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PubMed2002

Dissociating a common working memory network from different neural substrates of phonological and spatial stimulus processing.

Positron emission tomography was used to investigate common versus specific cortical regions for the maintenance of spatial versus phonological information in working memory (WM). Group and single-subject analyses of regional cerebral blood flow during a new 2 x 2 factorial n-back task were performed. Eight subjects had to memorize either phonological features or the location of serially presented syllables. Brain activation during phonological judgment and spatial judgment (0-back) was compared with that during two corresponding WM conditions (2-back). We observed a common network associated with the requirement of maintaining and sequencing items in WM. Seven or more subjects activated (posterior) superior frontal sulcus (pSFS, BA 6/8, global maximum) and/or adjacent gyri, posterior parietal cortex, and precuneus (BA 7). Less consistently, bilateral middle frontal gyrus (BA 9/46) was involved. Bilateral anterior (BA 39/40) and posterior (BA 7) intraparietal sulcus, as well as right pSFS, exhibited dominance for spatial WM. Although underlying stimulus processing pathways for both types of information were different, no region specific for phonological WM was found. Robust activation within the left inferior frontal gyrus (BA 44 and 45) was present, during both phonological WM and phonological judgment. We conclude that the controversial left prefrontal lateralization for verbal WM reflects more general phonological processing strategies, not necessarily required by tasks using letters. We propose a stimulus-independent role for the bilateral pSFS and its vicinity for maintenance and manipulation of different context-dependent information within working memory.

Adult↗
PubMed2006

Visual, auditory, and cross-modality dual-task costs: electrophysiological evidence for an amodal bottleneck on working memory consolidation.

When two masked, attended targets (T1 and T2) are presented within approximately half a second of each other, report of T2 is poor, compared with when the targets are presented farther apart in time--a phenomenon known as the attentional blink (AB; Raymond, Shapiro, & Arnell, 1992). Some researchers have suggested that an amodal bottleneck on working memory consolidation underlies the AB (see, e.g., Arnell & Jolicoeur, 1999). In the present work, T1 was masked, whereas T2 was unmasked. The modality of T1 (visual or auditory) and the modality of T2 (visual or auditory) were factorially manipulated across four experiments. For all modality combinations, T2's P3 event-related brain potential component was found to be delayed when T2 was presented soon after T1 (lag 3), compared with when T1 and T2 were presented farther apart (lag 8). Results suggest that the working memory consolidation bottleneck is amodal in nature, and provide evidence that visual, auditory, and cross-modality ABs all result from a bottleneck on consolidation operations.

Adolescent↗
PubMed2004

Spatial working memory among middle-aged and older patients with schizophrenia and volunteers using fMRI.

OBJECTIVE: Goldman-Rakic and Selemon (Schizophr. Bull. 23 (1997)) hypothesized that many of the symptoms of schizophrenia can be explained by deficits of working memory (WM) that are, in turn, caused by dysfunction of dorsolateral prefrontal cortex (DLPFC). We examined whether older patients with schizophrenia would show an aberrant neural response in the DLPFC or other brain sites when performing a spatial working memory (WM) task adapted from McCarthy et al. (Proc. Natl. Acad. Sci. U. S. A. 91 (1994)). METHOD: Middle-aged and older patients with schizophrenia or schizoaffective disorder and healthy volunteers performed a spatial WM task contrasted with two baselines, passive and active viewing (PV and AV, respectively), while blood oxygen level dependent (BOLD) images were acquired in a functional magnetic resonance study. RESULTS: Patients did not perform significantly less well on the spatial tasks compared to the volunteers. Although we found no significant group effects in spatial WM activation of DLPFC, we did observe areas in medial frontal cortex including the left anterior cingulate gyrus, parietal areas of the both hemispheres, multiple sites within the basal ganglia of the left hemisphere, and the left superior temporal gyrus where healthy volunteers showed greater BOLD response to WM. In a second pattern, patients showed a greater BOLD response to WM in left fusiform gyrus [Brodmann's Area (BA) 19], peri-rolandic areas, medial frontal area; right anterior cerebellum (culmen), middle occipital lobe, and postcentral/supramarginal gyri (BA 2/40). CONCLUSIONS: Middle-aged and older patients with schizophrenia display normal or near-normal spatial WM activation of DLPFC when the processing demands of the WM task are within their performance capacity. Nonetheless, even when patients perform nearly normally, they demonstrate an aberrant pattern of brain response.

Age Factors↗
PubMed1999

Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys.

The effects of systemically administered or iontophoretically applied clonidine (alpha-2 adrenergic agonist) and iontophoretically applied yohimbine (alpha-2 adrenergic antagonist) were examined on prefrontal cortical (PFC) neurons related to spatial working memory (SWM). Systemically administered clonidine (0.04 mg/kg) enhanced SWM-related PFC neuronal activity by 32.5 +/- 14.5%, (mean +/- SD; n = 25 neurons). The facilitatory effect of clonidine was antagonized by iontophoretically applied yohimbine. Iontophoretically applied clonidine enhanced SWM-related PFC neuronal activity by 38.2 +/- 18.6%, (n = 13 neurons), whereas similarly applied yohimbine suppressed it by 34.4 +/- 17.8% (n = 28 neurons). These results indicate that: a) systemically administered clonidine can facilitate SWM-related PFC neuronal activity through actions at alpha-2 adrenoceptors in the PFC; and b) conversely, blockade by yohimbine of alpha-2 adrenoceptors in the PFC suppresses SWM-related neuronal activity. The present study provides neurophysiological evidence that alpha-2 adrenoceptors in the PFC are involved in the cellular mechanisms underlying working memory.

Action Potentials↗
PubMed1999

Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

Adrenergic alpha-Agonists↗
PubMed1997

Ameliorating effects of RU 47213, a novel oral and long-lasting cholinomimetic agent, on working memory impairments in rats.

The anti-amnesic effects of RU 47213 [1-(4-chlorophenoxycarbonyl)-1,2,5, 6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime], a prodrug with oral and long-lasting cholinergic activity, were evaluated on working memory impairments, using tasks of unequal levels of difficulty involving the same reinforcement and motivation in rats: a spatial-based task in a radial maze and a delayed reinforced alternation task in a T-maze. Tetrahydroaminoacridine (THA; tacrine), a cholinesterase inhibitor was used as a reference. Groups of rats were trained in an automated radial maze or T-maze until they had attained an asymptotic level of performance. On test days, memory impairment was produced by administration of scopolamine (0.1 mg/kg s.c.) 15 min prior to testing. Both THA (1.3, and 5 mg/kg) and RU 47213 (0.2, 0.5, 1, and 2 mg/kg) given prior to testing markedly reduced or suppressed the scopolamine induced working memory deficits in both tasks. This activity was evidenced by either a significant decrease in the number of errors or an increase in the number of correct responses. These results show that RU 47213 possesses the capacity to reduce memory deficits induced by an impairment of cholinergic transmission in the rat.

Animals↗
PubMed2002

Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory.

Nicotine and other nicotinic receptor agonists have been found in a variety of studies to improve memory, while nicotinic receptor blockade can impair memory. The critical neural mechanisms for nicotinic involvement with memory are still under investigation. Initial evidence supports the involvement of the ventral hippocampus. Lesions in this area block nicotine-induced memory improvement and mecamylamine-induced impairment. Local ventral hippocampal application of the nicotinic channel blocker mecamylamine impairs memory in the 8-arm radial maze. Both alpha 4 beta 2 and alpha 7 nicotinic receptors seem to be involved. Ventral hippocampal infusions of high doses of the alpha 4 beta 2 nicotinic antagonist dihydro-beta-erythrodine (DH beta E) and the alpha 7 nicotinic antagonist methyllycaconitine (MLA) impair memory performance on the 8-arm radial maze. However, high doses of these drugs may limit specificity and they cause preconvulsant effects, which in themselves may affect memory. The current study used the more challenging 16-arm radial maze to determine the effects of lower doses of these drugs on memory and to differentiate effects on working and reference memory. Adult female Sprague-Dawley rats were trained on a working and reference memory task in the 16-arm radial maze and then were implanted with bilateral chronic guide cannulae directed to the ventral hippocampus. After recovery from surgery, the rats received acute intrahippocampal infusions of dose combinations of DH beta E and MLA. In the first study, DH beta E (0 and 6.75 microg/side) and MLA (0, 6.75, 13.5 and 27 microg/side) were administered in a counter-balanced order. In the second study, lower doses of DH beta E (0, 1.6375, 3.275 and 6.75 microg/side) were administered alone or with MLA (0 and 6.75 microg/side) in a counter-balanced order. In the first study, DH beta E caused a significant increase in both working and reference memory errors. MLA at a dose of 27 microg/side caused a significant increase in working memory errors, but this dose had no significant effect on reference memory errors. Interestingly, no additive effects were seen with combined administration of DH beta E and MLA in this study, and at the doses used, no effects were seen on response latency. In the second study, lower doses of DH beta E did not cause a significant deficit in working memory performance. Co-administration of MLA with these subthreshold doses did precipitate a memory impairment. The current results confirm the specificity of the memory deficits caused by these drugs. These results support the involvement of alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus as being critical for memory function.

Acetylcholine↗
PubMed1994

Impairment of spatial working memory of rats in radial maze performance induced by ethylcholine mustard aziridinium picrylsulfonate (AF64A-P): retention curve analysis.

The effects of the cholinergic neurotoxin, ethylcholine mustard aziridinium picrylsulfonate (AF64A-P), on the spatial working memory in eight-arm radial maze performance were studied. Rats well-trained on radial maze performance were injected intracerebroventricularly with AF64A-P (0.05 nmol/each side) or artificial cerebrospinal fluid (A-CSF, 5 microliters). AF64A-P produced a selective reduction of choline acetyltransferase activity in the hippocampus. Rats treated with AF64A-P showed a significant decrease in the number of correct responses in baseline performance compared to rats injected with A-CSF. To examine whether the deficits might result from the disruption of memory, tests of memory retention were studied. Various delay intervals (45, 90, 180, or 360 min) were interposed between the fourth and the fifth choice, and the number of correct responses in the choices 5-8 were then examined as a function of retention intervals. Significant interaction of deficits in arm-choice accuracy induced by AF64A-P with retention intervals in the choices 5-8 was observed. Oxotremorine, a muscarinic receptor agonist (0.025, 0.05 and 0.1 mg/kg, ip), was able to reverse this deficit in a dose-dependent manner. These observations reveal a pattern of impairment of spatial working memory during prolonged states of central cholinergic hypofunction induced by intracerebroventricular administration of AF64A-P, which binds irreversibly to its receptor site.

Animals↗
PubMed1992

Impairment of working memory by neuronal degeneration with NMDA in rat hippocampal CA-1.

Rats were trained on a three-panel runway task prior to injections of N-methyl-D-aspartate (NMDA; 40nmoles/µl/side) into the dorsal hippocampus. One week after the treatment, animals did not show any change in the number of errors on the first runway trial (reference memory), with one correct white and two incorrect black panels at each choice point, whereas they showed a marked increase in the number of errors on the following (2nd-6th) trials (working memory) with all black panels. The memory deficit persisted at least for 10 days. After the experiments, histological studies showed neuronal degeneration of hippocampal CA-1 pyramidal cells in all NMDA-treated rats but not in vehicle-treated rats. Pretreatment with the NMDA receptor antagonist MK-801 (3 or 10mg/kg, i.p) before the NMDA injections protected both the neuronal degeneration and the memory deficit. These findings suggest that selective neuronal degeneration induced by excessive stimulation of NMDA receptors in hippocampal CA-1 impaired working memory, but not reference memory.

Journal Article↗
PubMed1997

Working memory capacity and comprehension processes in deaf readers.

This research studied deaf students' performance on memory span and component reading tasks that incorporated processes involved in higher level comprehension. The instruments developed in the study provide the basis for the measurement of functional working memory capacity, vocabulary knowledge, domain-relevant knowledge, and inference abilities. Multiple regression analysis was used to construct models that show the contributions of the independent assessments to reading comprehension ability. Overall results suggest that working memory operates as a general executive system, as indicated by significant correlations between subjects' performance on reading and nonreading tasks. Limitations in vocabulary knowledge continue to pose problems in reading for deaf individuals. General or procedural knowledge also plays a part in reading comprehension processes.

Journal Article↗
PubMedDate not supplied

Effects of age on measures of complex working memory span in the beagle dog (Canis familiaris) using two versions of a spatial list learning paradigm.

The present study used two versions of a spatial list learning (SLL) paradigm to examine the effects of increased cognitive load on visuospatial working memory processes in young and old beagle dogs. In the first experiment, young, and a select group of old dogs were first presented with one item, then two, and then three, and were rewarded for responding to the novel position. The dogs were able to learn the task at short delays, but compared with young dogs, old dogs performed worse at delays of 10 sec, and could not reach longer delays. Analysis of errors indicated that memory was best for end items in the spatial list and that within sessions, the number of errors in later trials was greater than the number of errors in earlier trials. A second version of the task, a modified SLL (mSLL) was developed to control for the use of non-mnemonic strategies on the SLL task. In this version, the first two items were presented individually. Acquisition and maximal memory performance were better in the young relative to the old dogs. Similar to the original SLL design, memory for early list items was worse than memory for later list items in both young and old dogs. The within-session pattern of errors however, did not change from trial to trial on the mSLL. The present results suggest that multiple working memory processes are engaged during complex tests of visuospatial function and the neuroanatomical substrates controlling these processes are affected differentially by age in the beagle dog.

Aging↗
PubMed2000

Cholinergic enhancement improves performance on working memory by modulating the functional activity in distinct brain regions: a positron emission tomography regional cerebral blood flow study in healthy humans.

Previously, we have shown that physostigmine, an acetylcholinesterase inhibitor, improved performance on a working memory for faces task, as reflected by reduced reaction time (RT), and reduced task-specific regional cerebral blood flow (rCBF) in right prefrontal cortex and, further, that these reductions in RT and right frontal rCBF were significantly correlated. Here we investigated the relation between the effects of physostigmine on task performance and task-specific functional brain response throughout the cortex by examining correlations between physostigmine-related changes in rCBF in all brain areas and changes in RT. In subjects who received an infusion of physostigmine, reduced RT correlated (p<0.001) positively with reduced rCBF in right frontal cortex, left temporal cortex, anterior cingulate, and left hippocampus; and correlated with increased rCBF in medial occipital visual cortex. In subjects who received a placebo infusion of saline, no significant correlations between changes in RT and cortical rCBF were observed. The results show that cholinergically induced improvements in working memory performance are related to alterations in neural activity in multiple cortical regions, including increased neural activity in regions associated with early perceptual processing and decreased neural activity in regions associated with attention, memory encoding, and memory maintenance.

Adult↗
PubMed1995

Huperzine A ameliorates the spatial working memory impairments induced by AF64A.

Huperzine A, a novel, potent, reversible, and selective acetylcholinesterase (AChE) inhibitor has been expected to be superior to other AChE inhibitors now for the treatment of memory deficits in patients with Alzheimer's disease. We have assessed the effects of huperzine A on performance of AF64A-treated rats in the radial maze. AF64A (2 nmol per side, i.c.v.) caused significant impairment in rats' ability to perform the spatial working memory task. This behavioural impairment was associated with a significant decrease in the activity of choline acetyltransferase (ChAT) in the hippocampus. Huperzine A (0.4-0.5 mg kg-1, i.p.) significantly ameliorated the AF64A-induced memory deficit. These results suggest that AF64A is a useful agent for disrupting working memory processes by altering hippocampal cholinergic function, and such impairment can be effectively ameliorated by huperzine A.

Alkaloids↗
PubMed2004

Increased MEG activation in OCD reflects a compensatory mechanism specific to the phase of a visual working memory task.

We examined spatio-temporal patterns of evoked magnetoencephalographic signals (MEG) in patients with obsessive-compulsive disorder (OCD) during the Encoding, Retention, and Retrieval phases of a Delayed Matching-to-Sample working memory task (DMST). The question was whether the mechanisms of abnormally increased cortical excitability, frequently reported in OCD, relate to a global cortical disinhibition and unselective over-processing of stimuli or, alternatively, to a compensatory mechanism of effortful enhanced inhibitory control. The DMST-related network of activation in OCD was found similar to that of Controls, and to that reported in other neuroimaging studies. The pattern of increased MEG activation in OCD patients was phase specific. During the Encoding phase, the activation was enhanced in the region of anterior insula and reduced in the posterior-inferior parietal cortex. During Retention, the activation was reduced in the occipital, parietal, superior temporal sulcus, and dorsolateral prefrontal cortex (BA 6/8/9). During Retrieval, a significant increase of activation was found in the right anterior insula extending towards the orbital region and right superior temporal sulcus, along with reduced activation in the left parietal cortex. The performance accuracy was high in OCD and comparable to Controls, although the RTs were prolonged. The results are discussed as being consistent with the hypothesis of a compensatory mechanism of effortful inhibitory control. This mechanism may be a major contributor to the increased cortical activation during Encoding and, in particular, Retrieval of the DMST task in patients suffering OCD. The findings do not support the concept of a faulty working memory mechanism per se in OCD.

Adult↗
PubMed2004

Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory.

Metabotropic glutamate receptors (mGluRs), and in particular the mGluR group III receptors (subtypes 4, 6, 7, 8) are known to play a role in synaptic plasticity and learning. Here, we report the effect of mGluR7 gene ablation in different learning paradigms. In the acoustic startle response (ASR), no differences were seen between knockout (KO) mice and wildtype (WT) littermates in parameters including prepulse inhibition and habituation. In an open field test, no differences were seen between genotypes in motor activity, exploratory behaviour, and fearful behaviour. In a T-maze reinforced alternation working memory (WM) task, again no difference was seen between groups. However, when increasing the demands on working-memory in a 4-arm and 8-arm maze task, KO mice committed more WM errors than WT littermates thereby uncovering a highly significant difference between the two groups that persisted every day for the whole 9 days of the experiment. In a 4-arm maze with 2 arms baited, KO and wildtype mice committed the same number of LTM errors, whereas KOs committed more WM errors. Altogether, these findings suggest that a lack of mGluR7 mainly impairs short-term working but not long-term memory performance while having no effect on sensorimotor processing, non-associative learning, motor activity and spatial orientation. The effects on WM are task-dependent and become apparent in more complex but not simple learning tasks. We discuss how mGluR7 could influence WM.

Animals↗
PubMed2006

Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency- and time-dependent effects.

Although improvements in performance due to TMS have been demonstrated with some cognitive tasks, performance improvement has not previously been demonstrated with working memory tasks. In the present study, a delayed match-to-sample task was used in which repetitive TMS (rTMS) at 1, 5, or 20 Hz was applied to either left dorsolateral prefrontal or midline parietal cortex during the retention (delay) phase of the task. Only 5 Hz stimulation to the parietal site resulted in a significant decrease in reaction time (RT) without a corresponding decrease in accuracy. This finding was replicated in a second experiment, in which 5 Hz rTMS at the parietal site was applied during the retention phase or during presentation of the recognition probe. Significant speeding of RT occurred in the retention phase but not the probe phase. This finding suggests that TMS may improve working memory performance, in a manner that is specific to the timing of stimulation relative to performance of the task, and to stimulation frequency.

Adult↗
PubMedDate not supplied

Elaborations in adults' text recall: relations to working memory and text recall.

We examined differences in the elaborative statements produced by younger (mean age = 22.19) and older (mean age = 76.56) adults during text recall as well as relations between elaborative statements and text recall and working memory. Three types of elaborative statements were examined: personal (reactions to a text), inferential (inferences derivable about a text), and metacognitive (statements concerning understanding or memory of a text). Older adults made more personal elaborations during text recall than did younger adults. Younger and older adults did not differ in the amount of inferential or metacognitive elaborations they made, although all adults made more metacognitive comments when texts contained problematic information. Personal elaborations were negatively related to recall and accounted for a substantial portion of the age-related variance in recall. Personal elaborations were also negatively related to processing efficiency, and relations between personal elaborations and working memory and storage capacity were mediated by processing efficiency. The results are consistent with the view that an age-related increase in non-goal-path thoughts, due to inhibitory problems or a different style of text processing, may be related to age-related deficits in text processing.

Adolescent↗
PubMed2005

Neuropsychological predictors of BOLD response during a spatial working memory task in adolescents: what can performance tell us about fMRI response patterns?

The relationship between standardized neuropsychological test performance and functional magnetic resonance imaging (fMRI) response during cognitive tasks is largely unknown. This exploratory investigation examined the relationship between neuropsychological test performance and fMRI response to a spatial working memory (SWM) task among 49 typically developing adolescents. Participants were administered a variety of neuropsychological tests in the domains of working memory, visuospatial skills, executive functioning, attention, learning and memory, visuomotor skills and processing speed, and language functioning. Neuropsychological domain scores were used to predict fMRI response during a SWM task. Results suggest that in many brain regions, neuropsychological performance negatively predicts fMRI response, suggesting that those teens with better neuropsychological abilities required fewer neural resources to adequately perform the task. This study provides further understanding of how neuropsychological abilities relate to neural activity during fMRI tasks, and provides an important link between neuropsychological and fMRI research.

Adolescent↗