Brain Function and Connectivity in Methamphetamine Dependence: The Link to Neuroinflammation and the Effects of Ibudilast

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Candidate: I have had extensive training in fields of neuroimaging and the neurobiology of drug abuse. My work has focused on investigating the effects of dopamine signaling in neural circuits with a focus on risky decision-making and addiction-related phenotypes. This work has led to 12 publications in top-tier journals with 6 as first-author, multiple speaking engagements and 6 NIH fellowship awards. With a long-standing commitment to contribute to the health of veterans, I am dedicated to developing an independent research career at the VA focused on using multi-modal imaging to understand the pathophysiology of addiction but with a focus on treatment and interventions. Environment: I am pursuing this line of work at the VA Portland Health Care System and Oregon Health & Science University, which are physically connected by an indoor sky bridge and allows complete access to a multitude of collaborative laboratories and seminars. Through joint appointments I will have access to a full range of technical and computing resources along with scientific/consultative support services. The activities of the proposed project will occur with shared resources and facilities, including advanced imaging equipment such as the Siemens 3T PRISMA MAGNETOM Trio and positron emission tomography (PET). Research Methamphetamine (MA) use disorder is a major health problem facing our veterans. As veterans with MA-use disorder are more likely to experience a disruption in care, an integrated approach combining traditional treatment options and pharmacological interventions are essential in developing a comprehensive treatment program. Although both inflammation and MA use dysregulate dopamine function, the mechanistic link between MA-induced neuroinflammation and dopaminergic brain deficits has not been studied. This study will therefore test a model whereby MA-induced neuroinflammation and its reduction with ibudilast influences brain function and behavior in veterans with MA-use disorder. The first aim of the project will compare veterans with and without MA-use disorder to determine whether MA-induced neuroinflammation is associated with impairments in cognitive control and abnormalities in functional connectivity of neural networks and brain activation in response to reward in the mesocorticolimbic system. Neuroimaging measures will include PET to quantify neuroinflammation; resting-state functional magnetic resonance imaging (fMRI) to assess functional connectivity of neural networks and fMRI paired with the Monetary Incentive Delay Task (MID) to measure brain activation in response to reward. We will then assess whether a 6-week treatment of ibudilast, an anti-inflammatory reduces neuroinflammation and improves brain function and behavior in a randomized placebo-controlled study in veterans with MA-use disorder. If inflammation is associated with functional brain deficits and ibudilast is proven effective in restoring function and connectivity of neural networks, the results would be of great value in identifying biomarkers associated with stimulant use and has the potential to advance therapeutic strategies for addiction. Research and training goals In order to develop a broad set of research tools for this project and promote my goal as an independent researcher, my training plan is designed to broaden my skills in neuroimaging, pharmacotherapy and the design and development of clinical trials. The training will include formal didactic training, hands-on laboratory experience, one-on-one supervision, and a series of meetings and workshops sharply focused on these goals. In addition, I will receive career training from my mentor and co-mentors on laboratory best practices including personnel management and fiscal accounting. Formal workshops will extend this training by providing practical sessions and education seminars on communication and leadership skills. Training to acquire these new experimental capabilities allows me to take the next step in translational research and to investigate the mechanism of neural deficits at a more clinical level as proposed.