Neural correlates of set-shifting: decomposing executive functions in schizophrenia

Abstract

Background: Although there is considerable evidence that patients with schizophrenia have impaired executive functions, the neural mechanisms underlying these deficits are unclear. Generation and selection is one of the basic mechanisms of executive functioning. We investigated the neural correlates of this mechanism by means of functional magnetic resonance imaging (fMRI) in patients with schizophrenia and healthy controls.

Methods: We used the Wisconsin Card Sorting Test (WCST) in an event-related fMRI study to analyze neural activation patterns during the distinct components of the WCST in 36 patients with schizophrenia and 28 controls. We focused our analyses on the process of set-shifting. After participants received negative feedback, they had to generate and decide on a new sorting rule.

Results: A widespread activation pattern encompassing the inferior and middle frontal gyrus, parietal, temporal and occipital cortices, anterior cingulate cortex (ACC), supplementary motor area, insula, caudate, thalamus and brainstem was observed in patients with schizophrenia after negative versus positive feedback, whereas in healthy controls, significant activation clusters were more confined to the cortical areas. Significantly increased activation in the rostral ACC after negative feedback and in the dorsal ACC during matching after negative feedback were observed in schizophrenia patients compared with controls. Controls showed activation in the bilateral dorsolateral prefrontal cortex (Brodmann area 46), whereas schizophrenia patients showed activation in the right dorsolateral prefrontal cortex only.

Limitations: All patients were taking neuroleptic medication, which has an impact on cognitive function as well as on dopaminergic and serotonergic prefrontal metabolism.

Conclusion: Our data suggest that, in patients with schizophrenia, set-shifting is associated with increased activation in the rostral and dorsal ACC, reflecting higher emotional and cognitive demands, respectively.

Fig. 1

Wisconsin Card Sorting Test paradigm. Each trial starts with the presentation of a new card followed by an individual response period during which participants decide on the sorting rule. Directly after their responses, participants are informed if the response was correct or incorrect. For group analyses, 4 different events were defined: (A) receiving negative feedback, indicating that a shift is required; (B) matching after negative feedback (i.e., the execution after the required set shift); (C) receiving positive feedback, indicating that the current matching criterion is still adequate; and (D) matching after positive feedback (i.e., the execution of matching according to the current rule).

Fig. 2

Regions of increased brain activation after negative feedback (set-shifting) versus positive feedback (1-sample t tests, p < 0.05, family-wise error–corrected). All activations were rendered on a single subject template in Montreal Neurological Institute space. (A) Schizophrenia patients (n = 36) had activation clusters in the inferior and medial frontal gyrus, anterior cingulate cortex, supplementary motor area, insula, basal ganglia and thalamus. (B) Controls (n = 28) had more confined activation clusters in the inferior and medial frontal gyrus, supplementary motor area, insula and superior and inferior parietal lobes. (C) Region-of-interest analysis of the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 46, 9) in patients and controls showed activation of the right DLPFC in patients and activation of the bilateral DLPFC in controls.

Fig. 3

Regions of increased brain activation in schizophrenia patients compared with controls (2-sample t tests, p < 0.001, uncorrected) and bar graphs of contrast estimates (MarsBaR28) of all regions with significant activation differences between patients and controls. All activations were rendered on a single subject template in Montreal Neurological Institute space. (A) Significantly increased activation after negative feedback (set-shifting) versus activation after positive feedback in the right rostral anterior cingulate cortex (ACC) in schizophrenia patients. (B) Significantly increased activation during matching after negative feedback (execution of set-shifting) versus activation during matching after positive feedback in the left dorsal ACC in schizophrenia patients. CG = Cingulate gyrus, IFG = inferior frontal gyrus, STG = superior temporal gyrus.