Fig. 1. Study overview schematics.

(A) Illustration of pharmacological study design. Following an orientation session (O), all participants completed six fMRI assessments over the course of the 6- to 8-week study duration. Before the onset of a study pill regimen (pre-pill), participants completed assessments wearing transdermal nicotine and placebo patches on different days. Subsequently, participants underwent varenicline (mean ± SD, 17.0 ± 4.2 days) and placebo pill administration (16.5 ± 3.4 days) and again completed nicotine and placebo patch scans toward the end of both PILL periods. Double-headed arrows indicate the randomization and counterbalancing of drug orders across participants. *Nicotine and placebo patch scan sessions were separated by 2.9 ± 1.7 days. **Neuroimaging assessments occurred 13.9 ± 2.3 days after the onset of each PILL period. Neurocognitive assessments were conducted 1 week after the onset of each PILL period. #A washout interval did not separate varenicline and placebo pill epochs. (B) Illustration of performance feedback task. Following a variable fixation interval and a warning stimulus indicating an upcoming event, participants viewed a sequence of two balls moving across the screen at different speeds from different starting locations. After a short “video” clip of motion, the balls disappeared before reaching the finish line, and participants indicated via a button press response which ball they believed would have reached the finish line first. Performance feedback was delivered at the end of each trial in a two-factor FEEDBACK [informative (i) versus noninformative (n)] * RESPONSE [correct (C) versus error (E)] fashion. A fifth feedback type was presented when participants failed to give a response [no-response (N) trials]. Task difficulty was dynamically manipulated on each trial and for each participant by modifying the time difference between the two balls’ intended arrival at the finish line.