Functional and Structural Brain Circuits Underlying Smoking

National Institute On Drug Abuse

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Abstract

1. Time varying connectivity across the brain changes as a function of nicotine abstinence state. The nicotine withdrawal syndrome (NWS) includes affective and cognitive disruptions whose incidence and severity vary across time during acute abstinence. However, most network-level neuroimaging uses static measures of resting-state functional connectivity and assumes time-invariance and is thus unable to capture dynamic brain-behavior relationships. Recent advances in resting-state functional connectivity signal processing allow characterization of time-varying functional connectivity (TVFC), which characterizes network communication between networks that reconfigure over the course of data collection. Therefore, TVFC may more fully describe network dysfunction related to the NWS. To isolate alterations in the frequency and diversity of communication across network boundaries during acute nicotine abstinence, we scanned 25 cigarette smokers in the nicotine-sated and abstinent states and applied a previously validated method to characterize TVFC at a network and a nodal level within the brain. During abstinence, we found brain-wide decreases in the frequency of interactions between network nodes in different modular communities (i.e., temporal flexibility). In addition, within a subset of the networks examined, the variability of these interactions across community boundaries (i.e., spatiotemporal diversity) also decreased. Finally, within 2 of these networks, the decrease in spatiotemporal diversity was significantly related to NWS clinical symptoms. Using multiple measures of TVFC in a within-subjects design, we characterized a novel set of changes in network communication and linked these changes to specific behavioral symptoms of the NWS. These reductions in TVFC provide a meso-scale network description of the relative inflexibility of specific large-scale brain networks during acute abstinence. 2. Nicotinic modulation of the Default Mode Network is bidirectional. Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects. The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation. Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified. Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal. The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.