Direction and magnitude of nicotine effects on the fMRI BOLD response are related to nicotine effects on behavioral performance

Abstract

Considerable variability across individuals has been reported in both the behavioral and fMRI blood oxygen level-dependent (BOLD) response to nicotine. We aimed to investigate (1) whether there is a heterogeneous effect of nicotine on behavioral and BOLD responses across participants and (2) if heterogeneous BOLD responses are associated with behavioral performance measures. In this double-blind, placebo-controlled, cross-over study, 41 healthy participants (19 smokers)--drawn from a larger population-based sample--performed a visual oddball task after acute challenge with 1 mg nasal nicotine. fMRI data and reaction time were recorded during performance of the task. Across the entire group of subjects, we found increased activation in the anterior cingulate cortex, middle frontal gyrus, superior temporal gyrus, post-central gyrus, planum temporal and frontal pole in the nicotine condition compared with the placebo condition. However, follow-up analyses of this difference in activation between the placebo and nicotine conditions revealed that some participants showed an increase in activation while others showed a decrease in BOLD activation from the placebo to the nicotine condition. A reduction of BOLD activation from placebo to nicotine was associated with a decrease in reaction time and reaction time variability and vice versa, suggesting that it is the direction of BOLD response to nicotine which is related to task performance. We conclude that the BOLD response to nicotine is heterogeneous and that the direction of response to nicotine should be taken into account in future pharmaco-fMRI research on the central action of nicotine.

Fig. 1

BOLD activation for the group-level analysis (second-level mixed-effects FLAME; N = 39, cluster-corrected threshold Z = 2.3, p = 0.05)

Fig. 2

BOLD activation for the placebo versus nicotine contrast (paired t test) (second-level mixed-effects FLAME. N = 39, cluster-corrected threshold Z = 2.3, p = 0.05)

Fig. 3

Scatter plots showing the relationship between fMRI BOLD and behavioral responses to nicotine. a The difference in mean reaction time (RT) and the difference in mean percent signal (BOLD in the placebo vs nicotine ROI between the placebo and nicotine conditions. Difference values were calculated by subtracting the value for the placebo condition from the value for the nicotine condition. For mean percent signal change, a negative difference value represents a decrease in activation from placebo to nicotine. A positive value represents an increase from placebo to nicotine. For mean RT, a negative value indicates a reduction in reaction time from placebo to nicotine and a positive value represents an increase in reaction time from placebo to nicotine. A decrease in reaction time from placebo to nicotine is related to a decrease in BOLD activation from placebo to nicotine (b). The difference in reaction time standard deviation (RT_SD) and the difference in mean percent signal change in the placebo vs nicotine ROI between the placebo and nicotine conditions. For RT_SD, a negative value indicates a reduction in reaction time variability from placebo to nicotine and a positive value represents an increase in reaction time variability from placebo to nicotine. A decrease in reaction time variability from placebo to nicotine is related to a decrease in BOLD activation from placebo to nicotine

Fig. 4

BOLD activation for the placebo versus nicotine contrast with reaction time data included as a covariate (second-level mixed-effects FLAME, N = 39, cluster-corrected threshold Z = 2.3, p = 0.05). The left panel shows activation associated with the nicotine effects on mean reaction time. The right panel shows activation associated with the nicotine effects on reaction time standard deviation