Neurobiological impact of nicotinic acetylcholine receptor agonists: an activation likelihood estimation meta-analysis of pharmacologic neuroimaging studies

Abstract

Background: Nicotinic acetylcholine receptor (nAChR) agonists augment cognition among cigarette smokers and nonsmokers, yet the systems-level neurobiological mechanisms underlying such improvements are not fully understood. Aggregating neuroimaging results regarding nAChR agonists provides a means to identify common functional brain changes that may be related to procognitive drug effects.

Methods: We conducted a meta-analysis of pharmacologic neuroimaging studies within the activation likelihood estimation framework. We identified published studies contrasting a nAChR drug condition versus a baseline and coded each contrast by activity change direction (decrease or increase), participant characteristics (smokers or nonsmokers), and drug manipulation employed (pharmacologic administration or cigarette smoking).

Results: When considering all studies, nAChR agonist administration was associated with activity decreases in multiple regions, including the ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), parahippocampus, insula, and the parietal and precentral cortices. Conversely, activity increases were observed in lateral frontoparietal cortices, the anterior cingulate cortex, thalamus, and cuneus. Exploratory analyses indicated that both smokers and nonsmokers showed activity decreases in the vmPFC and PCC, and increases in lateral frontoparietal regions. Among smokers, both pharmacologic administration and cigarette smoking were associated with activity decreases in the vmPFC, PCC, and insula and increases in the lateral PFC, dorsal anterior cingulate cortex, thalamus, and cuneus.

Conclusions: These results provide support for the systems-level perspective that nAChR agonists suppress activity in default-mode network regions and enhance activity in executive control network regions in addition to reducing activation of some task-related regions. We speculate these are potential mechanisms by which nAChR agonists enhance cognition.

Keywords: Activation likelihood estimation (ALE); Default mode network (DMN); Executive control network (ECN); Nicotine; Pharmacologic functional magnetic resonance imaging (fMRI); Withdrawal.

Copyright © 2015 Society of Biological Psychiatry. All rights reserved.

Figures

Figure 1

Schematic illustration of meta-analytic assessments. Foci from included contrasts were coded according to direction of change (decreases: blue; increases: red), participant GROUP (nonsmoker or smoker) and nAChR MANIPULATION method (pharmacological administration or cigarette smoking). *One study (2 foci, 1 contrast) was excluded from the GROUP assessment as the reported drug effect was collapsed across smokers and nonsmokers.

Figure 2

Overall impact of nAChR agonist administration. Across all studies, nAChR agonists were associated with decreased activity (blue; baseline > drug) notably in the vmPFC, subgenual ACC, PCC, right parahippocampus, and bilateral insulae. In addition, nAChR agonists were associated with increased activity (red; drug > baseline) notably in the dmPFC, dorsal ACC, thalamus, cuneus, lingual gyrus, and lateral prefrontal and parietal regions. Functionally defined and publically available templates (84) of the DMN (purple transparency) as well as the left and right ECN (yellow transparency) are overlaid for visualization of overlap between convergent activity modulations and these large-scale networks. Numbering (decreases) and lettering (increases) correspond to coordinates listed in Table 1. See Supplemental Figures S1-S5 and Tables S4-S5 for ancillary analyses further characterizing the nature of and context in which these activity modulations were observed. See Supplemental Figure S6 and Table S6 for statistical comparison between these two ALE images.

Figure 3

Group effects: Common and distinct drug-effects among smokers and nonsmokers. A) Decreases: Among both groups, nAChR agonists were associated with activity decreases overlapping in the vmPFC, PCC, and right inferior parietal cortex (green). Nonsmokers showed greater decreases in the right inferior parietal cortex (purple). B) Increases: Among both groups, nAChR agonists were associated with activity increases overlapping in the cingulate gyrus, left dlPFC, and left inferior parietal cortex (green). Smokers showed greater increases in the right dlPFC (orange), while nonsmokers showed greater increases in bilateral parietal, right prefrontal, and cingulate regions (purple). See Supplemental Table S7 for the complete list of identified clusters and corresponding coordinates. See Supplemental Figure S7 for the separate ALE images from the two groups.

Figure 4

Manipulation effects (smokers only): Common and distinct impact of pharmacological administration and cigarette smoking. A) Decreases: Pharmacological administration and smoking were associated with activity decreases overlapping in the vmPFC, subgenual ACC, PCC, and left mid-insula (green). Cigarette smoking was associated with greater decreases in the right anterior insula (purple), whereas pharmacological administration was associated with greater decreases in the lingual gyrus (orange). B) Increases: Pharmacological administration and cigarette smoking were associated with activity increases overlapping in the dorsal ACC, thalamus, cuneus and dlPFC (green). Pharmacological administration was associated with greater increases in the ACC (orange). See Supplemental Table S8 for the complete list of identified clusters and corresponding coordinates. See Supplemental Figure S8 for the separate ALE images from the two manipulation methods.