Nicotine withdrawal syndrome (NWS) manifests as affective, somatic, and cognitive disruptions, significantly impacting smoking cessation success. The heterogeneity of NWS symptoms and the variable efficacy of cessation aids suggest underlying phenotypic diversity among smokers. This variance may be linked to allostatic load, where chronic stress from nicotine dependence interacts with additional stressors to impair coping mechanisms and increase relapse risk. Cognitively demanding tasks can also induce stress, and nicotine withdrawal is associated with impaired cognitive control, including sustained attention deficits. These deficits are predictive of relapse, especially at high task difficulty. This study hypothesized that combining cognitive demand and nicotine abstinence as stressors would reveal distinct smoker subgroups with differential attentional deficits to withdrawal. The dual stressor approach aims to uncover the neurobiological mechanisms underlying these differences, potentially identifying novel therapeutic targets for improving cessation outcomes.

Existing research highlights the substantial individual variability in the experience of nicotine withdrawal. Some smokers report significant cravings, attentional lapses, and anxiety, while others experience milder symptoms. The effectiveness of FDA-approved cessation aids (bupropion, varenicline, NRT) also varies considerably across individuals. Genetic factors, such as variations in the CYP2A6 gene, have been implicated in predicting treatment response. Studies using fMRI have explored the neural correlates of nicotine withdrawal, focusing on resting-state functional connectivity changes in networks involved in emotion regulation (amygdala, insula, Default Mode Network). These studies suggest that combining stressors may be a useful strategy to identify subgroups within the smoker population.

Fifty-nine right-handed smokers were recruited, with 14 excluded due to incomplete data or other factors. The remaining 45 participants completed two fMRI sessions: one while nicotine sated and another after approximately 48 hours of abstinence. During each session, they performed a modified Parametric Flanker Task (PFT), designed to induce varying levels of cognitive control demand. Subjective measures of withdrawal, craving, and affect were also assessed. Behavioral data included response speed, accuracy, and errors of omission (EOm). fMRI data were analyzed using two pipelines: a task-evoked pipeline to identify brain regions with differential activation in high-demand conditions, and a task-regressed pipeline to examine functional connectivity (FC) differences between subgroups. Statistical analyses included ANOVAs, t-tests, and regression analyses to examine the relationships between behavioral performance, subjective ratings, and brain activity.

Based on accuracy in the high-demand PFT condition, smokers were divided into High Task Performers (HTP) and Low Task Performers (LTP) subgroups. HTPs showed significantly higher accuracy (88.68% ± 5.19 SD) than LTPs (51.04% ± 4.72 SD) in both nicotine states. Importantly, HTPs demonstrated a significantly greater increase in errors of omission during abstinence (p = 0.01). Neuroimaging data revealed that HTPs exhibited greater BOLD responses in attentional control regions (bilateral insula, dorsal ACC, frontoparietal cortex) during both nicotine states for correct responses versus errors of commission. Functional connectivity analysis identified two circuits: Precentral Cx→Insula and Insula→Occipital Cx, with abstinence-induced FC strength increases observed only in HTPs. Furthermore, abstinence-induced FC and behavioral (EOm) differences were positively correlated for HTPs in a Precentral Cx→Orbitofrontal cortical circuit. Subjective measures of withdrawal, craving, and affect did not differ significantly between subgroups.

This study demonstrates a novel approach to understanding smoker heterogeneity by utilizing a ‘dual-stressor’ paradigm. The findings highlight the importance of objectively measuring cognitive performance to identify subgroups within a seemingly homogeneous population. The observed differences in sustained attention, brain activation, and functional connectivity between HTPs and LTPs suggest distinct neurobiological mechanisms underlying their responses to nicotine withdrawal. The absence of subgroup differences in subjective measures underscores the importance of objective assessments for characterizing individual responses to abstinence. The identified brain regions and circuits are implicated in attentional control and NWS, potentially providing targets for personalized interventions.

This study successfully identified distinct smoker subgroups based on their performance on a cognitively demanding task and their response to nicotine abstinence. The HTP subgroup showed a specific vulnerability to sustained attention deficits during withdrawal, distinguishable from LTPs. These findings highlight the importance of considering individual differences when developing and implementing smoking cessation treatments. Future research should explore the potential of these findings to develop personalized interventions targeting specific neurobiological mechanisms.

The study's limitations include the variable inter-session interval between scanning sessions and the lack of counterbalancing of nicotine states. The PFT, while assessing both selective and sustained attention, may not be the most direct measure of sustained attention. The sample size, while substantial, may limit the generalizability of the findings to other populations. The lack of a control group without nicotine exposure slightly limits the definitive attribution of the observed effects solely to nicotine withdrawal. However, a comparison to a healthy control group is presented in the supplemental materials.