Dataset Information

Cerebral and behavioral signs of impaired cognitive flexibility and stability in schizophrenia spectrum disorders

ABSTRACT: Highlights • Patients are impaired regarding both, cognitive flexibility and stability.• Deficient prediction error discrimination is related to reduced striatal activation.• Decreased ACC and hippocampus activation predicts impaired rule switch detection.• Decreased frontal and insular activation predicts impaired distractor shielding.

Background

Manifold cognitive deficits have been reported in schizophrenia spectrum disorders, including disturbances in flexible updating to altered circumstances as well as stabilization deficits in the face of distractors. In this functional magnetic resonance imaging study, we examined the neural correlates of these deficits as two complementary components of predictive processing.

Methods

In 22 patients with schizophrenia spectrum disorders and 22 healthy matched control participants, we applied a serial predictive switch-drift task to assess flexibility as successful detection of prediction-rule switches, and stability as successfully ignoring distractors (“drifts”).

Results

Patients compared with controls less reliably detected rule switches and also less efficiently inhibited drifts. A reduced striatal response to switches or drifts correlated with weaker switch-drift-discrimination in patients, suggesting impaired gating of prediction errors. The increase in activity in anterior cingulate cortex and hippocampus for detected vs. undetected switches was reduced in patients compared to controls, which may reflect impaired behavioral adaptation following prediction errors. The comparison between shielding against distractions and undetected switches showed increased activity in the inferior frontal cortex and posterior insula in controls but not in patients.

Conclusion

Our results suggest new insights into the specific disruption of predictive flexibility and stability in schizophrenia spectrum disorders, which is characterized by impaired striatal gating and inadequate cortical encoding of predictive errors.

SUBMITTER: Standke I

PROVIDER: S-EPMC8551223 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions. METHODS:Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n=20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight-Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses. RESULTS:As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC). CONCLUSION:Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left hemisphere dominance. Increased connectivity in the DAN with the IFC and ACC in relation to cognitive insight may facilitate enhanced mental flexibility in this sample.

Project description:Abstract Background Schizophrenia spectrum disorders (SSD) are often characterised by a plateau or decline in cognitive abilities early in the prodrome. The cause of developmental alteration remains unknown, and investigation of genetic involvement in cognitive function in these disorders may assist the understanding of the underlying neurobiological mechanisms involved. Variation at two single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) gene have previously shown an influence on COMT protein levels and cognition; rs4680 and rs4818. Here we investigate the influence of the nonsynonymous “Val/Met” SNP rs4680 and a second functional SNP, rs4818, on tasks of cognitive flexibility and attention. Methods The sample comprised 48 healthy controls (HC; age = 31.95 ± 12.80; 25 males, 23 females), and 43 with a diagnosis of SSD (age = 41.64 ± 10.36; 26 males, 17 females). Measures of cognitive flexibility and attention included the Wisconsin Card Sorting Test (WCST), Continuous Performance Test-Identical Pairs version (CPT-IP), Trail Making Test (TMT), and the D-KEFS Colour Word Interference Test (CWIT). Due to small cohort sizes, in our preliminary analyses we chose to compare people who should be most severely affected because of inheriting COMT haplotypes associated with poor cognitive functioning (GG rs4818 / GG rs4680: G-G haplotype) to those with haplotypes associated with better cognitive functioning (CC rs4818 / AA rs4680: C-A haplotype). Multivariate analysis of variance factors included COMT haplotype, diagnosis (HC and SSD), and gender, with Bonferroni correction for multiple comparisons; age was included as a covariate. Analyses were also conducted based on a non-functional SNP of the COMT gene; rs165599, as a negative control. Results SSD exhibited reduced cognitive performance compared to HC; F(4, 75) = 8.810, p < .001. Investigation of C-A haplotype revealed an interaction with diagnosis on cognitive performance; F(8, 154) = 2.075, p = .041; SSD had reduced performance compared to HC for the WCST, CPT-IP, and TMT in C-A haplotypes (all p < .05). COMT haplotype also interacted with gender on cognitive performance (C-A haplotype; F(8, 154) = 2.315, p = .023, G-G haplotype; F(8, 154) = 2.706, p = .008). Males who were C-A non-carriers and /or G-G haplotype (high COMT activity groups) performed better on CPT-IP (both p < .05) and worse on CWIT (both p < .05) compared to females. Control SNP rs165599 revealed no main effects or significant interactions (all p > .05). Discussion The role of the COMT gene in the cognitive abilities of SSD remains contentious as gene expression does not differ from a healthy population. This preliminary analysis revealed an interaction between diagnosis and COMT haplotype, however, this only reached statistical significance for the C-A haplotype, where SSD with C-A haplotype and C-A non-carriers had reduced performance compared to HC on most tasks except TMT. The different effects found across the tasks, which probed various elements of cognitive flexibility and attention, supports a nuanced role of COMT in cognitive function. Further, high COMT activity was beneficial for males on CPT-IP but not CWIT compared to females. Gender interaction remains a significant consideration in studies of the COMT gene, likely involving the catechol-estrogens which are substrates of COMT. As expected there was no significant results with control SNP rs165599, indicating that findings were due to the influence of SNPs rs4680 and rs4818 on COMT activity.