Dorsolateral Prefrontal Cortex Activity During Maintenance and Manipulation of Information in Working Memory in Patients With Schizophrenia

Cannon, Tyrone D.; Glahn, David C.; Kim, Junghoon; Erp, Theo G.M. van; Karlsgodt, Katherine H.; Cohen, Mark S.; Nuechterlein, Keith H.; Bava, Sunita; Shirinyan, David

doi:10.1001/archpsyc.62.10.1071

Cited by 178 publications

(151 citation statements)

References 60 publications

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“…Study participants performed two spatial delayed response tasks, one contrasting maintenance and manipulation of spatial memoranda consisting of arrays of three dots [stMNM (32,33)] and the other assessing parametrically increasing memory loads [SCAP (33)] consisting of arrays of increasing numbers of dots. Behavioral data were analyzed in SPSS, using repeated measures ANOVA.…”

Section: Methodsmentioning

confidence: 99%

“…Using a combination of cognitive testing and fMRI, we next determined whether human patients with NF1 also demonstrate working memory deficits related to corticostriatal dysfunction. We used two visuospatial working memory tasks that parallel the operant delayed nonmatch to sample task used with Nf1 +/− mice and are known to activate a network of cortical and striatal brain structures (32,33). Within the prefrontal cortex, fMRI analysis focused on the DLPFC, an area in primates that is functionally homologous to mPFC in rodents (13,14,34).…”

Section: Nf1mentioning

confidence: 99%

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Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Shilyansky

Karlsgodt

Cummings

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Neurofibromatosis type I (NF1) is one of the most common singlegene causes of learning disabilities. Here, we use behavioral working memory probes and electrophysiological studies in a mouse model of NF1 (Nf1 heterozygous null mutants; Nf1 +/− ) to demonstrate that (i) Neurofibromin regulates prefrontal and striatal inhibitory networks, specifically activity-dependent GABA release and (ii) is required for working memory performance, with inhibitiondependent working memory deficits seen in Nf1 +/− mice. We find that increased inhibition in medial prefrontal cortex (mPFC) is sufficient to alter persistent activity in a biophysical model of an mPFC microcircuit, suggesting a possible mechanism for Nf1 +/− working memory deficits. Accordingly, working memory assays applied during functional MRI (fMRI) studies in human subjects with NF1 reveal hypoactivation of corticostriatal networks, which is associated with impaired working memory performance. Collectively, these integrative mouse and human studies reveal molecular and cellular mechanisms contributing to working memory deficits in NF1.GABA | Ras | prefrontal cortex | learning disability | neurofibromatosis type I N eurofibromatosis type 1 (NF1) is a valuable model for understanding mechanisms of learning disabilities (1). NF1 is a common genetic disorder (incidence 1:3,000) that results from mutations in a single gene (Nf1) that encodes the neurofibromin protein (2, 3). Specific deficits in the domains of visuospatial and executive functions are among the most common cognitive deficits associated with this syndrome (1,4,5). Previous mechanistic studies in a mouse model of NF1 (Nf1 heterozygous null mutants or Nf1 +/− ) demonstrated that neurofibromin modulates Rasdependent GABA release in the hippocampus, which in turn modulates long-term potentiation (LTP) and hippocampaldependent learning (6, 7). However, the mechanisms underlying frontal executive dysfunction in NF1, including prominent working memory deficits (5), are unknown. Therefore, to investigate mechanisms underlying working memory deficits associated with the NF1 mutation we carried out parallel experiments in mice and humans.Working memory is a cognitive construct involving the ability to hold and update information transiently in mind in the service of higher-order cognitive activities. Executive functions, including working memory, are thought to depend on common corticostriatal networks (8-11). Therefore, our experiments focused on frontal corticostriatal circuitry, with an emphasis on the dorsolateral prefrontal cortex (DLPFC) in humans, thought to be critical for working memory (12), and its functionally analogous structure in rodents, the medial prefrontal cortex (mPFC) (13,14).Here, we report Ras-dependent increases in GABA release in the mPFC and striatum of the Nf1 +/− mouse model. Increased GABAergic inhibition is likely to be responsible for the working memory deficits that we found in the Nf1 +/− mice because these deficits could be reversed with a drug that decreased inhibition. Further,...

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Section: Methodsmentioning

confidence: 99%

Section: Nf1mentioning

confidence: 99%

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Shilyansky

Karlsgodt

Cummings

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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145

150

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“…All other regions required that they be defined functionally, as anatomical definitions of STS, VLPFC, and Fusiform gyrus encompass portions of the brain beyond the sub-areas involved specifically in social cognition. ROIs for bilateral STS and bilateral VLPFC were defined using statistical results from a one sample ttest of positive activation during trust judgments using all 48 participants (p<.05 FWE whole brain corrected) (Cannon et al, 2005). A region of interest for the FFA was defined by use of the localizer task in which data were combined across all participants, and significant activations from a faces > tools contrast (p<.001 uncorrected) were examined.…”

Section: Masks Defining Regions Of Interestmentioning

confidence: 99%

Neural bases for impaired social cognition in schizophrenia and autism spectrum disorders

Pinkham

Hopfinger

Pelphrey

et al. 2008

Schizophrenia Research

337

279

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Schizophrenia and autism both feature significant impairments in social cognition and social functioning, but the specificity and mechanisms of these deficits remain unknown. Recent research suggests that social cognitive deficits in both disorders may arise from dysfunctions in the neural systems that underlie social cognition. We explored the neural activation of discrete brain regions implicated in social cognitive and face processing in schizophrenia subgroups and autism spectrum disorders during complex social judgments of faces. Twelve individuals with autism spectrum disorders (ASD), 12 paranoid individuals with schizophrenia (P-SCZ), 12 non-paranoid individuals with schizophrenia (NP-SCZ), and 12 non-clinical healthy controls participated in this cross sectional study. Neural activation, as indexed by blood oxygenation level dependent (BOLD) contrast, was measured in a priori regions of interest while individuals rated faces for trustworthiness. All groups showed significant activation of a social cognitive network including the amygdala, fusiform face area (FFA), superior temporal sulcus (STS), and ventrolateral prefrontal cortex (VLPFC) while completing a task of complex social cognition (i.e. trustworthiness judgments). ASD and P-SCZ individuals showed significantly reduced neural activation in the right amygdala, FFA, and left VLPFC as compared to controls and in the left VLPFC as compared to NP-SCZ individuals during this task. These findings lend support to models hypothesizing well-defined neural substrates of social cognition and suggest a specific neural mechanism that may underlie social cognitive impairments in both autism and paranoid schizophrenia.

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“…Repetitive TMS was targeted at the junction of the middle and anterior one-third of the middle frontal gyrus (Talairach coordinates (x, y, z) ¼ À50, 30, 36), corresponding with the posterior regions of the Brodmann area 9 (BA9), and overlapping with the superior region of BA46 ( Figure 2). The selection of this site was based on a recent meta-analysis of functional imaging studies that examined WM and the activation of the DLPFC (Cannon et al, 2005;Mendrek et al, 2005;Tan et al, 2005).…”

Section: Dlpfc Site Localizationmentioning

confidence: 99%

Potentiation of Gamma Oscillatory Activity through Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex

Barr

Farzan

Rusjan

et al. 2009

Neuropsychopharmacol

100

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Neuronal oscillations in the gamma (g) frequency range (30-50 Hz) have been associated with cognition. Working memory (WM), a cognitive task involving the on-line maintenance and manipulation of information, elicits increases in g oscillations with greater cognitive demand, particularly in the dorsolateral prefrontal cortex (DLPFC). The generation and modulation of g oscillations have been attributed to inhibitory interneuron networks that use g -aminobutyric acid (GABA) as their principal neurotransmitter. Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive method to stimulate the cortex that has been shown to modify cognition and GABA inhibitory mechanisms, particularly with higher frequencies (ie, 10-20 Hz). We measured the effect of high-frequency rTMS applied to the DLPFC on g-oscillations elicited during the N-back WM task in healthy individuals. Active rTMS significantly increased g-oscillations generated during the N-back conditions with the greatest cognitive demand. Further, no significant changes were found in other frequency ranges, suggesting that rTMS selectively modulates g-oscillations in the frontal brain regions. These findings provide important insights into the neurophysiological mechanisms that underlie higher-order cognitive processes, and suggest that rTMS may be used as a cognitive enhancing strategy in neuropsychiatric disorders that suffer from cognitive deficits.

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Dorsolateral Prefrontal Cortex Activity During Maintenance and Manipulation of Information in Working Memory in Patients With Schizophrenia

Cited by 178 publications

References 60 publications

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Neural bases for impaired social cognition in schizophrenia and autism spectrum disorders

Potentiation of Gamma Oscillatory Activity through Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex

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