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PubMed2005

The effects of working memory demands on the neural correlates of prospective memory.

Event-related brain potentials (ERPs) were used to examine the reciprocal costs of working and prospective memory loads on the neural correlates of the realization of delayed intentions and the detection of target stimuli. The electrophysiological data revealed several interesting results: (1) distinct modulations of the ERPs were elicited by working memory targets and prospective memory cues, (2) working memory load modulated the amplitude of the N300 elicited by prospective memory cues, (3) prospective memory load was associated with a broadly distributed sustained modulation that began shortly after stimulus onset, and (4) brain-behavior correlations between the neural correlates of prospective memory and working memory varied with the working memory demands of the ongoing activity. These findings appear to indicate that attentional processes associated with the detection of prospective memory cues are sensitive to the working memory demands of the ongoing activity and that different processes may support prospective memory depending on the working memory demands of the ongoing activity.

Adolescent↗
PubMed1998

Spermidine, a polyamine site agonist, attenuates working memory deficits caused by blockade of hippocampal muscarinic receptors and mGluRs in rats.

Spermidine, an agonist of the polyamine site on the NMDA receptor/channel complex, did not affect the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task with a three-panel runway setup, when injected bilaterally at 1 or 10 microg/side into the dorsal hippocampus. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine (3. 2 microg/side) significantly increased the number of working memory errors. The increase in working memory errors by intrahippocampal 3. 2 microg/side scopolamine was significantly reduced by concurrent infusion of 10 microg/side spermidine. Likewise, spermidine (10 microg/side) was effective in attenuating the increase in working memory errors induced by intrahippocampal administration of AIDA (3. 2 microg/side), a potent and selective antagonist of the class I metabotropic glutamate receptor (mGluR). These results suggest that enhanced NMDA function via polyamine modulatory site on the NMDA receptor/channel can compensate dysfunction of hippocampal cholinergic and mGluR-mediated neurotransmission involved in working memory function.

Animals↗
PubMed1999

Synaptic basis of cortical persistent activity: the importance of NMDA receptors to working memory.

Delay-period activity of prefrontal cortical cells, the neural hallmark of working memory, is generally assumed to be sustained by reverberating synaptic excitation in the prefrontal cortical circuit. Previous model studies of working memory emphasized the high efficacy of recurrent synapses, but did not investigate the role of temporal synaptic dynamics. In this theoretical work, I show that biophysical properties of cortical synaptic transmission are important to the generation and stabilization of a network persistent state. This is especially the case when negative feedback mechanisms (such as spike-frequency adaptation, feedback shunting inhibition, and short-term depression of recurrent excitatory synapses) are included so that the neural firing rates are controlled within a physiological range (10-50 Hz), in spite of the exuberant recurrent excitation. Moreover, it is found that, to achieve a stable persistent state, recurrent excitatory synapses must be dominated by a slow component. If neuronal firings are asynchronous, the synaptic decay time constant needs to be comparable to that of the negative feedback; whereas in the case of partially synchronous dynamics, it needs to be comparable to a typical interspike interval (or oscillation period). Slow synaptic current kinetics also leads to the saturation of synaptic drive at high firing frequencies that contributes to rate control in a persistent state. For these reasons the slow NMDA receptor-mediated synaptic transmission is likely required for sustaining persistent network activity at low firing rates. This result suggests a critical role of the NMDA receptor channels in normal working memory function of the prefrontal cortex.

Animals↗
PubMed2002

Prefrontal dopamine D1 receptors and working memory in schizophrenia.

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D1 receptor availability was measured with positron emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [11C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 +/- 0.39 ml/gm) compared with control subjects (1.27 +/- 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.

Adult↗
PubMed2004

Effects of antiepileptic drugs on working memory as assessed by spatial alternation performance in rats.

Patients with epilepsy can have impaired cognitive abilities. Many factors contribute to this impairment, including the adverse effects of antiepileptic drugs (AEDs). However, there are few systematic data on the effects of AEDs on specific cognitive domains, such as working memory. The purpose of the present study was to evaluate the effects of AEDs on working memory as measured by delayed spatial alternation behavior in nonepileptic rats. The GABA-related AEDs triazolam and phenobarbital significantly disrupted performance, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blockers carbamazepine and topiramate produced modest but significant disruption of performance, whereas the effects of lamotrigine were not significant and phenytoin produced a modest but significant improvement in performance but at doses that abolished responding in some animals. Levetiracetam had no effect on working memory. In contrast, ethosuximide significantly disrupted working memory. The disruptions produced by triazolam and phenobarbital were similar in magnitude to the effects of the muscarinic antagonist scopolamine. The present results indicate that AEDs can disrupt working memory, but there are differences among AEDs in the magnitude of the disruption that do not appear to be correlated with mechanism of action.

Analysis of Variance↗
PubMed2004

A test of the integrity of the components of Baddeley's model of working memory in attention-deficit/hyperactivity disorder (ADHD).

BACKGROUND: The integrity of working memory in attention-deficit/hyperactivity disorder (ADHD) was tested within the framework of Baddeley's model. METHODS-1: Buffers and rehearsal mechanisms were assessed by presenting children with or without ADHD (ages 8 to 15) with 1-7 target letters and a probe after 2-10 s. They decided if the probe was the same (verbal task) or in the same location (spatial task) as any of the targets. RESULTS-1: There was no interaction between group and delay or memory load in either task. METHODS-2: The central executive was assessed on a dual task. RESULTS-2: Although children with ADHD did not differ from controls in simple response time (RT) or in digits recalled, they showed greater decrements in RT when performing the 2 tasks concurrently. CONCLUSIONS: Findings suggest that children with ADHD (1) do not have generalized impairments in working memory, (2) rehearse verbal and spatial information in the same manner as healthy children, (3) may have an impairment in the central executive component of working memory, which controls ability to divide attention between two tasks.

Adolescent↗
PubMed2004

Interference with spatial working memory: an eye movement is more than a shift of attention.

In the present experiments, we examined whether shifts of attention selectively interfere with the maintenance of both verbal and spatial information in working memory and whether the interference produced by eye movements is due to the attention shifts that accompany them. In Experiment 1, subjects performed either a spatial or a verbal working memory task, along with a secondary task requiring fixation or a secondary task requiring shifts of attention. The results indicated that attention shifts interfered with spatial, but not with verbal, working memory, suggesting that the interference is specific to processes within the visuospatial sketchpad. In Experiment 2, subjects performed a primary spatial working memory task, along with a secondary task requiring fixation, an eye movement, or an attention shift executed in the absence of an eye movement. The results indicated that both eye movements and attention shifts interfered with spatial working memory. Eye movements interfered to a much greater extent than shifts of attention, however, suggesting that eye movements may contribute a unique source of interference, over and above the interference produced by the attention shifts that accompany them.

Attention↗
PubMed2005

Active maintenance of sentence meaning in working memory: evidence from EEG coherences.

The active maintenance of sentence meaning in working memory was investigated using event-related electroencephalogram (EEG) coherences. Participants read a sentence, retained it for 2.5 s, and then verified a statement about its meaning. The sentences contained either three semantically related nouns or unrelated nouns and started either with a what phrase (WH sentences) or not (non-WH sentences), imposing either a high or low demand on verbal working memory. Comprehension accuracy showed an interaction of semantic relatedness and sentence type due to the presence of a relatedness effect (lower accuracy in the unrelated condition) in WH sentences but not in non-WH sentences. During the post-sentence retention interval, EEG coherences also displayed this interaction of relatedness and sentence type. A semantic relatedness effect was obtained in the WH sentences (high demand) but not in the non-WH sentences (low demand). In addition, compared to a pre-sentence baseline and sentence presentation, coherences increased in the 10-14 Hz band during retention and decreased in the 4-6 Hz band. These coherence changes spanned prefrontal and posterior brain regions, possibly reflecting increased synchronization in projection loops between attention control systems in prefrontal cortex and activated meaning representations in semantic memory in posterior cortex. These findings suggest that short-term retention of the meaning of a sentence involves active maintenance in a capacity-limited working memory, accompanied by a heightened inner direction of attention after sentence presentation.

Adult↗
PubMed2003

Age differences in working memory--the roles of storage and selective access.

Twenty-four young (23 years) and 24 old (71 years) adults performed arithmetic tasks with working memory loads ranging from 1 to 4. Age groups were equivalent in mean accuracy and speed of arithmetic operations under minimal working memory load, but old adults were slower than young with memory demands >1. Access to a new object in working memory as the basis of computation required additional time. This object-switching cost increased with increases in memory demand, but was unaffected by age, indicating that old adults have no deficit in selective access to working memory.

Adult↗
PubMed1997

Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys.

With advancing age, monkeys develop deficits in spatial working memory resembling those induced by lesions of the prefrontal cortex (PFC). Aged monkeys also exhibit marked loss of dopamine from the PFC, a transmitter known to be important for proper PFC cognitive function. Previous results suggest that D1 agonist treatment can improve spatial working memory abilities in aged monkeys. However, this research was limited by the use of drugs with either partial agonist actions or significant D2 receptor actions. In our study, the selective dopamine D1 receptor full agonists A77636 and SKF81297 were examined in aged monkeys for effects on the working memory functions of the PFC. Both compounds produced a significant, dose-related effect on delayed response performance without evidence of side effects: low doses improved performance although higher doses impaired or had no effect on performance. Both the improvement and impairment in performance were reversed by pretreatment with the D1 receptor antagonist, SCH23390. These findings are consistent with previous results demonstrating that there is a narrow range of D1 receptor stimulation for optimal PFC cognitive function, and suggest that very low doses of D1 receptor agonists may have cognitive-enhancing actions in the elderly.

Adamantane↗
PubMed1999

Effects of age on working memory: an event-related potential study.

The effects of age on behavioural performance and event-related potentials recorded during a working memory task using digits presented either acoustically or visually, were studied in 37 healthy subjects with an age range from 19 to 71 years. With increasing age, psychological tests showed a progressive decline in visuo-spatial performance and both auditory and visual reaction times (RT) increased. There were multiple and varying effects of age on both early and late ERP components. For both auditory and visual responses, increasing age was associated with an increased amplitude of early positive waves (auditory P100 and visual P145) and, in the oldest subjects, significant delays of the major late positive waves. Other changes were modality-specific with a progressive shift of amplitude maxima in the early negative waves of the visual ERPs (from an N190 peak maximal at Pz in the young, to an N270 peak maximal at Cz in the older subjects) and an altered amplitude distribution of late potentials (after the P250 wave) in the auditory responses. The age at which ERP changes occurred varied-significant latency prolongations and increases in the amplitude of the major frontal positive waves occurred only in the oldest subjects, whereas a redistribution of late auditory ERPs also occurred in the intermediate age group. There was no interaction between age and increasing memory load, suggesting that there is no specific effect of age on memory scanning in this age range for these levels of task difficulty. Thus, although performance in working memory was apparently unaffected by age, as judged by behavioural parameters (apart from slowing of the reaction times), ERPs revealed significant changes in both early and late electrical brain processes associated with working memory as age increases. These changes which were not symptomatically manifest and only revealed by sensitive tests, may represent subtle dysfunction of working memory (or associated processes) which does not prevent the successful completion of our task, compensatory mechanisms (which are essential to successfully complete the task), or a combination of both age-induced dysfunction and compensatory mechanisms.

Acoustic Stimulation↗
PubMedDate not supplied

Imaging and neural modelling in episodic and working memory processes.

Neuroimaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have revealed the involvement of distributed brain regions in memory processes mainly by the use of subtraction strategy based data analyses. Covariance analysis based data analysis strategies have been introduced more recently which allow functional interactions between brain regions of a neuronal network to be assessed. This contribution focuses on studies aiming to (1) establish the functional topography of episodic and working memory processes in young and old normal volunteers, (2) to assess functional interactions between modules of networks of brain regions by means of covariance based analyses and systems level modelling, (3) to characterise the temporal dynamics by the use of magnetoencephalography (MEG) and (4) to relate neuroimaging data to the underpinning neural networks. Male normal young and old volunteers without neurological or psychiatric illness participated in neuroimaging studies (PET, fMRI, MEG). Studies were approved by the ethical committee and federal authorities. Our results in young volunteers show distributed brain areas that are involved in memory processes (episodic and working memory) and show much of an overlap with respect to the network components. Systems level modelling analyses support the hypothesis of bihemispheric, asymmetric networks subserving memory processes and revealed both similarities in general and differences in the interactions between brain regions during episodic encoding and retrieval as well as working memory. Changes in memory function with ageing are evident from functional topographic studies in old volunteers activating more brain regions as compared to young volunteers. There are more and stronger influences of prefrontal regions in elderly volunteers comparing the functional models between old and young subjects. We discuss the way that the systems level models of the PET and fMRI results have implications for the underlying neural network functioning of the brain. This is done by developing simplifying assumptions, which lead from the equations describing the activities of the coupled neural modules to the systems level model equations. The resulting implications for the neural interactions are then discussed, in terms of a set of synaptically coupled neural modules. Finally, we consider how a similar analysis could be extended from the spatial to the temporal domain thus including the EEG and MEG results. The implication of preliminary MEG results presented here for the temporality arising in the interaction between the coupled neural modules in a working memory paradigm is discussed in terms of the previously developed neural network models arising from the PET and fMRI data.

Adult↗
PubMed1997

Is binding to nicotinic acetylcholine and dopamine receptors related to working memory in rats?

Nicotinic acetylcholine (ACh) and dopamine (DA) receptor activation has been found to be important for working memory. The regional distribution of these receptors in the brain has been well characterized. However, the relationship of the region-specific nicotinic ACh and DA binding density to memory performance has not been well assessed. In the current studies the relationship of receptor binding and memory function was examined. Receptor binding and memory performance were assessed in rats in three types of conditions: 1) chronic nicotine and mecamylamine vs. vehicle infusion; 2) lesions of the fimbria-fornix or medial basalocortical projection vs. sham lesions; and 3) 2-year-old aged rats vs. 3-month-old young adult rats. Nicotinic ACh receptors were labeled by [3H]N-methyl-carbamylcholine ([3H]MCC), D1 receptors by [3H]SCH 23390, and D2 receptors by [125I]iodosulpiride. Working memory was assessed using the radial-arm maze and T-maze delayed spatial alternation tasks. Chronic nicotine infusion substantially increased nicotinic receptor binding in a variety of brain areas and significantly improved working memory performance in the radial-arm maze. However, nicotinic receptor binding did not correlate well with memory performance. The nicotinic antagonist mecamylamine did not block nicotine-induced increased nicotinic binding, but it did block nicotine-induced memory improvement. Aged rats relative to young adults showed both a decrease in nicotinic binding and impaired memory performance. However, chronic effects of nicotine on nicotinic receptor binding and memory performance did not correlate in the aged rats. Nicotine also increased nicotinic receptor binding in the aged rats in brain areas except for the VTA, but did not improve memory performance. Lesions of the medial basalocortical projection or the fimbria-fornix did not cause significant changes in nicotinic binding in their target fields, but they did cause significant deficits in memory performance. Finally, there were no significant correlations of nicotinic binding in any brain region and memory performance. DA receptor binding was not altered by chronic nicotine or mecamylamine infusion, fimbria-fornix lesions, medial basalocortical lesions, or in aged rats. However, DA receptor binding did correlate with memory performance. There was a positive correlation of T-maze accuracy and D1 receptor binding in the frontal cortex and a negative correlation of T-maze accuracy and D1 receptor binding in the VTA and dentate gyrus. In contrast, a positive correlation was seen between radial-arm maze accuracy and D1 receptor binding in the VTA. Radial-arm maze accuracy was positively correlated with D2 receptor binding in the striatum and dentate gyrus. There are significant relationships between the extent of DA receptor binding and working memory, but relationship between nicotinic ACh receptor binding density and memory is weak.

Animals↗
PubMed2004

Working memory and processing speed deficits in systemic lupus erythematosus as measured by the paced auditory serial addition test.

As many as 66% of systemic lupus erythematosus (SLE) patients have been reported to have cognitive deficits. These deficits are often associated with information processing speed and working memory. Similarly, processing speed and working memory impairments are the hallmark of cognitive dysfunction in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT) places high demands on processing speed and working memory. Fisk and Archibald, however, demonstrated that the total score of the PASAT does not accurately reflect impairments in these cognitive processes. They found that MS patients used a chunking strategy to obtain correct responses and reduce the cognitive demands of the task. In the present study, PASAT performance was examined for 45 SLE patients and 27 controls using alternative scoring procedures. Although the total number of correct responses did not differ between SLE and controls at the 2.4 or 2.0 s presentation rates, SLE patients had fewer dyads (correct consecutive responses) than controls at the faster rate, and more chunking responses than controls at both rates. Disease activity, disease duration, depression, fatigue, and corticosteroids could not account for these differences. The findings suggest that SLE patients, like MS patients, chunk responses more often than controls, and that this scoring procedure may better reflect the working memory and processing speed deficits present in SLE.

Acoustic Stimulation↗
PubMed2000

Verbal working memory and sentence comprehension in children with specific language impairment.

In this study we examined the influence of verbal working memory on sentence comprehension in children with SLI. Twelve children with SLI, 12 normally developing children matched for age (CA), and 12 children matched for receptive vocabulary (VM) completed two tasks. In the verbal working memory task, children recalled as many real words as possible under three processing load conditions (i.e., no-load condition; single-load condition, where words were recalled according to physical size of word referents; and dual-load condition, where words were recalled by semantic category and physical size of word referents). In the sentence comprehension task, children listened to linguistically nonredundant (shorter) and linguistically redundant (longer) sentences. Results of the memory task showed that the children with SLI recalled fewer words in the dual-load condition than their CA peers, who showed no condition effect. The SLI and VM groups performed similarly overall, but both groups showed poorer recall in the dual-load condition than in the other conditions. On the sentence comprehension task, children with SLI comprehended fewer sentences of both types than the CA children and fewer redundant sentences relative to themselves and to the VM children. Results were interpreted to suggest that children with SLI (a) have less functional verbal working memory capacity (i.e., ability to coordinate both storage and processing functions) than their CA peers and (b) have greater difficulty managing both their working memory abilities and general processing resources than both age peers and younger children when performing a "complex" off-line sentence processing task.

Child↗
PubMed2006

Processing speed interacts with working memory efficiency in multiple sclerosis.

Information processing speed was assessed using the visual threshold serial addition test (VT-SAT), a computerized modification of the PASAT designed to assess processing speed by controlling for performance accuracy. Persons with MS (N=43) and healthy individuals (N=32) were administered the VT-SAT varying working memory loads (1-back versus 2-back). Results indicated that at the lower working memory load (1-back) all individuals with MS were able to achieve a working memory performance level equivalent to healthy individuals, but required significantly more processing time to do so. In contrast, at the higher working memory load (2-back), about 70% of MS participants were able to achieve a performance level equivalent to healthy individuals, but again required significantly more processing time. The results are discussed in the context of the dynamic nature of the relationship between processing speed and working memory performance, emphasizing the dependence of this relationship on other cognitive and disease-related factors.

Adult↗
PubMed1990

The game of bridge as an exercise in working memory and reasoning.

Fifty bridge players and 50 nonplayers, between the ages of 55 and 91, were given tests of working memory, reasoning, reaction time, and vocabulary. Data were analyzed using multivariate and univariate analyses of variance with age as a covariate. Results indicated that the players outperformed nonplayers in measures of working memory and reasoning, but not vocabulary and reaction time. Results were consistent with the hypothesis that bridge, which provides specific experience in working memory and reasoning, should enhance performance in tasks tapping these abilities and not enhance performance in unrelated abilities. Because the data were correlational, the rival hypothesis that bridge playing selects for individuals who perform better at working memory and reasoning tasks could not be rejected.

Aged↗
PubMed2000

Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats.

Performance on working memory tasks, a measure of prefrontal cortical function, is impaired by exposure to mild stress as well as the anxiogenic drug, FG7142. Previous studies have shown that like stress, FG7142 increases catecholamine release in the prefrontal cortex (PFC) and that high levels of dopamine (DA) D(1) and norepinephrine (NE) alpha-1 receptor stimulation underlie the FG7142-induced cognitive impairment. Both the FG7142-induced DA turnover and working memory deficit can be blocked by pretreatment with the nonselective NE alpha-2/imidazoline I1 receptor agonist, clonidine. The present study examined the alpha-2 adrenoceptor subtype underlying this reversal in FG7142-induced working memory deficits by comparing the efficacy of clonidine with the more selective alpha-2A adrenoceptor agonist, guanfacine. The anxiogenic drug, FG7142 (0, 10, 20, or 30 mg/kg), dose-dependently impaired delayed alternation performance. Clonidine pretreatment (0.1 mg/kg, 30 min prior to FG7142) partially reversed the FG7142-induced impairment while guanfacine pretreatment (0.11 mg/kg) completely blocked the FG7142-induced impairment. Neither clonidine nor guanfacine had any effect on performance when administered alone. This study suggests that stimulation of the NE alpha-2A receptor subtype is sufficient to ameliorate the cognitive deficit induced by FG7142. Clonidine's sedative and hypotensive side effects limit its therapeutic usefulness; however, selective alpha-2A receptor agonists may be effective in treating prefrontal cognitive deficits in stress-related neuropsychiatric disorders with fewer side effects.

Adrenergic alpha-2 Receptor Agonists↗