Ventromedial Frontoinsular Connectivity is Associated with Long-term Smoking Behavior Change in Aging

Abstract

AbstractA central question in the field of cognitive aging and behavioral neuroscience is what enables some individuals to successfully change their behavior more than others? Smoking is a significant risk factor for cognitive decline, particularly in vulnerable populations, including those who are at an elevated risk for Alzheimer’s disease (AD). Developing effective smoking reduction strategies is therefore a public health priority. The goal of the current study is to better understand the brain mechanisms underlying long-term smoking behavior change in cognitively normal, but at-risk, older adults. Neuroimaging and human lesional studies have implicated the insula and its functional network in subjective interoceptive awareness of cigarette craving and smoking-cue reactivity. We sought to characterize the extent to which anterior insular resting-state functional connectivity MRI predicted long-term smoking reduction (mean: 2.7 years, range 8 months – 4 years) using a seed-to-voxel approach. Twenty-three (18 women; 26%APOE4carriers; 61.5 years, SD = 3.7) cognitively unimpaired older individuals who smoked cigarettes at their baseline visit and have a first-degree family history of AD (at least one parent or multiple siblings affected) were included from a prospective longitudinal cohort, PREVENT-AD (Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease) in the current study. We found that reduced long-term smoking behavior was associated with diminished functional connectivity between bilateral anterior insula and ventromedial prefrontal cortex (vmPFC). In a second pre-registered replication study within a larger, independent sample of one hundred and eighteen cognitively normal older adults who smoked cigarettes at baseline from the UK Biobank (73 women; 27.9 %APOE4carriers; 60.3 years, SD = 2.7), we found that baseline diminished resting-state functional connectivity between anterior insula and vmPFC predicted long-term smoking reduction (mean 5.2 years; ranging from 3 years to 7 years). To our knowledge, this is the largest study to examine the neural substrates of long-term smoking cessation in human aging. Our results suggest that frontoinsular circuits may be a therapeutic target for smoking reduction and disease prevention in older adults at risk for AD.