The Olfactory Systems Role in Evoking and Relieving Craving Associated Physiological Symptoms and Neural Reward Response in Alcohol Use and Comorbid Mood and Anxiety Disorders

Alcohol use disorder (AUD) is a chronic relapsing condition attributed to physiological appetitive urges and/or cravings invoked by environmental stimuli. A powerful yet often neglected sensory stimuli that elicits alcohol craving is olfaction a sensory domain that is integral to ingestive behaviors. Odors of alcoholic beverages serve as conditioned stimuli (CS) to evoke craving responses both at a physiological and a neural level. Olfactory dysfunction is known to prevail in individuals with AUD. However the literature lacks evidence of the association between olfactory function and craving response and if manipulation of the olfactory system could be leveraged to suppress craving and relapse in individuals with AUD outside the treatment setting. Thus there is an unmet clinical need to fill this research gap.

For the phase 1 this proposal aims to determine in in-patients with AUD and comorbid mood and anxiety symptoms 1) (Aim 1) the individual variability in olfactory function (subjective and objective assessment) that differentiates an odor cue-invoked craving response (questionnaire) stress response (subjective) and display of physiological symptoms as well as differences in cardiac activity and in skin conductance as measured through a sentinel wearable wrist device and sensors both in absence and presence of a bar like virtual reality environment and 2) (Aim 2) the neural mechanisms behind craving responses using functional magnetic resonance imaging (fMRI) Magnetic Resonance Spectroscopy (MRS) and Diffusion Tensor Imaging (DTI). To this end 100 individuals with AUD (during in-patient stay) and 50 healthy controls will undergo a battery of olfactory tests and odor cue-evoked craving response tests, stress tests and physiological symptoms evaluation. In addition, cardiac activity, and skin temperature (as a readout of emotional arousal) will be measured through questionnaires and a wearable device. All eligible participants will undergo an odor cue task-based fMRI scan to assess the neural patterns evoked by alcohol (vs. non-alcohol) odor cues. We hypothesize that: (1) a sub-population of individuals with AUD with a lower smell deficit (i.e., hyposmia vs. no deficit, or normosmia) will reveal an elevated hedonic rating to stronger alcohol (vs. non-alcohol) odor cues, aligning positively with their recorded craving strength, stress and physiological symptoms; and (2) alcohol vs. non-alcohol odors in AUD (vs. non-AUD) elevates craving and reward-related neural activation, while alcohol-specific odors will invoke trigeminal activation in individuals with AUD irrespective of their olfactory function state, and olfactory regions will be less activated in participants with normosmia (vs. hyposmia) in alignment with their craving responses.

For the phase 2 (Aim 3) a systematic odor simulated virtual reality (VR) paradigm as a second order counterconditioning strategy will be used during a randomized, controlled trial conducted to assess the effect of an odor simulated VR in suppressing craving symptoms. Patients with AUD will be assigned either to odor VR or to the standard of care group for 2 weeks. Their craving response, stress and physiological symptoms will be monitored throughout treatment and neural patterns, metabolic changes in brain and structural brain patterns will be assessed by MRI modalities including fMRI, MRS and DTI, before and after treatment.