Article

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: 4.43). 03/2009; 108(1-3):143-50. DOI: 10.1016/j.schres.2008.12.025
Source: PubMed

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.

Download full-text

Full-text

Available from: Katherine H Karlsgodt, Jul 07, 2015
0 Followers
 · 
135 Views
  • Source
    [Show abstract] [Hide abstract]
    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 · 4.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia is considered a neurodevelopmental disorder, but whether the adolescent period, proximal to onset, is associated with aberrant development in individuals at clinical high risk (CHR) for psychosis is incompletely understood. While abnormal gray and white matter development has been observed, alterations in functional neuroimaging (fMRI) parameters during adolescence as related to conversion to psychosis have not yet been investigated. Twenty CHR individuals and 19 typically developing controls (TDC), (ages 14-21), were recruited from the Center for Assessment and Prevention of Prodromal States (CAPPS) at UCLA. Participants performed a Sternberg-style verbal working memory (WMem) task during fMRI and data were analyzed using a cross-sectional design to test the hypothesis that there is a deviant developmental trajectory in WMem associated neural circuitry in those at risk for psychosis. Eight of the CHR adolescents converted to psychosis within 2 years of initial assessment. A voxel-wise regression examining the relationship between age and activation revealed a significant group-by-age interaction. TDC showed a negative association between age and functional activation in the WMem circuitry while CHR adolescents showed a positive association. Moreover, CHR patients who later converted to overt psychosis showed a distinct pattern of abnormal age-associated activation in the frontal cortex relative to controls, while non-converters showed a more diffuse posterior pattern. Finding that age related variation in baseline patterns of neural activity differentiate individuals who subsequently convert to psychosis from healthy subjects suggests that these differences are likely to be clinically relevant.
    10/2013; DOI:10.1016/j.pscychresns.2013.08.004