural mechanisms of inhibitory processing and decision- making in adolescents who abuse marijuana, which has implications for early intervention and remediation.

? DESCRIPTION (provided by applicant):Project Summary This cooperative agreement (U01) application responds to NIH RFA-DA-15-015, Adolescent Brain Cognitive Development (ABCD) study, 5/9 Research Site of the Prospective Research in Studies of Maturation (PRISM) Consortium. The Consortium's objective is to establish a national, multisite, longitudinal cohort to prospectively examine the neurodevelopmental and behavioral effects of substance use (SU) from early adolescence through the period of risk for SU and SU disorders. This 10-year longitudinal study of 11,000 children will measure brain development, SU, cognition, emotion, executive function, mental health, physical health, environment, and collect biospecimens for future genetics and epigenetic studies. The Consortium has an optimized research protocol and 4 specific aims: 1) Using advanced multi-modal neuroimaging to evaluate premorbid factors and the impact associated with diverse patterns of SU on the structure and function of the developing brain. 2) Disentangle the predictors and consequences of diverse patterns of SU on physical health, psychosocial and cognitive development, academic achievement, motivation and emotional regulation. 3) Examine how the quantity and combination of substances used affect the expression of psychopathology and, conversely, how the emergence of psychopathology influences SU. 4) Assess how each substance used contributes to the use of other substances (gateway interactions). The Utah site has three sets of specific aims involving (1) Imaging; (2) Family/Genetics; and (3) Special Populations. Imaging Aims: (a) participation in the MRS/QSM substudy with JHU and UH (see JHU project for details) and (b) participation in the perfusion imaging substudy along with Penn, UCLA, and UH (see Penn project for details). Family/Genetics Aims: (a) Cross register all Utah subjects with data contained in the Utah Population Database (UPDB: http://healthcare.utah.edu/huntsmancancerinstitute/research/updb/, the UPDB is the only database of its kind in the United States and one of few such resources in the world). The central component of the UPDB is an extensive set of Utah family histories, in which family members are linked to demographic and medical information and (b) over-enroll siblings, which is made possible by the large family size and the relatively short inter-pregnancy interval of Utahns. Special Population Aims: (a) evaluate a unique adolescent population, those who use marijuana but who have never used other drugs and (b) over-enroll Native American participants, who are known to have substantially higher rates of alcohol-related mortality. Our site is uniquely qualified to be part of the Consortium because of our extensive experience with cognitive assessment and imaging studies of drug-using youth. In addition, the UPDB creates an unprecedented research opportunity at our site. We believe that our contributions in these areas complement those of other outstanding consortium members to collectively achieve the overall goals of the PRISM Consortium.

Project Summary/Abstract: Chronic pain is a prevalent disorder affecting approximately 100 million Americans. Treatment of chronic pain has heavily relied on opioid drugs, however; the use of opioids is accompanied with significant shortcomings including lack of efficacy in the long term and the risk for dependence that has contributed significantly to the national opioid epidemic. Thus, development and identification of novel strategies for pain management in chronic pain is a critical unmet need. A burgeoning body of literature suggests that the Cannabis plant has analgesic properties, with reported therapeutic effects ranging from substantial to conclusive in both preclinical and clinical studies. The main psychoactive constituent in the cannabis plant, tetrahydrocannabinol (THC) has demonstrated analgesic effects, however; its use is limited by adverse psychoactive and cognitive effects. However, not all isomers of THC demonstrate psychoactive effects. For example, cannabidiol (CBD) has been shown to demonstrate analgesic properties without psychoactive effects. The biological mechanisms underlying the analgesic efficacy of CBD are relatively unexplored and hence mechanistic studies investigating this research question are needed. CBD has a complex pharmacology with agonist and antagonist activity at several receptors including but not limited to endocannabinoid CB1 and CB2 receptors, serotonin 5-HT1A receptors, gamma-amino butyric acid receptors (GABA-A), and vanilloid receptors. In addition, CBD is a potent anti-inflammatory and has shown to decrease levels of cytokines and other pro-inflammatory signaling molecules. The goal of the proposed study, which responds to RFA-AT-19-009, is to evaluate changes in brain chemistry after a short-term (5-day) administration of a cannabis extract enriched in CBD using proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS allows the measurement of in vivo levels of brain metabolites such as N-acetylaspartate, creatine, lactate, glutamate, GABA, glutamine (Gln), and myoinositol (mI). MRS studies of chronic pain have demonstrated changes in glutamate and GABA signaling in critical pain-processing regions of the brain. Furthermore, chronic pain has also been associated with increased levels of pro-inflammatory signaling molecules. Thus, pharmacological agents that can modulate central glutamate and GABAergic tone may exhibit potent analgesic activity. With the proposed study, we aim to investigate whether a short-term administration of a cannabis extract enriched in CBD can modulate glutamate and GABAergic signaling in critical pain-processing regions of the brain such as the anterior cingulate cortex (ACC) and insula. Furthermore, we plan to investigate the effects of CBD on peripheral and neural markers of inflammation. The successful completion of the study will advance the evidence-based application of CBD as a potential treatment for pain conditions and will also provide substrates that can be targeted to reduce neuroinflammation.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child?s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.