Experimental Manipulation of the Emotional Salience of Cannabis Use-Related Information - PROJECT SUMMARY Given the rising prevalence of daily cannabis use, the tremendous public health burden of Cannabis Use Disorder (CUD), and the low treatment-seeking rates in people with CUD, it is becoming increasingly important to understand the mechanisms through which disordered use is maintained and recovery is thwarted. Recognizing and giving credence to the negative consequences of chronic drug use is a vital prerequisite for behavior change. Emerging evidence suggests that the closely connected medial orbitofrontal cortex (mOFC) and rostral anterior cingulate cortex (rACC) are key neurobiological substrates involved in these processes. A neural measure related to mOFC activity, along with mOFC itself, have been implicated in the processing of self-referential substance use-related statements. Further, altered OFC and rACC connectivity was associated with denial of substance-related problems, while rACC activation was inversely correlated with perceived need to change substance use. Additionally, a neural signal related to ACC activity was altered in individuals with severe CUD who had reduced self-awareness of their behavior during a drug choice task. Altogether, these studies point to aberrant mOFC/rACC activity and connectivity, though the studies have been limited by their low prevalence and correlational nature, suggesting the need for causal testing of mOFC/rACC’s involvement in these important processes. Theta burst stimulation (TBS), a type of repetitive transcranial magnetic stimulation (rTMS), is a safe and effective option for acute noninvasive causal manipulation of neural activity that has successfully induced neural and behavioral effects after a single session of stimulation. The proposed project was conceptualized and designed to provide training in TMS methodology, magnetic resonance imaging (MRI) and functional MRI (fMRI) methodologies, and experimental task development pertaining to addiction insight theory to the applicant, along with further professional development that will help accelerate his career goals as an independent clinical scientist. Approximately 34 individuals with severe CUD recruited to the proposed study will be randomized to receive either continuous TBS (cTBS) or intermittent TBS (iTBS), along with sham TBS. Specific Aim 1 involves localizing the effects of TBS in terms of changes to cerebral blood flow to mOFC or other areas engaged through the TBS manipulation. Specific Aim 2 will test mOFC as a neural mechanism involved in cannabis use problem recognition using an improved version of our previously validated Auditory Self-Referential Processing Task. Finally, Specific Aim 3 will determine if mOFC modulation affects behavioral choice insight in drug choice contexts during our previously validated Probabilistic Choice Task. The results from this novel and rigorous project will provide critical knowledge of the neurobiological mechanisms underlying the processing of drug use-related self-referential information, which could inform future interventions to improve insight into substance use disorders and other maladaptive behaviors and increase treatment-seeking rates for a debilitating set of disorders.
