Maintenance and Manipulation in Spatial Working Memory: Dissociations in the Prefrontal Cortex

Glahn, David C.; Kim, Junghoon; Cohen, Mark S.; Poutanen, Veli-Pekka; Therman, Sebastian; Bava, Sunita; Erp, Theo G.M. van; Manninen, Marko; Huttunen, Matti; Lönnqvist, Jouko; Standertskjöld‐Nordenstam, C.‐G.; Cannon, Tyrone D.

doi:10.1006/nimg.2002.1161

Cited by 145 publications

(118 citation statements)

References 54 publications

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“…Consistent findings were observed in the second task, a parametric probe of spatial working memory capacity (SCAP) (32). NF1 individuals showed significantly lower accuracy relative to controls overall (P = 0.03; Fig.…”

Section: Nf1supporting

confidence: 76%

“…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.

145

150

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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: Nf1supporting

confidence: 76%

Section: Methodsmentioning

confidence: 99%

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.

145

150

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“…We used a computerized version of the SWM task (Sternberg, 1966;Glahn et al, 2002) to assess encoding and maintenance of WM (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Electroencephalography Correlates of Spatial Working Memory Deficits in Attention-Deficit/Hyperactivity Disorder: Vigilance, Encoding, and Maintenance

et al. 2014

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In the current study we sought to dissociate the component processes of working memory (WM) (vigilance, encoding and maintenance) that may be differentially impaired in attention-deficit/ hyperactivity disorder (ADHD). We collected electroencephalographic (EEG) data from 52 children with ADHD and 47 typically developing (TD) children, ages 7-14 years, while they performed a spatial Sternberg working memory task. We used independent component analysis and time-frequency analysis to identify midoccipital alpha (8 -12 Hz) to evaluate encoding processes and frontal midline theta (4 -7 Hz) to evaluate maintenance processes. We tested for effects of task difficulty and cue processing to evaluate vigilance. Children with ADHD showed attenuated alpha band event-related desynchronization (ERD) during encoding. This effect was more pronounced when task difficulty was low (consistent with impaired vigilance) and was predictive of memory task performance and symptom severity. Correlated with alpha ERD during encoding were alpha power increases during the maintenance period (relative to baseline), suggesting a compensatory effort. Consistent with this interpretation, midfrontal theta power increases during maintenance were stronger in ADHD and in high-load memory conditions. Furthermore, children with ADHD exhibited a maturational lag in development of posterior alpha power whereas age-related changes in frontal theta power deviated from the TD pattern. Last, subjects with ADHD showed age-independent attenuation of evoked responses to warning cues, suggesting low vigilance. Combined, these three EEG measures predicted diagnosis with 70% accuracy. We conclude that the interplay of impaired vigilance and encoding in ADHD may compromise maintenance and lead to impaired WM performance in this group.

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“…In younger adults, activation of the WM network is affected by memory load (23)(24)(25)(26). The load-dependent change of the blood oxygen level-dependent (BOLD) signal can be characterized as a dose-response function.…”

mentioning

confidence: 99%

Performance level modulates adult age differences in brain activation during spatial working memory

Nagel

Preuschhof

et al. 2009

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

189

166

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Working memory (WM) shows pronounced age-related decline. Functional magnetic resonance imaging (fMRI) studies have revealed age differences in task-related brain activation. Evidence based primarily on episodic memory studies suggests that brain activation patterns can be modulated by task difficulty in both younger and older adults. In most fMRI aging studies on WM, however, performance level has not been considered, so that age differences in activation patterns are confounded with age differences in performance level. Here, we address this issue by comparing younger and older low and high performers in an eventrelated fMRI study. Thirty younger (20 -30 years) and 30 older (60 -70 years) healthy adults were tested with a spatial WM task with three load levels. A region-of-interest analysis revealed marked differences in the activation patterns between high and low performers in both age groups. Critically, among the older adults, a more ''youth-like'' load-dependent modulation of the blood oxygen level-dependent signal was associated with higher levels of spatial WM performance. These findings underscore the need of taking performance level into account when studying changes in functional brain activation patterns from early to late adulthood.aging ͉ fMRI ͉ premotor cortex ͉ performance load

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Maintenance and Manipulation in Spatial Working Memory: Dissociations in the Prefrontal Cortex

Cited by 145 publications

References 54 publications

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Electroencephalography Correlates of Spatial Working Memory Deficits in Attention-Deficit/Hyperactivity Disorder: Vigilance, Encoding, and Maintenance

Performance level modulates adult age differences in brain activation during spatial working memory

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