Nucleus Accumbens Functional Connectivity Changes Underlying Alcohol Expectancies in Bipolar Disorder and Prospective Alcohol Outcomes: a Within-Subject Randomized Placebo-Controlled Alcohol Administration fMRI Study

Elizabeth Lippard ^1,2* Dylan Kirsch ³ Vanessa Le ⁴ Skyler Lee ² Nadia Bibb ² Kaitlyn Meek ² Raquel Kosted ² Ansley Huffman ² Almeida, J.R.C. ² Kim Fromme ¹ Stephen Strakowski ⁵

• ¹ The University of Texas at Austin, Austin, United States
• ² Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
• ³ Los Angeles County, California, Los Angeles, California, United States
• ⁴ Medical School, University of Texas Southwestern Medical Center, Dallas, Texas, United States
• ⁵ School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States

Alcohol use disorder (AUD) occurs at higher rates in individuals with bipolar disorder compared to the general population. A paucity of data are available on specific mechanisms that may contribute to bipolar and alcohol use disorderAUD co-occurrence. We recently reported differences in alcohol expectancies and placebo response during alcohol administration in earlystage bipolar disorder, compared to healthy young adults. This current report investigated subjective and neural response following placebo beverage consumption in young adults with bipolar disorder. As part of a within-subject placebo-controlled alcohol administration study, 54 young adults (53% with bipolar disorder type I, agemean+SD=23+2 years, 64% female) completed resting state functional MRI (rsfMRI) scans at baseline (pre-beverage) and following placebo and alcohol consumption (counter-balanced). Participants completed subjective response measures during placebo and alcohol beverage conditions. Between-group differences in subjective response and placebo-related changes in functional connectivity of the Nucleus Accumbens (NAc) with other brain regions, compared to a pre-beverage rsfMRI baseline condition. Fisher-transformed correlation coefficients between ROIs and seed-toclusters showing a significant group-by-condition (placebo, pre-beverage rsfMRI) interaction were calculated. Associations with prospective alcohol use and problems were explored in a subgroup with longitudinal data. Young adults with bipolar disorder reported greater intoxication during the placebo condition, compared to healthy young adults (main effects of group: p<0.05).Compared to pre-beverage rsfMRI, the placebo condition related to increased connectivity between bilateral NAc and regions within the sensorimotor network in bipolar disorder.Comparison participants showed the opposite pattern of placebo-related changes in connectivity (group-by-condition, p-FDR<0.05). Greater anxiolytic effects endorsed during placebo and associated increases in NAc functional connectivity related to greater alcohol use and alcohol problems at follow-up in bipolar disorder (p<0.05). Results suggest differences in placebo response in bipolar disorder, including distinct neural correlates, that may relate to prospective alcohol use/problems. Given the theoretical association between placebo response and selfreported alcohol expectancies, findings could open the door to interventions aimed at changing expectancies.