Meta-analysis of 41 Functional Neuroimaging Studies of Executive Function in Schizophrenia

Department of Psychiatry, University of California-Davis School of Medicine, Sacramento, CA 95817, USA.
Archives of general psychiatry (Impact Factor: 14.48). 09/2009; 66(8):811-22. DOI: 10.1001/archgenpsychiatry.2009.91
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Prefrontal cortical dysfunction is frequently reported in schizophrenia. It remains unclear whether this represents the coincidence of several prefrontal region- and process-specific impairments or a more unitary dysfunction in a superordinate cognitive control network. Whether these impairments are properly considered reflective of hypofrontality vs hyperfrontality remains unresolved.
To test whether common nodes of the cognitive control network exhibit altered activity across functional neuroimaging studies of executive cognition in schizophrenia and to evaluate the direction of these effects.
PubMed database.
Forty-one English-language, peer-reviewed articles published prior to February 2007 were included. All reports used functional neuroimaging during executive function performance by adult patients with schizophrenia and reported whole-brain analyses in standard stereotactic space. Tasks primarily included the delayed match-to-sample, N-back, AX-CPT, and Stroop tasks.
Activation likelihood estimation modeling reported activation maxima as the center of a 3-dimensional gaussian function in the meta-analysis, with statistical thresholding and correction for multiple comparisons.
In within-group analyses, healthy controls and patients activated a similarly distributed cortical-subcortical network, prominently including the dorsolateral prefrontal cortex (PFC), ventrolateral PFC, anterior cingulate cortex (ACC), and thalamus. In between-group analyses, patients showed reduced activation in the left dorsolateral PFC, rostral/dorsal ACC, left thalamus (with significant co-occurrence of these areas), and inferior/posterior cortical areas. Increased activation was observed in several midline cortical areas. Activation within groups varied modestly by task.
Healthy adults and schizophrenic patients activate a qualitatively similar neural network during executive task performance, consistent with the engagement of a general-purpose cognitive control network, with critical nodes in the dorsolateral PFC and ACC. Nevertheless, patients with schizophrenia show altered activity with deficits in the dorsolateral PFC, ACC, and mediodorsal nucleus of the thalamus. Increases in activity are evident in other PFC areas, which could be compensatory in nature.

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Available from: Michael Minzenberg, Oct 05, 2015
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    • "Impaired working memory (WM) is a robust feature of schizophrenia and is thought to reflect prefrontal cortex (PFC) dysfunction [27]. Although much attention has been devoted to altered engagement of the lateral PFC, presenting as both hypo-and hyperfrontality [15], the disorder is also associated with a failure to deactivate the medial PFC (mPFC) during task performance. "
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    ABSTRACT: Impaired working memory is a core feature of schizophrenia and is linked with altered engagement the lateral prefrontal cortex. Although altered PFC activation has been reported in people with increased risk of psychosis, at present it is not clear if this neurofunctional alteration differs between familial and clinical risk states and/or increases in line with the level of psychosis risk. We addressed this issue by using functional MRI and a working memory paradigm to study familial and clinical high-risk groups. We recruited 17 subjects at ultra-high-risk (UHR) for psychosis, 10 non-affected siblings of patients with schizophrenia (familial high risk [FHR]) and 15 healthy controls. Subjects were scanned while performing the N-back working memory task. There was a relationship between the level of task-related deactivation in the medial PFC and precuneus and the level of psychosis risk, with deactivation weakest in the UHR group, greatest in healthy controls, and at an intermediate level in the FHR group. In the high-risk groups, activation in the precuneus was associated with the level of negative symptoms. These data suggest that increased vulnerability to psychosis is associated with a failure to deactivate in the medial PFC and precuneus during a working memory task, and appears to be most evident in subjects at clinical, as opposed to familial high risk. Copyright © 2015. Published by Elsevier Masson SAS.
    European Psychiatry 04/2015; 30(5). DOI:10.1016/j.eurpsy.2015.03.003 · 3.44 Impact Factor
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    • "Furthermore, structural changes of the ACC have been detected using brain imaging of patients with schizophrenia (reviewed in Fornito et al., 2009). Functional imaging reveals deficits in the activation of the ACC during tests of executive function in schizophrenia patients (Minzenberg et al., 2009). For example, schizophrenia patients show impaired performance of the Stroop task, which measures information processing skills that require activation of the ACC (Krabbendam et al., 2009). "
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    ABSTRACT: GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n=21) and a comparison group of individuals without a history of psychiatric illness (n=18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Aε. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression of GABA-Aα1-3, GABA-Aβ2, GABA-Aγ2, and GAD67 in the medicated group compared to the unmedicated group. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 02/2015; DOI:10.1016/j.schres.2015.01.025 · 3.92 Impact Factor
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    • "Finally, we investigated whether genotype affected the functional connectivities seeded from the inferior frontal gyrus (IFG) (based on the above analysis) to the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). The choice of the DLPFC and ACC was based on recent meta-analyses of fMRI studies that have identified the DLPFC and ACC, in addition to the IFG, as commonly activated brain regions by different tasks of working memory and attentional control (Duncan and Owen, 2000; Minzenberg et al, 2009). In this analysis, we used both task fMRI data from the N-back and Stroop tasks and resting-state fMRI data, the latter of which reflects brain activity with no burden of a cognitive task. "
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    ABSTRACT: Nitric oxide (NO), a gaseous neurotransmitter, has been implicated in the pathogenesis of schizophrenia. Accordingly, several polymorphisms of the gene that codes for the main NO-producing enzyme, the Nitric oxide synthase 1 (NOS1), have been found convey a risk for schizophrenia. This study examined the role of NOS1 gene polymorphisms in cognitive functions and related neural mechanism. First, with a sample of 580 schizophrenia patients and 720 healthy controls, we found that rs3782206 genotype had main effects on the 1-back task (P=0.005), the 2-back task (P=0.049), the AY condition of the dot-pattern expectancy [DPX] task (P=0.001), and the conflict effect of the attention network [ANT] test (P< 0.001 for RT differences and P=0.002 for RT ratio) and interaction effects with diagnosis on the BX condition of the DPX (P=0.009), the AY condition of the DPX (P< 0.001), and the Stroop conflict effect (P=0.003 for RT differences and P=0.038 for RT ratio). Simple effect analyses further showed that the schizophrenia risk allele (T) of rs3782206 was associated with poorer performance in 5 measures for the patients (1-back, P=0.025; BX, P=0.017; AY, P< 0.001; ANT conflict effect [RT differences], P=0.005; Stroop conflict effect [RT differences], P=0.019) and 3 measures for the controls ( for the 2-back task, P=0.042; for the ANT conlict effect [RT differences], P=0.013; for the ANT conflict effect [RT ratios], P=0.028). Then, with a separate sample of 78 healthy controls, we examined the association between rs3782206 and brain activation patterns during the N-back task and the Stroop task. Whole brain analyses found that the risk allele carriers showed reduced activation at the right inferior frontal gyrus (IFG) during both tasks. Finally, we examined functional connectivity seeded from the right IFG to the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) under three conditions (the N-back task, the Stroop task, and the resting-state). Results showed reduced connectivity with the DLPFC for the risk allele carriers mainly in the Stroop task and the resting-state. Taken together, results of this study strongly suggested a link between NOS1 gene polymorphism at rs3782206 and cognitive functions and their neural underpinnings at the IFG. These results have important implications for our understanding of the neural mechanism underlying the association between NOS1 gene polymorphism and schizophrenia.Neuropsychopharmacology accepted article preview online, 10 December 2014. doi:10.1038/npp.2014.323.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2014; 40(6). DOI:10.1038/npp.2014.323 · 7.05 Impact Factor
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