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Impact of schizophrenia-risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals.

ABSTRACT: Working memory (WM) dysfunction is a hallmark feature of schizophrenia. Functional imaging studies using WM tasks have documented both prefrontal hypo- and hyperactivation in schizophrenia. Schizophrenia is highly heritable, and it is unclear which susceptibility genes modulate WM and its neural correlates. A strong linkage between genetic variants in the dysbindin 1 gene and schizophrenia has been demonstrated. The aim of this study was to investigate the influence of the DTNBP1 schizophrenia susceptibility gene on WM and its neural correlates in healthy individuals. Fifty-seven right-handed, healthy male volunteers genotyped for DTNBP1 SNP rs1018381 status were divided in heterozygous risk-allele carriers (T/C) and homozygous noncarriers (C/C). WM was assessed by a 2-back vs. 0-back version of the Continuous Performance Test (CPT), while brain activation was measured with fMRI. DTNBP1 SNP rs1018381 carrier status was determined and correlated with WM performance and brain activation. Despite any differences in behavioral performance, risk-allele carriers exhibited significantly increased activation of the bilateral middle frontal gyrus (BA 9), a part of the dorsolateral prefrontal cortex (DLPFC), compared to noncarriers. This difference did not correlate with WM performance. The fMRI data provide evidence for an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on bilateral middle frontal gyrus activation during a WM task. The increased activation in these brain areas may be a consequence of "inefficient" or compensatory DLPFC cognitive control functions.

SUBMITTER: Markov V

PROVIDER: S-EPMC6871017 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Impact of schizophrenia-risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals.

Markov Valentin V Krug Axel A Krach Sören S Jansen Andreas A Eggermann Thomas T Zerres Karl K Stöcker Tony T Shah N Jon NJ Nöthen Markus M MM Treutlein Jens J Rietschel Marcella M Kircher Tilo T

Human brain mapping 20100201 2

Working memory (WM) dysfunction is a hallmark feature of schizophrenia. Functional imaging studies using WM tasks have documented both prefrontal hypo- and hyperactivation in schizophrenia. Schizophrenia is highly heritable, and it is unclear which susceptibility genes modulate WM and its neural correlates. A strong linkage between genetic variants in the dysbindin 1 gene and schizophrenia has been demonstrated. The aim of this study was to investigate the influence of the DTNBP1 schizophrenia s ...[more]

PMID: 19650139

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Project description:Background: The simplistic approaches to language circuits are continuously challenged by new findings in brain structure and connectivity. The posterior middle frontal gyrus and area 55b (pFMG/area55b), in particular, has gained a renewed interest in the overall language network. Methods: This is a retrospective single-center cohort study of patients who have undergone awake craniotomy for tumor resection. Navigated transcranial magnetic simulation (nTMS), tractography, and intraoperative findings were correlated with language outcomes. Results: Sixty-five awake craniotomies were performed between 2012 and 2020, and 24 patients were included. nTMS elicited 42 positive responses, 76.2% in the inferior frontal gyrus (IFG), and hesitation was the most common error (71.4%). In the pMFG/area55b, there were seven positive errors (five hesitations and two phonemic errors). This area had the highest positive predictive value (43.0%), negative predictive value (98.3%), sensitivity (50.0%), and specificity (99.0%) among all the frontal gyri. Intraoperatively, there were 33 cortical positive responses-two (6.0%) in the superior frontal gyrus (SFG), 15 (45.5%) in the MFG, and 16 (48.5%) in the IFG. A total of 29 subcortical positive responses were elicited-21 in the deep IFG-MFG gyri and eight in the deep SFG-MFG gyri. The most common errors identified were speech arrest at the cortical level (20 responses-13 in the IFG and seven in the MFG) and anomia at the subcortical level (nine patients-eight in the deep IFG-MFG and one in the deep MFG-SFG). Moreover, 83.3% of patients had a transitory deterioration of language after surgery, mainly in the expressive component (p = 0.03). An increased number of gyri with intraoperative positive responses were related with better preoperative (p = 0.037) and worse postoperative (p = 0.029) outcomes. The involvement of the SFG-MFG subcortical area was related with worse language outcomes (p = 0.037). Positive nTMS mapping in the IFG was associated with a better preoperative language outcome (p = 0.017), relating to a better performance in the expressive component, while positive mapping in the MFG was related to a worse preoperative receptive component of language (p = 0.031). Conclusion: This case series suggests that the posterior middle frontal gyrus, including area 55b, is an important integration cortical hub for both dorsal and ventral streams of language.

Project description:ObjectiveWorking memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS.MethodAdult patients with COS (n = 32, 21.3 ± 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 ± 0.8 years), and healthy controls (n = 39, 20.0 ± 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 ± 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report.ResultsPatients with COS who were included scored significantly lower than controls on all tasks (p < .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p < .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p < .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected).ConclusionDecreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo-activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype.Clinical trial registration informationEvaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198.

Dataset Information

Impact of schizophrenia-risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals.

Publications

Impact of schizophrenia-risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals.

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