Project Summary/Abstract Women have been underrepresented in neuroimaging studies of opioid use disorder (OUD) and even fewer neuroimaging studies have targeted female-specific health factors, such as the menstrual cycle. This is concerning because women have disproportionately higher rates of relapse and treatment drop out, and cycling levels of estrogen are known to impact drug-craving, with hormone levels around ovulation potentially increasing vulnerability of relapse, though the neural mechanism leading to this result is unclear. Recent preclinical work has shown a clear interaction between ovarian hormone changes, dopamine-dependent circuitry, and sensitivity to reward cues and addictive substances. Parallel data in healthy women shows an uptick in subjects’ propensity for risk-taking, a dopamine sensitive neurocognitive process, surrounding ovulation, the phase of the menstrual cycle when estrogen is the highest. This suggests dopamine modulation of substance-use related behavior during this time, but longitudinal studies examining dopamine-dependent behaviors in parallel with the menstrual cycle in women with OUD remain lacking. To address this, I will conduct a serial and longitudinal fMRI study of risky decision-making in women with OUD and comparison controls across a full menstrual cycle (8 sessions/person). Computational modeling will be used to quantify risk-taking propensity through known-risk tolerance (a person-specific parameter of risk-taking propensity when the probability of reward is known) and ambiguity tolerance (a separable mechanism when the exact probability of reward is unknown). Previous work in my laboratory has found ambiguity tolerance to be a more state-sensitive measure, finding its fluctuation is predictive of opioid reuse, and thus a focus of this study. Aim 1 will identify the relationship between intra- individual changes in cycling hormone levels (estrogen and progesterone) and risk-taking (through known-risk and ambiguity tolerance), hypothesizing an increase in ambiguity tolerance during ovulation. Success of this aim could provide potential behavioral risk markers for drug-reuse in women with OUD informing sex-specific interventions. Aim 2 will assess the relationship between menstrual cycle phases and changing neural signatures of the subjective value of risky and ambiguous options, based on person- and session-specific trial-by-trial valuation based on computational risk-taking propensity. As neural signals of subjective value are dopamine- dependent, increased sensitivity, as hypothesized, in canonical value regions (e.g. ventral striatum) surrounding ovulation may be indicative of stronger dopamine modulation during this time. Thus, this research will identify underlying hormonal and neural mechanisms contributing to sex differences in clinical features of OUD. By completing the proposed research aims, training goals, and experiential learning activities, I will gain training in neuroeconomic theory, advanced neuroimaging methods, and clinical translation that is key to my development as an independent researcher looking to contribute to advancing of psychiatric treatment and diagnosis.

Project Narrative The ovulatory phase of the menstrual cycle seems to align with increased risk-taking and sensitivity to reward cues, such as drug rewards. These observations combined with the historic underrepresentation of women (/sex- specific underrepresentation of females) in research studies and differential opioid use disorder treatment outcomes seen by sex, indicate a crucial need to better understand the interaction between ovarian hormones and reward processes in opioid use disorder. In doing so, new neural and behavioral targets for sex-specific personalized treatment protocols may be elucidated.