Nicotine-induced activation of caudate and anterior cingulate cortex
in response to errors in schizophrenia
Lauren V. Moran
Luke E. Stoeckel
Carolyn E. Caine
Justin T. Baker
Amy C. Janes
A. Eden Evins
Diego A. Pizzagalli
Received: 15 June 2017 / Accepted: 20 November 2017 /Published online: 27 November 2017
Springer-Verlag GmbH Germany, part of Springer Nature 2017
Background Nicotine improves attention and processing speed in individuals with schizophrenia. Few studies have investigated
the effects of nicotine on cognitive control. Prior functional magnetic resonance imaging (fMRI) research demonstrates blunted
activation of dorsal anterior cingulate cortex (dACC) and rostral anterior cingulate cortex (rACC) in response to error and
decreased post-error slowing in schizophrenia.
Methods Participants with schizophrenia (n = 13) and healthy controls (n = 12) participated in a randomized, placebo-controlled,
crossover study of the effects of transdermal nicotine on cognitive control. For each drug condition, participants underwent fMRI
while performing the stop signal task where participants attempt to inhibit prepotent responses to Bgo (motor activation)^ signals
when an occasional Bstop (motor inhibition)^ signal appears. Error processing was evaluated by comparing Bstop error^ trials
(failed response inhibition) to Bgo^ trials. Resting-state fMRI data were collected prior to the task.
Results Participants with schizophrenia had increased nicotine-induced activation of right caudate in response to errors compared
to controls (DRUG × GROUP effect: p
< 0.05). Both groups had significant nicotine-induced activation of dACC and
rACC in response to errors. Using right caudate activation to errors as a seed for resting-state functional connectivity analysis,
relative to controls, participants with schizophrenia had significantly decreased connectivity between the right caudate and
dACC/bilateral dorsolateral prefrontal cortices.
Conclusions In sum, we replicated prior findings of decreased post-error slowing in schizophrenia and found that nicotine was
associated with more adaptive (i.e., increased) post-error reaction time (RT). This proof-of-concept pilot study suggests a role for
nicotinic agents in targeting cognitive control deficits in schizophrenia.
Keywords Functional magnetic resonance imaging
The prevalence of smoking in individuals with schizophrenia is
at least threefold higher than the smoking rates in the general
population, contributing to higher rates of smoking-related
morbidity and mortality in schizophrenia (Grant et al. 2004;
Kelly et al. 2011). Higher rates of tobacco dependence in those
with schizophrenia may be due to shared neurobiological ab-
normalities in schizophrenia and nicotine dependence (Lyons
et al. 2002; Moran et al. 2013a). In addition, reduced negative
affect, normalization of sensory gating, and improvements in
cognitive performance with nicotine and nicotinic agonists
have been described in individuals with schizophrenia (Smith
et al. 2002; Leonard et al. 2007;Barretal.2008;Jubeltetal.
2008; Mann-Wrobel et al. 2011; Dutra et al. 2012). Cognitive
deficits are a core feature of schizophrenia and predict poor
A. Eden Evins and Diego A. Pizzagalli contributed equally to this work.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00213-017-4794-3) contains supplementary
material, which is available to authorized users.
* Lauren V. Moran
McLean Hospital, 115 Mill Street, AB3S, Belmont, MA 02478, USA
Department of Psychiatry, Harvard Medical School,
Belmont, MA 02478, USA
Department of Psychiatry, Massachusetts General Hospital,
Boston, MA 02114, USA
Psychopharmacology (2018) 235:789–802