This K01 Mentored Research Scientist Award will provide the mentorship and support necessary to establish the Candidate as an independent researcher in translational psychiatric neuroscience, with a focus on bridging neuropsychopharmacology, brain imaging, and treatment studies in anxiety disorders through an integrative approach. The training component of this application builds on the Candidate's expertise in basic science research investigating the neural circuits involved in regulating extinction of fear memories, as well as her skills in basic neuroimaging methods/analysis and implementation of pharmaco-fMRI studies in healthy controls. Her advanced training will be focused on three key objectives: 1) enhanced knowledge of neuropsychopharmacology;2) advanced training in neuroimaging (fMRI) research methodology, analyses and implementation of pharmaco-fMRI in post-traumatic stress disorder (PTSD) patients;and 3) advanced understanding of the clinical aspects (etiology, assessment, and treatment) of PTSD. The career development activities will be mentored by Dr. Israel Liberzon (Primary Mentor), Dr. Sheila Rauch (Co-Mentor), Dr. Scott Peltier (Co-Mentor), Dr. K. Luan Phan (Co-Mentor), and Dr. Mohammed Milad (Consultant);a team of researchers that collectively possess non-overlapping, but highly related expertise and exceptional records of mentoring junior faculty. The proposed K01 project will take place within the Department of Psychiatry at the University of Michigan. The University of Michigan is noted for its interdisciplinary research initiatives and the Department of Psychiatry is exceptional with its subspecialty Clinics and laboratories dedicated to translational research. It is an intellectually stimulating yet supportive environment that promotes numerous opportunities for scholarly interactions, which foster collaborations, and has an established track record for mentoring junior investigators. The research component will investigate the cannabinoid system as a potential pharmacological target for improving the retention of fear extinction and its effect on the underlying neural circuits in patients with PTSD A common, empirically-validated approach to treat PTSD is Prolonged Exposure Therapy (PE), one component of which involves repeated exposure to fear-linked cues to produce "extinction" of fear. PE is generally effective, but a significant number of patients have incomplete responses or fail to sustain improvements over time. New strategies to improve efficacy and sustainability could significantly enhance remission rates and reduce the public health burden of this common disorder. Limited efficacy and lack of sustainability could be due to the fact that extinction learning, which is the active ingredient of exposure-based therapy, is vulnerable to the return of fear. Prior studies have shown that retention of extinction learning depends upon limbic-frontal brain networks (hippocampus [HPC], ventromedial prefrontal cortex [vmPFC]). PTSD patients show deficits in these regions, and in fact exhibit poor extinction retention. Adjunct interventions that address vmPFC-HPC dysfunction and redress extinction retention deficits could be particularly potent in enhancing both the efficacy and sustainability of exposure therapy for PTSD. Compelling new evidence from work by the Candidate has shown that an acute oral dose of ?9- tetrahydrocannibinol (THC), a type 1 cannabinoid receptor (CB1) agonist, given prior to extinction learning in healthy volunteers, facilitates the ability to maintain and successfully retrieve extinction memory via increased activation and functional connectivity of the vmPFC and HPC. Given that extinction retention deficits and vmPFC-HPC dysfunction have been observed in patients with PTSD, and that enhancing cannabinoid transmission helps extinction recall, the cannabinoid system is a promising target for improving the learning that goes on in therapy and perhaps increasing efficacy and durability of PE in treating PTSD (e.g., shortening treatment while strengthening and prolonging gains). However, direct tests of cannabinoid effects on extinction recall and associated neural circuits have not yet been conducted in PTSD patients. The objective of the proposed project is to test the hypotheses that administration of THC will enhance recall of fear extinction in patients with PTSD and that these effects will be mediated via increased activation and functional connectivity of the vmPFC and HPC. The Candidate will couple a standard Pavlovian fear extinction paradigm in fMRI and skin conductance response (SCR) recordings to compare the effects of THC (vs. placebo [PBO]) administered prior to extinction learning in 80 trauma-exposed individuals with (n=40) and without (n =40) PTSD and 40 healthy adult volunteers, testing extinction recall 24 hours after extinction learning. This randomized, double- blind, placebo-controlled study will provide the most direct translational and critical test of THC effects in PTSD, advancing our understanding of the neurobiology of extinction learning and potentially hastening the development of novel pharmacological modulators of the cannabinoid system to maximize the efficacy of exposure therapy for anxiety disorders. The knowledge, skills, and data obtained during this career development period will be synthesized into a R01 award application to test whether cannabinoid agonists can be used as an 'extinction recall enhancer'when coupled with conventional, validated exposure therapies to enhance the efficacy, improve extinction retention, and/or expedite the pace of treatment response in PTSD and other anxiety disorders.
Exposure therapy is a first-line approach in the treatment of post-traumatic stress disorder (PTSD) and works by repeated exposure to trauma-related thoughts, feelings, and situations in order to reduce the distress they cause. Exposure therapy is generally effective, but a significant number of patients have incomplete responses or fail to sustain improvements over time. The goal of the current proposal is to investigate the cannabinoid system as a potential pharmacological target for improving the learning that goes on in therapy and perhaps increasing efficacy and durability of exposure therapy in treating PTSD (e.g. shortening treatment while strengthening and prolonging gains).