Re-evaluating dorsolateral prefrontal cortex activation during working memory in schizophrenia

Department of Psychology, UCLA, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095-1563, USA.
Schizophrenia Research (Impact Factor: 3.92). 03/2009; 108(1-3):143-50. DOI: 10.1016/j.schres.2008.12.025
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ABSTRACT Previous neuroimaging studies of working memory (WM) in schizophrenia have generated conflicting findings of hypo- and hyper-frontality, discrepancies potentially driven by differences in task difficulty and/or performance. This study proposes and tests a new model of the performance-activation relationship in schizophrenia by combining changes by load with overall individual differences in performance. Fourteen patients with recent-onset schizophrenia and eighteen controls underwent functional magnetic resonance imaging while performing a parametric verbal WM task. Group level differences followed a linear "cross-over" pattern, such that in controls, activation in the dorsolateral prefrontal cortex (DLPFC) increased as performance decreased, while patients showed the opposite. Overall, low performing patients were hypoactive and high performing patients hyperactive relative to controls. However, patients and controls showed similar functions of activation by load in which activation rises with task difficulty but levels off or slightly decreases at higher loads. Moreover, across all loads and at their own WM capacity, higher performing patients showed greater DLPFC activation than controls, while lower performing patients activated least. This study establishes a novel framework for predicting the relationship between functional activation and WM performance by combining changes of activation by WM load occurring within each subject with the overall differences in activation associated with general WM performance. Essentially, increasing task difficulty correlates asymptotically with increasing activation in all subjects, but depending on their behavioral performance, patients show overall hyper- versus hypofrontality, a pattern potentially derived from individual differences in underlying cellular changes that may relate to levels of functional disability.

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Available from: Katherine H Karlsgodt, Sep 27, 2015
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    • "judgments, schizophrenia patients failed to recruit prefrontal regions of the SIN [Kubicki et al., 2003; Kuperberg et al., 2008]. In contrast, in WM studies, people with schizophrenia show reduced efficiency in the MDN, such that greater activation was required to match the performance of controls, even under moderate cognitive loads [Callicott et al., 2003; Karlsgodt et al., 2009; Metzak et al., 2012, Components 2 and 3]. Therefore, in this study, we expected that (1) the MDN and SIN would be spatially and temporally separable in both people with schizophrenia and healthy controls, (2) coordinated activity in both networks would increase as the semantic distance between word pairs increased in both groups, (3) coordinated activity in the MDN would be increased for people with schizophrenia relative to healthy controls for closely associated word pairs due to inefficient processing, and (4) coordinated activity in the SIN would be reduced for people with schizophrenia relative to healthy controls for distantly associated word pairs due to a frontotemporal disconnection syndrome thought to be characteristic of schizophrenia. "
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    ABSTRACT: Impairment in controlled semantic association is a central feature of schizophrenia, and the goal of the current functional magnetic resonance imaging study was to identify the neural correlates of this impairment. Thirty people with schizophrenia and 30 healthy age- and gender-matched control subjects performed a task requiring participants to match word pairs that varied in semantic distance (distant vs. close). A whole-brain multivariate connectivity analysis revealed three functional brain networks of primary interest engaged by the task: two configurations of a multiple demands network, in which brain activity did not differ between groups, and a semantic integration network, in which coordinated activity was reduced in schizophrenia patients relative to healthy controls, for distantly relative to closely related word pairs. The hypoactivity during controlled semantic integration in schizophrenia reported here, combined with hyperactivity in automatic semantic association reported in the literature, suggests an imbalance between controlled integration and automatic association. This provides a biological basis for Bleuler's concept of schizophrenia as a "split mind" arising from an impaired ability to form coherent associations between semantic concepts. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 05/2015; 36(8). DOI:10.1002/hbm.22820 · 5.97 Impact Factor
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    • "Schizophrenia patients are thought to require additional neural resources to achieve a comparable WM performance as healthy individuals. Depending on the WM load this can result in increased DLPFC response, which has been termed " neural inefficiency " (Brauns et al., 2011; Ehrlich et al., 2011; Karlsgodt et al., 2009; Manoach et al., 1999; Potkin et al., 2009b). An important class of molecules that we expect to affect risk for schizophrenia possibly via modulation of intermediate phenotypes for schizophrenia are microRNAs (miRNAs) and their target genes (Hansen et al., 2007). "
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    ABSTRACT: Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data 01 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identity markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (ERIIA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2015; 59. DOI:10.1016/j.pnpbp.2015.01.006 · 3.69 Impact Factor
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    • "Fusar-poli et al. (2010) fMRI 15 Visuospatial working memory task n Hard vs. intermediate level of difficulty 12. Broome, Matthiasson, Woolley, Valmaggia, and Johns (2009) fMRI 15 Object-location memory task with manipulation of the mnemonic load n Hard vs. intermediate level of difficulty 13. Hirano, Obata, Kashikura, and Nonaka (2008) fMRI 33 N-back N-back vs. zero-back 14. Karlsgodt et al. (2009) fMRI 18 Sternberg-style item recognition task Higher memory load trial vs. lower memory load trial 15. Kirschen, Chen, and Desmond (2010) fMRI 16 Sternberg task Higher working memory load vs. lower working memory load 16. "
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    ABSTRACT: Objectives We hypothesize that time perception and executive functions are interrelated and share neuroanatomical basis, and that fluctuations in levels of cognitive effort play a role in mediating that relation. The main goal of this study was to identify brain structures activated both by increases in cognitive activity and during time perception tasks. Methods We performed a multimodal meta-analysis to identify common brain regions in the findings of (a) an SDM meta-analysis of neuroimaging studies assessing the brain response to increasing levels of cognitive difficulty, and (b) an ALE meta-analysis on neuroimaging of time perception (Ortuño, Guillén-Grima, López-García, Gómez, & Pla, 2011). Results and conclusions Consistent with results of previous, separate meta-analyses, the current study supports the hypothesis that there exists a group of brain regions engaged both in time perception tasks and during tasks requiring cognitive effort. Thus, brain regions associated with working memory and executive functions were found to be engaged during time estimation tasks, and regions associated with time perception were found to be engaged by an increase in the difficulty of non-temporal tasks. The implication is that temporal perception and cognitive processes demanding cognitive control become interlinked when there is an increase in the level of cognitive effort demanded.
    Neuropsychologia 05/2014; 58. DOI:10.1016/j.neuropsychologia.2014.03.016 · 3.30 Impact Factor
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