Abstract
Nicotine Withdrawal Syndrome (NWS)-associated cognitive deficits are notably heterogeneous, suggesting underlying endophenotypic variance. However, parsing this variance in smokers has remained challenging. In this study, we identified smoker subgroups based on response accuracy during a Parametric Flanker Task (PFT) and then characterized distinct neuroimaging endophenotypes using a nicotine state manipulation. Smokers completed the PFT in two fMRI sessions (nicotine sated, abstinent). Based on response accuracy in the stressful, high cognitive demand PFT condition, smokers split into high (HTP, n = 21) and low task performer (LTP, n = 24) subgroups. Behaviorally, HTPs showed greater response accuracy (88.68% ± 5.19 SD) vs. LTPs (51.04% ± 4.72 SD), independent of nicotine state, and greater vulnerability to abstinence-induced errors of omission (EOm, p = 0.01). Neurobiologically, HTPs showed greater BOLD responses in attentional control brain regions, including bilateral insula, dorsal ACC, and frontoparietal Cx for the [correct responses (–) errors of commission] PFT contrast in both states. A whole-brain functional connectivity (FC) analysis with these subgroup-derived regions as seeds identified two circuits: Precentral Cx↔Insula and Insula↔Occipital Cx, with abstinence-induced FC strength increases seen only in HTPs. Finally, abstinence-induced FC and behavior (EOm) differences were positively correlated for HTPs in a Precentral Cx↔Orbitofrontal cortical circuit. In sum, only the HTP subgroup demonstrated sustained attention deficits following 48-hr nicotine abstinence, a stressor in dependent smokers. Unpacking underlying smoker heterogeneity with this ‘dual (task and abstinence) stressor’ approach revealed discrete smoker subgroups with differential attentional deficits to withdrawal that could be novel pharmacological/behavioral targets for therapeutic interventions to improve cessation outcomes.
Highlights
Following acute smoking abstinence, most smokers exhibit components of the Nicotine Withdrawal Syndrome (NWS), manifest as a set of aversive affective, somatic, and cognitive disruptions peaking in the initial days of a quit attempt [1]
Cohort behavioral and subjective measures There was a main effect of DEMAND, with lower Speed, SpdCV and Accuracy for the high DEMAND condition and a main effect of STATE, with Accuracy lower and Errors of Omission (EOm) higher during nicotine abstinence
To identify task activation differences to serve as functional connectivity (FC) seeds, a multivariate model approach (AFNI: 3dMVM) was used with a SUBGROUP contrast (HTP vs. Low task performers (LTP)) of correct trials vs. error trials at the high DEMAND condition
Summary
Most smokers exhibit components of the Nicotine Withdrawal Syndrome (NWS), manifest as a set of aversive affective, somatic, and cognitive disruptions peaking in the initial days of a quit attempt [1]. The timing and severity of the NWS symptoms are salient to and predictive of long-term smoking cessation, with more symptoms generally associated with lower success [2, 3]. Genetically informed biomarkers such as the nicotine metabolite ratio induced by variations in the hepatic enzyme cytochrome P450 (CYP2A6 [13]) predict success with NRT and lend further credence to the underlying population diversity. Taken together, these studies indicate considerable variance related to NWS symptom duration, intensity, and cessation outcomes in the aggregate smoker population
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