Nicotine-induced activation of caudate and anterior cingulate cortex in response to errors in schizophrenia

Abstract

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 "go (motor activation)" signals when an occasional "stop (motor inhibition)" signal appears. Error processing was evaluated by comparing "stop error" trials (failed response inhibition) to "go" 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 _corrected < 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: Anterior cingulate; Caudate; Error; Functional magnetic resonance imaging; Schizophrenia.

Figure 1

Post-error reaction time (RT): Participants with schizophrenia had significantly decreased post-error RT compared to control participants (GROUP effect: p=0.046). Nicotine was associated with increased post-error RT (DRUG effect: p=0.03).

Figure 2

Stop Error – Go contrast from Stop Signal Task using whole-brain voxelwise fMRI analysis corrected for multiple comparisons (p_corrected<0.05). A. Significant DRUG × GROUP interaction where individuals with schizophrenia had increased nicotine-induced activation of the right caudate in response to errors compared to placebo. In contrast, there was no significant DRUG effect for control participants; individuals with schizophrenia had significantly greater right caudate activation than controls under the nicotine condition (C). B. Significant DRUG effects in the rostral anterior cingulate (rACC: yellow, D) and the dorsomedial anterior prefrontal cortex (aPFC: red, E) with increased nicotine-induced activation in both regions. Data in C-E represent mean contrast parameter extracted from clusters identified using whole-brain analysis for the Stop Error – Go contrast (averaged over each region).

Figure 3

A. Dorsal anterior cingulate (dACC) region of interest (ROI). B. Significant DRUG effect for the Stop Error – Go contrast associated with increased nicotine-induced activation of dACC (p=0.02). There was no significant GROUP effect or DRUG × GROUP interactions. Data shown represent mean contrast parameter from Stop Error – Go contrast averaged over each ROI.

Figure 4

Resting state functional connectivity analysis. A. Right caudate activation from the Stop Error - Go contrast associated with a significant DRUG × GROUP effect (increased nicotine-induced activation in schizophrenia) was used as a seed region: decreased connectivity between the right caudate seed and dorsal anterior cingulate (dACC) and bilateral dorsolateral prefrontal cortices was found in participants with schizophrenia (green). B. Rostral anterior cingulate cortex (rACC) and anterior prefrontal cortex (aPFC) activations from the Stop Error – Go contrast with significant DRUG effect (increased nicotine-induced activation) were used as seed regions (rACC: yellow; aPFC: red): decreased connectivity between these seed regions and right cuneus was found in participants with schizophrenia. Areas of overlap shown in blue.