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

Biol Psychiatry. 2015 Nov 15;78(10):711-20. doi: 10.1016/j.biopsych.2014.12.021. Epub 2015 Jan 7.


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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiology*
  • Brain Mapping
  • Humans
  • Likelihood Functions
  • Magnetic Resonance Imaging
  • Nicotinic Agonists / pharmacology*
  • Positron-Emission Tomography
  • Receptors, Nicotinic / physiology*
  • Smoking / physiopathology


  • Nicotinic Agonists
  • Receptors, Nicotinic