Anterior cingulate cortex activation is related to learning potential on the WCST in schizophrenia patients
Highlights
► Patients with schizophrenia use different strategies to achieve WCST performance. ► The ACC is relevant to learn set-shifting strategies in patients with schizophrenia. ► WCST learning potential measures cognitive resources in schizophrenia.
Introduction
Cognitive dysfunction is a core characteristic of schizophrenia, and neurocognitive deficits account for 30–60% of the variance in measures of functional outcome (Green, Kern, & Heaton, 2004). Given the impact of such deficits, enhancement of cognitive functions has been of major interest for schizophrenia clinicians and researchers. One approach that has received considerable attention involves retesting cognitive performance after training. On a behavioral level, patients with schizophrenia – although able to learn a wide range of functions – seem to differ in their capabilities to profit from training. Optimized performance after practice or after enhanced instruction is a better predictor of social functioning than naïve performance (Woonings, Appelo, Kluiter, Slooff, & van der Bosch, 2002); thus, the ability to learn, usually referred to as “learning potential” or “learner status”, mediates the relationship between basic cognitive abilities and more complex domains of functioning (Green, Kern, Braff, & Mintz, 2000).
fMRI has elucidated the neural activation patterns of learning in patients with schizophrenia (Heinze et al., 2006, Koch et al., 2007, Koch et al., 2010, Rowland et al., 2010, Schloesser et al., 2009). Heinze et al. (2006) observed stronger activation in the temporoparietal cortex in successful versus unsuccessful verbal learning during encoding in patients with schizophrenia and interpreted these activations as compensation for the lack of hippocampal and cerebellar activation compared to controls. Koch et al. (2010) divided their sample into poor- versus good-learning patients with schizophrenia and reported an initial increase in activation in the fronto-parieto-cerebellar network in poor learners (compared to good learners) with subsequent signal decreases in a short-term learning paradigm. These studies differ with respect to their research strategies, which might account for their divergent results (comparing trials with good and bad performance versus sub-grouping participants according to their performance). However, some evidence suggests that patients with schizophrenia may perform similarly to controls by employing alternative or compensatory strategies (Koch et al., 2007, Murray et al., 2010, Rowland et al., 2010). Thus, the differentiation of patients with schizophrenia with regard to their learning potential is still controversial.
The remediation of executive function is important in overall rehabilitation because these skills affect the patient’s capacity to function in the community (Green, 1996, Martínez-Arán et al., 2002). Since Bellack, Mueser, Morrison, Tierney, and Podell (1990) and Green, Satz, Ganzell, and Vaclav (1992) successfully trained patients with schizophrenia, the Wisconsin Card Sorting Test (WCST) has repeatedly been used to assess the modifiability of executive functioning deficits. Wiedl, Wienobst, Schoettke, Green, and Nuechterlein (2001) used these principles of training to implement a standard test/training phase/standard test version of the WCST and found a significant association between learner status and rehabilitation placement. Higher learning potential is also correlated with better work-skill performance (Sergi, Kern, Mintz, & Green, 2005), readiness for psychosocial rehabilitation (Fiszdon et al., 2006) and long-term criteria of work rehabilitation (Watzke, Brieger, Schottke, & Wiedl, 2008) in patients with schizophrenia.
Thus, there is increasing evidence that instructional techniques can improve WCST performance in some, but not all, patients with schizophrenia (Choi & Kurtz, 2009) and that the degree of improvement of WCST performance is predictive of salient criteria of functional outcome. Recently, we replicated Wiedl’s cognitive distinction of high-achievers, learners and non-retainers in 104 patients. The learner status was not related to chronicity of illness, amount of medication, or psychopathology (Pedersen, Wiedl, & Ohrmann, 2009). In addition, we observed a positive correlation between learning potential and N-acetylaspartate (NAA) levels in the anterior cingulate cortex (ACC) in another sample of patients with schizophrenia. Learning potential in healthy controls, however, was related to NAA-levels in the dorsolateral prefrontal cortex (Ohrmann et al., 2008). Because NAA is a marker of neuronal integrity and functionality, we hypothesized that the neural integrity of the ACC only has specific relevance for learning capacity in patients with schizophrenia. Using single voxel spectroscopy, we had to restrict our analyses to two brain areas due to the limited time patients tolerated the scanner; thus, we could not draw conclusions as to the significance of other brain areas involved in WCST performance. Nevertheless, these data underline the hypothesis of alternative or compensatory neural networks related to performance in cognitive paradigms in schizophrenic patients compared to controls.
To date, activation patterns in subgroups of patients with schizophrenia who perform differently on the WCST have not been compared using fMRI; hence, in this study we used event-related fMRI to examine the neural correlates of learner status in patients with schizophrenia. We classified patients as high-achievers, learners or non-retainers based on the standard test/training phase/standard test version of the WCST (Wiedl, Schoettke, Green, & Nuechterlein, 2004). Event-related fMRI data were acquired during a computerized version of the WCST. We also included a group of healthy control participants (characterized as high-achievers).
Performance on the WCST is strongly related to shifting functions. Prentice, Gold, and Buchanan (2008) hypothesized that specific deficits in negative feedback processing are responsible for the impairment of WCST performance in schizophrenia, in that patients do not reliably shift categories on the WCST based on error feedback. Therefore, we focused our analyses on the set-shifting component of the WCST. We hypothesized that activation in the ACC would be strongest in patients characterized as high-achievers and learners because the ACC was most salient for learning potential in our spectroscopy study (Ohrmann et al., 2008). A pattern of high ACC activation in high-achievers, medium ACC activation in learners, and low ACC activation in non-retainers resembles increased and decreased prefrontal activation in patients with schizophrenia in working memory tasks where task-load moderates DLPFC activation (Van Snellenberg, Torres, & Thornton, 2006). Consequently, the perceived WCST task-load might differ between the schizophrenia groups resulting in an increased activation of the ACC in high-achievers and absent activation of the ACC in non-retainers compared to controls. Additionally, we hypothesized that differential activation patterns would be related to different learning potentials in the frontoparietal network, which underlies WCST performance according to Buchsbaum et al.’s meta-analysis (2005).
Section snippets
Participants
We recruited 39 inpatients with schizophrenia from the Department of Psychiatry at the University of Muenster. We also investigated 31 healthy control participants. All participants had normal vision, were right-handed (Oldfield, 1971) and native German speakers. Participants gave written informed consent prior to the study, which was approved by the local Ethics Committee. We excluded one patient and one control participant from this study due to diagnostic reasons, two patients due to scanner
Differences between groups in set-shifting related activation (whole-brain analysis)
An one-way ANOVA with the between-subjects factor group (C, HA, L, and NR) on the contrast between negative and positive feedback (set-shifting) revealed a significant main effect of group in three neighboring regions of the right anterior cingulate cortex (x/y/z = 12/43/9, 4 voxel, Z = 3.33, p < .001; x/y/z = 4/40/−9, 3 voxel, Z = 3.45, p < .001; x/y/z = 10/50/−1, 3 voxel, Z = 3.23, p < .001), in the right inferior frontal gyrus (x/y/z = 36/33/−9, 17 voxel, Z = 4.43, p < .001), and in the left temporoparietal cortex (x/y
Discussion
We investigated the neural correlates of learning potential in patients with schizophrenia by combining the test/training/test version of the WCST with an event-related fMRI approach. Interestingly, all three cortical regions with activation patterns related to learning potential in patients with schizophrenia (i.e., the rostral anterior cingulate cortex, the temporoparietal region and the inferior frontal gyrus) are part of the frontoparietal network. This network has been tied to executive
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