Brain Connectivity Lab Brain activity following positive and negative performance feedback among abstinent smokers Jessica Flannery Graduate Student Department of Psychology Florida International University Neuroinformatics and Brain Connectivity Lab http://neurolab.fiu.edu Neuroinformatics and Brain Connectivity Lab

Background Why do people continue to smoke? Nicotine withdrawal symptoms, include: - anxiety, irritability ( sensitivity to negative outcomes) reward dysregulation ( sensitivity to positive outcomes) Habenula: epithalmic nucleus linked with anxiety, reward, cognitive & motor functions Inhibits dopaminergic cell firing Possess a high density of nAChRs activity hypothesized to contribute to a hypo-dopaminergic state during nicotine withdrawal Questions of interest: *Task effects: Negative outcomes  Hb activity? Group effects: Increased Hb activity in smokers? Drug effects: Hb activity reduced by drugs? Carroll et al. (2015) Addiction Biol. Fedota et al. (2015) Neuropsychopharm. Ullsperger et al., 2003 J Neuro Savitz et al., 2011 Biol. Psychiat.

Performance Feedback Task Motion Prediction Task Probe Hb, insula, ACC and striatal activity Dynamically adaptive (error rates ~35%) Participants: *24 smokers 20 non-smokers 200 trials FIG. 1: (A) Anticipated drug-effects. (B) Task feedback. Task. To probe Hb, insula, ACC, and VS functioning, participants completed a “motion prediction task” [9] in which they were presented with positive and negative feedback. Participants predicted which of two moving balls, starting from different locations and traveling at different speeds, would first reach a finish line after viewing a clip of the balls’ motion. Task difficulty was dynamically-adapted to maintain error rates at ~35% so that participants remained uncertain about their performance until feedback delivery. Feedback was delivered in a two-factor design. Participant RESPONSEs (correct vs. error) were followed by FEEDBACK (informative vs. non-informative) that either did or did not provide information about trial outcomes (FIG. 1B). Task-related regions are anticipated to show differential activations on error-trials versus correct-trials followed by informative, but not non-informative feedback (i.e., a RESPONSE x FEEDBACK interaction). Participant RESPONSES (correct vs. error) followed by FEEDBACK (informative vs. non-informative)

Behavioral Results Response type: -Correctly: 59.6 ± 1.1% Erroneously: 35.6 ± 0.2% No response: 4.8 ± 1.0% Reaction Time: difficulty manipulation was effective: RT’s slower for Erroneous responses (620 ± 17ms) than for Correct responses (583 ± 17ms) making sure that the difficulty was tailored to each individual such that high uncertainty about whether the response was correct was induced evaluation of the responses and strategy adjustment, participants were dependent on the feedback. Indicating that the dynamically-adaptive task effectively maintained equal numbers of trials across sessions and participants. participants responded correctly on 59.6 ± 1.1%, erroneously on 35.6 ± 0.2%, and gave no response on 4.8 ± 1.0% of the trials (Fig. 2A). Reaction times were slower for erroneous responses (620 ± 17ms) than for correct responses, suggesting that the difficulty manipulation was effective (583 ± 17 ms), F(1,22) = 63.9, p < 0.001 (Fig. 2B).

Imaging Results (task effects) Structural Habenula 2 24 N subjects R L R L y = -24 y = -24 Anterior Cingulate Ventral Striatum x = 6 Initial assessment of task-related effects in smokers confirmed differential activations following positive versus negative feedback in the Hb, insula, ACC, and VS. Specifically, a whole-brain RESPONSE x FEEDBACK interaction analysis (pcorrected < 0.01) indicated that Hb activity was increased on error-trials followed by informative (negative) feedback relative to correct-trials followed by informative (positive) feedback (FIG. 2BC). No difference was observed in Hb activity on error- versus correct-trials followed by non-informative feedback. Critically, this functional activity was localized within the same area identified when overlapping the structurally-defined Hb coordinates from each smoker’s anatomical MRI (FIG. 2AB). Similar effects were observed in the insula and ACC. In contrast, VS activity was increased on correct-trials followed by informative (positive) feedback relative to error-trials followed by informative (negative) feedback (FIG. 3). R L Anterior insula y = 8 z = -4 correct > error error > correct Whole-brain Response X Feedback interaction pcorrected < 0.01 R L

Conclusions & Future Work Task Effects: Habenula (insula, ACC) activity increased following negative feedback Ventral striatum activity increased following positive feedback. Probe of brain regions implicated in nicotine withdrawal Group effects: abstinent smokers (vs. nonsmokers) will show elevated Hb, insula, and ACC activity and decreased VS activity Drug effects: varenicline (pharmacological smoking cessation aid) & nicotine administered to abstinent smokers: decrease Hb, insula, and ACC activity following negative feedback increase VS activity following positive feedback. Hb activity was increased on error-trials followed by informative (negative) feedback relative to correct-trials followed by informative (positive) feedback Administer nicotine (PATCH) and varenicline (PILL) alone and in combination to abstinent smokers AND nonsmokers.

Acknowledgements Nursing Debi Zimmerman Kathy Demuth Sue Baskin Joyce Lutz Becky Price Bill Mantler Barb Glover Anita Hagan Janet Kivet Mary Kay Willing Carol Ward Karen McCullough NBC Lab Matt Sutherland Angie Laird Michael Riedel Jessica Bartley Dane Marguglio Kailey MacNamara Katie Bottenhorn Ranjita Poudel Taylor Salo Jason Hays Karina Falcone Stephanie Rosas NIDA-K01DA037819 (MTS) NIMH-R01MH074457 (ARL) NSF-DRL-1420627 (ARL) NRB (NIDA-IRP) Eliscia Smith Angie Neal Allison Carroll Loretta Spurgeon Kim Slater Betty Jo Salmeron Carolina Smith Mary Lee Hong Gu Lolita Butler Tom Ross Elliot Hong Yihong Yang Elliot Stein Recruiting Margaret Kroen Shannon Pfistner Jason Dietz