Nicotine-related beliefs induce dose-dependent responses in the human brain

Abstract

Beliefs have a powerful influence on our behavior, yet their neural mechanisms remain elusive. Here we investigate whether beliefs could impact brain activities in a way akin to pharmacological dose-dependent effects. Nicotine-dependent humans were told that nicotine strength in an electronic cigarette was either 'low', 'medium' or 'high', while nicotine content was held constant. After vaping, participants underwent functional neuroimaging and performed a decision-making task known to engage neural circuits affected by nicotine. Beliefs about nicotine strength induced dose-dependent responses in the thalamus, a key binding site for nicotine, but not in other brain regions such as the striatum. Nicotine-related beliefs also parametrically modulated the connectivity between the thalamus and ventromedial prefrontal cortex, a region important for decision-making. These findings reveal a high level of precision in the way beliefs influence the brain, offering mechanistic insights into humans' heterogeneous responses to drugs and a pivotal role of beliefs in addiction.

Fig. 1 |. Experimental paradigm and sanity check measures.

a, A diagram of the experimental paradigm for each visit of the participants. Participants completed three visits. In each visit, we collected saliva samples for cotinine measurement and assessed exhaled carbon monoxide (CO) levels, instructed participants about nicotine strength and then had them vape the e-cigarette. Afterwards, we measured their brain activities using fMRI as participants engaged in a decision-making task and collected a second saliva sample post-scan. b, A STROBE flow chart of participant recruitment and analysis of smokers (purple) and nonsmoking HCs (orange). c, Subjective beliefs about nicotine strength increased as a function of instructed nicotine strength (n = 20 participants, rmANOVA P = 0.0004). d, The consumed nicotine was similar across three belief conditions (n = 20 participants, rmANOVA P = 0.178), e–g, Cotinine concentration (n = 17 participants, rmANOVA P = 0.393) (e), CO level (n = 17 participants, rmANOVA P = 0.698) (f) and nicotine craving (n = 17 participants, rmANOVA P = 0.195) (g) did not differ between instructed belief conditions. The vertical bars depict group means, and the points represent participants. Orange and teal rectangles depict belief rating, and nicotine consumption measurements, respectively. The error bars depict the s.e.m. ***P < 0.001.

Fig. 2 |. Belief about nicotine strength induced dose-dependent responses in the thalamus.

a, Whole-brain effects of instructed beliefs about nicotine on value-tracking signals (rmANOVA, cluster-level P_FWE = 0.006, k = 50, group F map). b, Parameter estimates representing reward-related activities extracted from an independent thalamus mask (purple boxes) across belief conditions in smokers (N = 20 participants, rmANOVA P = 0.036) compared with non-smoking healthy controls (HCs) (orange box, n = 31 participants). The vertical bars depict group means, and the points represent participants. The inset shows the anatomical mask of the thalamus used for signal extraction. The error bars show the s.e.m. *P < 0.05. c, A permutation test for instructed beliefs effects (N = 1,000, P = 0.002, one-sided). A histogram of surrogate distribution shows beta estimates (purple bars). The vertical red line denotes the mean of true beta values. d, The decoding accuracy of the belief condition from thalamic neural patterns. The vertical red line denotes the decoding accuracy for ground truth data. The purple histogram is a surrogate distribution composed of decoding accuracy for the same neural data with shuffled labels. The P value is derived nonparametrically through a one-sided permutation test (n = 10,000). e, The correlation between thalamic signals and subjective belief rating regarding perceived nicotine strength (Spearman’s correlation, r = 0.27, P = 0.035). The black dashed line is the linear fit.

Fig. 3 |. Belief about nicotine strength did not modulate striatal reward-related responses.

a, Diagrams of whole-brain effects of cross-condition brain activation tracking market return across all instructed belief conditions. Group F map, where the heatmap signifies t values. b, Parameter estimates representing reward-related activities extracted from an independent NAcc mask across belief conditions in smokers (teal boxes) (rmANOVA P = 0.945; permutations P = 0.94) compared with nonsmoking HCs (orange box). The vertical bars depict group means, and the points represent participants. The error bars show the s.e.m. c, The decoding accuracy of belief conditions from accumbens neural patterns. The vertical red line denotes the decoding accuracy for ground truth data. The teal histogram is a surrogate distribution of the decoding accuracy for the same neural data with shuffled labels. The P value is derived nonparametrically through a one-sided permutation test (P = 0.372, N = 10,000).

Fig. 4 |. Belief about nicotine strength modulated thalamus–vmPFC functional connectivity in a dose-dependent fashion.

a, The effects of instructed beliefs on the PPI (group F map) between the thalamus and the vmPFC. b, Parameter estimates extracted from a, representing the functional coupling strength between the thalamus and vmPFC (rmANOVA P = 0.0011, n = 20 participants) compared with nonsmoking HCs (orange box, n = 18 participants). The vertical bars depict group means, and the points represent participants. The error bars show the s.e.m. **P < 0.05.