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PubMed1999

Treatment with the noradrenergic alpha-2 agonist clonidine, but not diazepam, improves spatial working memory in normal young rhesus monkeys.

Noradrenergic alpha-2 agonists such as clonidine and guanfacine improve working memory performance in aged monkeys. Guanfacine also improves cognition in young monkeys, but there are conflicting reports of the effects of clonidine in young adult human and nonhuman primates. In the present study, high doses of clonidine (0.02-0.1 mg/kg) significantly improved performance of the delayed response task, a test of spatial working memory, in young adult monkeys. Lower doses (0.0001-0.01 mg/kg), similar to those used in human studies (0.001-0.003 mg/kg), had no effect on task performance. In contrast, monkeys experimentally depleted of catecholamines by chronic reserpine treatment have been improved by both dose ranges. These results provide further support for the hypothesis that alpha-2 agonists improve cognition via actions at post-synaptic alpha-2 receptors, and suggest that conflicting results with clonidine in previous studies of prefrontal cortical function may result from insufficient dosage.

Adrenergic Uptake Inhibitors↗
PubMed2004

Working memory: its role in dyslexia and other specific learning difficulties.

This paper reports a study contrasting dyslexic children against a control group of children without special educational needs (SEN) and a group with varied SENs. Children's abilities were compared on tasks assessing phonological processing, visuo-spatial/motor coordination and executive/inhibitory functioning; being targeted for assessment based on theoretical proposals related to the working memory model. Primary and secondary school level children were tested: 21 assessed as dyslexic with no comorbid difficulties, 26 children assessed with difficulties including dyspraxia, emotional/behavioural problems and attention deficits, 40 children with no known education-related deficits were controls. Results indicated both SEN groups performed worse than controls on working memory phonological loop measures. However, SEN groups could only be differentiated on phonological awareness measures: the dyslexics showing lower scores. Dyslexics performed as well as controls on working memory visuo-spatial scratch pad measures and one of two additional visual-motor coordination tasks, whereas the performance of the other SEN children was lowest on the majority of these measures. Central executive and interference measures engendered mixed performances, both SEN groups showing evidence of deficits in one or more of these areas of functioning, although, of the two SEN groups, the dyslexics seem to have performed the worse when digit name processing was required.

Adolescent↗
PubMed1996

Regional and cellular fractionation of working memory.

This chapter recounts efforts to dissect the cellular and circuit basis of a memory system in the primate cortex with the goal of extending the insights gained from the study of normal brain organization in animal models to an understanding of human cognition and related memory disorders. Primates and humans have developed an extraordinary capacity to process information "on line," a capacity that is widely considered to underlay comprehension, thinking, and so-called executive functions. Understanding the interactions between the major cellular constituents of cortical circuits-pyramidal and nonpyramidal cells-is considered a necessary step in unraveling the cellular mechanisms subserving working memory mechanisms and, ultimately, cognitive processes. Evidence from a variety of sources is accumulating to indicate that dopamine has a major role in regulating the excitability of the cortical circuitry upon which the working memory function of prefrontal cortex depends. Here, I describe several direct and indirect intercellular mechanisms for modulating working memory function in prefrontal cortex based on the localization of dopamine receptors on the distal dendrites and spines of pyramidal cells and on interneurons in the prefrontal cortex. Interactions between monoamines and a compromised cortical circuitry may hold the key to understanding the variety of memory disorders associated with aging and disease.

Animals↗
PubMed1996

Concurrent blockade of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors disrupts working memory in the rat.

In order to clarify the roles of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors in working and reference memory performance of rats, the effects of intrahippocampal administration of selective antagonists for both receptors on these behaviours were examined with a three-panel runway task. In the working memory task, the potent and competitive N-methyl-D-aspartate receptor antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), when injected bilaterally at 10 and 32 ng/side into the dorsal hippocampus. Intrahippocampal injection of CPP at a dose of 3.2 ng/side had no effect on the number of working memory errors. The metabotropic glutamate receptor antagonist, (+)-alpha-methyl-4-carboxyphenylglycine (+)-(MCPG), injected into the hippocampus at doses up to 3.2 micrograms/side, did not significantly affect the number of working memory errors. Combined administration of (+)-MCPG (3.2 micrograms/side) and CPP (3.2 ng/side) into the hippocampus, neither of which had an individual effect on errors, significantly increased the number of working memory errors. However, intrahippocampal administration of the relatively inactive isomer, (-)-MCPG, at 3.2 micrograms/side did not affect working memory errors, whether given independently or concurrently with the behaviourally ineffective dose of CPP (3.2 ng/side). In the reference memory task, intrahippocampal injection of CPP at doses up to 32 ng/side had no effect on the number of errors. Intrahippocampal (+)-MCPG at doses up to 3.2 micrograms/side did not affect the number of reference memory errors, whether administered alone or together with 3.2 ng/side of CPP. These results indicate that blockade of hippocampal metabotropic glutamate receptors aggravates impairment of working memory resulting from deficiency of N-methyl-D-aspartate receptor-mediated glutamatergic neurotransmission, suggesting that mechanisms regulated by co-activation of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors are involved in working memory performance of rats.

Animals↗
PubMed2006

Temporal dynamics of basal ganglia response and connectivity during verbal working memory.

Research on the neural basis of working memory (WM) has generally focused on neocortical regions; comparatively little is known about the role of subcortical structures. There is growing evidence that the basal ganglia are involved in WM, but their contribution to different component processes of WM is poorly understood. We examined the temporal dynamics of basal ganglia response and connectivity during the encoding, maintenance and response phases of a Sternberg WM task. During the encoding and maintenance phases, WM-load-dependent activation was observed in the left anterior caudate, anterior putamen and globus pallidus; activation in the right anterior caudate was observed only during the maintenance phase. During the response phase, the basal ganglia were equally active in both the high-load and low-load WM conditions. Caudate and putamen activations were primarily localized to the (rostral) associative parts of the basal ganglia, consistent with the putative role of these regions in cognitive processing. Effective connectivity analyses revealed increased WM-load-dependent interaction of the left anterior caudate with the left posterior parietal cortex during all three phases of the task; with the visual association cortex, including the fusiform gyrus and inferior temporal gyrus, only during the encoding phase; with the ventrolateral prefrontal cortex during the encoding and maintenance phases; with the pre-supplementary motor area during the maintenance and response phases; and with the dorsolateral prefrontal and anterior cingulate cortices only during the response phase. Taken together with known neuroanatomy of the basal ganglia, these results suggest that the anterior caudate helps to link signals in distinct functional networks during different phases of the WM task. Our study offers new insight into the integrative and adaptive role of the basal ganglia in higher cognitive function.

Adolescent↗
PubMed1997

Prefrontal cortex fMRI signal changes are correlated with working memory load.

We investigated whether a nonspatial working memory (WM) task would activate dorsolateral prefrontal cortex (DLPFC) and whether activation would be correlated with WM load. Using functional magnetic resonance imaging we measured regional brain signal changes in 12 normal subjects performing a continuous performance, choice reaction time task that requires WM. A high WM load condition was compared with a non-WM choice reaction time control condition (WM effect) and a low WM load condition (load effect). Significant changes in signal intensity occurred in the DLPFC, frontal motor regions and the intraparietal sulcus (IPS) in both comparisons. These findings support the role of DLPFC and IPS in WM and suggest that signal changes in DLPFC correlate with WM load.

Adult↗
PubMed1994

Age-related differences in updating working memory.

Age-related differences in updating working memory were investigated in two experiments using a running memory task. In the first experiment, the task of the young and elderly subjects was to watch strings of four to 10 consonants and then to recall serially the four most recent items. Results revealed no age effect. A second experiment was then carried out using a memory load that was close to memory span: lists of six to 12 consonants were presented and subjects had to recall the last six items. Age interacted with list length but not with serial position. This dissociation is discussed in terms of Baddeley's (1986) model.

Adult↗
PubMed2006

Elevations of endogenous kynurenic acid produce spatial working memory deficits.

Kynurenic acid (KYNA) is a tryptophan metabolite that is synthesized and released by astrocytes and acts as a competitive antagonist of the glycine site of N-methyl-D-aspartate receptors at high concentrations and as a noncompetitive antagonist of the alpha7-nicotinic acetylcholine receptor at low concentrations. The discovery of increased cortical KYNA levels in schizophrenia prompted the hypothesis that elevated KYNA concentration may underlie the working memory dysfunction observed in this population that has been attributed to altered glutamatergic and/or cholinergic transmission. The present study investigated the effect of elevated endogenous KYNA on spatial working memory function in rats. Increased KYNA levels were achieved with intraperitoneal administration of kynurenine (100 mg/kg), the precursor of KYNA synthesis. Rats were treated with either kynurenine or a vehicle solution prior to testing in a radial arm maze task at various delays. Elevations of endogenous KYNA resulted in increased errors in the radial arm maze. In separate experiments, assessment of locomotor activity in an open field and latency to retrieve food reward from one of the maze arms ruled out the possibility that deficits in the maze were attributable to altered locomotor activity or motivation to consume food. These results provide evidence that increased KYNA levels produce spatial working memory deficits and are among the first to demonstrate the influence of glia-derived molecules on cognitive function. The implications for psychopathological conditions such as schizophrenia are discussed.

Animals↗
PubMed2000

Working memory and interference: a comment on Jenkins, Myerson, Hale, and Fry (1999).

Jenkins, Myerson, Hale, and Fry (1999) showed that slopes relating complex spans to simple spans were considerably smaller than one, indicating that persons with higher simple spans suffered more interference when the span task was combined with a processing demand. They argued that this finding ruled out accounts of working memory based on interference and/or inhibition of interfering information. We demonstrate that the effect is mainly an artifact from regression to the mean, owing to the low reliability of span scores as used by Jenkins et al. Data from 133 young adults for two verbal and two spatial span tasks show that the slopes relating complex to simple performance are considerably higher for sum scores than for span scores. Furthermore, an adequate test for an interference or an inhibition account of working memory is to predict interference from complex span tasks, not from simple span tasks. Interference effects in the verbal span tasks were negatively correlated with an independent measure of working memory capacity, consistent with the interference/inhibition account.

Adult↗
PubMed1993

Functional activation of the human frontal cortex during the performance of verbal working memory tasks.

Regional cerebral blood flow was measured with positron emission tomography during the performance of verbal working memory tasks. The same type of verbal response (i.e., reciting numbers) was required in the control and the two experimental tasks. In the control task, the subjects were required to count aloud. In the two experimental tasks, the subjects were required to maintain within working memory the numbers they generated (self-ordered task) or the numbers generated by the experimenter (externally ordered task). Examination of the difference in activation between these conditions revealed strong bilateral activation within the mid-dorsolateral frontal cortex during both experimental tasks. There was, however, no evidence of additional activation within the mid-dorsolateral frontal cortex when monitoring self-generated responses as compared with the monitoring of externally generated responses. These results provide evidence regarding the role of the mid-dorsolateral frontal cortex in mnemonic processing that are in agreement with recent findings from work with non-human primates.

Adult↗
PubMed1999

A study of injected dose for brain mapping on the ECAT HR+: activation maps for a parametric verbal working memory task.

The success of the 15O-water PET technique to localize statistically significant changes in regional cerebral blood flow is dependent on factors such as the activity level injected and the magnitude of the flow change. Undetectable changes may occur if insufficient activity is injected leading to high levels of statistical noise or the task performed results in only small changes in blood flow. To explore the relationship between injected activity and statistical significance, we performed a series of studies with the ECAT EXACT HR+, a high resolution PET tomograph. A parametric verbal working memory task (the N-back task) was selected to examine the relationship between regional cerebral blood flow and working memory load across a range of injected doses of 15O-water. At each activity level the volunteers were required to perform four different levels of the N-back task, a task in which a letter displayed on a monitor is matched with the letter displayed N letters previously. With increasing N, this task places increased load on working memory. For this study, 5, 10, and 15 mCi of 15O-water were injected into nine normal volunteers. The complete sequence of four tasks (N = 0, 1, 2, and 3) at three activity levels was repeated twice, for a total of 24 injections of 15O-water. We show that the peak count rate performance for the HR+ is approached at injected activity levels of 15O-water around 15 mCi. For this particular choice of N-back task, robust activation maps can nevertheless be obtained with as little as 5 mCi injected dose.

Adult↗
PubMed1995

Cholinergic manipulations in the medial septal area: age-related effects on working memory and hippocampal electrophysiology.

Aged rats have impairments in several types of cognitive functions, including spatial working memory (WM), that are dependent upon the septohippocampal cholinergic system. The present series of experiments was designed to assess the effectiveness of pharmacological manipulations of the medial septal area (MSA) in order to influence the physiology of the septohippocampal pathway and, therefore, the brain functions in which this pathway participates. Aged (22MO) and young (4MO) Fischer-344 rats received microinfusions into the MSA with either saline, the muscarinic agonist, oxotremorine (OXO), or the muscarinic antagonist, scopolamine (SCOP). Working memory was tested in a T-maze spatial alternation task, prior to infusion, immediately after infusion, and 90 min after infusion. Hippocampal theta activity and the population excitatory postsynaptic potential (pEPSP) of the dentate gyrus to perforant path stimulation were recorded immediately following behavioral testing at each of the three time periods. In 22MO rats, intraseptal OXO (0.5 micrograms, 2 micrograms, 5 micrograms) produced a dose-dependent improvement in choice accuracy, a shift of the hippocampal theta peak to a lower frequency and a higher peak power, and an increase in the initial slope of pEPSP. OXO, 0.1 microgram, did not have an effect on behavior or hippocampal physiology and OXO, 10 micrograms, produced an impairment in performance. In 4MO rats, OXO did not affect choice accuracy, nor the pEPSP slope, but altered hippocampal theta peak frequency and power similarly as in 22MO. The lowest behaviorally effective dose, 0.5 microgram OXO, did not influence WM performance when infused into the lateral ventricles (intracerebroventricularly) of either 22MO or 4MO rats. SCOP (2 micrograms, 5 micrograms, 15 micrograms) decreased choice accuracy in a dose-dependent fashion in both 22MO and 4MO rats. However, in 22MO rats, the behavioral dose-response curve for scopolamine was shifted towards greater sensitivity. SCOP produced a shift of the hippocampal theta to a higher frequency and a lower peak power, and a decrease in the initial slope of pEPSP. In 4MO rats, SCOP altered hippocampal theta similarly to 22MO, but did not affect the pEPSP slope. These results indicate that (1) cholinergic receptors in the MSA are a useful target for drugs to improve WM in aging rats, (2) age-related changes in the activity of the septohippocampal pathway may increase its sensitivity to drugs which alter its activity, and (3) alterations in hippocampal physiology may contribute differently to changes in WM in young and in old rats.

Aging↗
PubMed1991

Effect of the kappa-receptor agonist, U-50,488H, on cerebral ischemia-induced impairment of working memory assessed in rats by a three-panel runway task.

The effect of U-50,488H, a selective kappa-receptor agonist, on memory functions in an animal model of cerebral ischemia was investigated by use of a three-panel runway task. A 5-min period of ischemia caused a significant increase in the number of errors (pushes made on the two incorrect panels of the three panel-gates at four choice points) in a working memory task but it did not impair a reference memory task. U-50,488H at 10 and 32 mg/kg, administered i.p. immediately after blood flow restoration significantly reduced the increase in errors expected to occur in a working memory task assessed 24 h after 5 min of ischemia. This protective effect of U-50,488H on amnesia in the ischemic rat was antagonized by the kappa-receptor antagonist, MR-2266. We conclude that U-50,488H prevents the impairment of working memory following transient forebrain ischemia, an event mediated by the activation of the kappa-opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Interactions between 192-IgG saporin and intraseptal cholinergic and GABAergic drugs: role of cholinergic medial septal neurons in spatial working memory.

Rats were administered 192-IgG saporin (SAP) or vehicle into the medial septum-vertical limb of the diagonal band (MS-vDB). Starting 1 week later, the effects of intraseptal scopolamine, oxotremorine, and muscimol were tested in a T-maze alternation task. Choice accuracy in the absence of infusions did not differ between control and SAP-treated rats. Intraseptal scopolamine or muscimol impaired the choice accuracy of SAP-treated but not control rats. Oxotremorine impaired accuracy similarly in control and SAP-treated rats. The enhanced effects of scopolamine and muscimol produced by SAP are consistent with the hypothesis that cholinergic MS-vDB neurons are used in spatial working memory. The finding that SAP alone did not alter choice accuracy provides further evidence that cholinergic MS-vDB neurons are not necessary for spatial working memory. Thus, cholinergic MS-vDB neurons are involved in but not necessary for spatial working memory.

Animals↗
PubMed2006

Interaction between a verbal working memory network and the medial temporal lobe.

The irrelevant speech effect illustrates that sounds that are irrelevant to a visually presented short-term memory task still interfere with neuronal function. In the present study we explore the functional and effective connectivity of such interference. The functional connectivity analysis suggested an interaction between the level of irrelevant speech and the correlation between in particular the left superior temporal region, associated with verbal working memory, and the left medial temporal lobe. Based on this psycho-physiological interaction, and to broaden the understanding of this result, we performed a network analysis, using a simple network model for verbal working memory, to analyze its interaction with the medial temporal lobe memory system. The results showed dissociations in terms of network interactions between frontal as well as parietal and temporal areas in relation to the medial temporal lobe. The results of the present study suggest that a transition from phonological loop processing towards an engagement of episodic processing might take place during the processing of interfering irrelevant sounds. We speculate that, in response to the irrelevant sounds, this reflects a dynamic shift in processing as suggested by a closer interaction between a verbal working memory system and the medial temporal lobe memory system.

Humans↗
PubMed2002

Delayed working memory consolidation during the attentional blink.

After the detection of a target (T1) in a rapid stream of visual stimuli, there is a period of 400-600 msec during which a subsequent target (T2) is missed. This impairment in performance has been labeled the attentional blink. Recent theories propose that the attentional blink reflects a bottleneck in working memory consolidation such that T2 cannot be consolidated until after T1 is consolidated, and T2 is therefore masked by subsequent stimuli if it is presented while T1 is being consolidated. In support of this explanation, Giesbrecht & Di Lollo (1998) found that when T2 is the final item in the stimulus stream, no attentional blink is observed, because there are no subsequent stimuli that might mask T2. To provide a direct test of this explanation of the attentional blink, in the present study we used the P3 component of the event-related potential waveform to track the processing of T2. When T2 was followed by a masking item, we found that the P3 wave was completely suppressed during the attentional blink period, indicating that T2 was not consolidated in working memory. When T2 was the last item in the stimulus stream, however, we found that the P3 wave was delayed but not suppressed, indicating that T2 consolidation was not eliminated but simply delayed. These results are consistent with a fundamental limit on the consolidation of information in working memory.

Adolescent↗
PubMed1998

Social environment alters both ontogeny of dopamine innervation of the medial prefrontal cortex and maturation of working memory in gerbils (Meriones unguiculatus).

Male gerbils (Meriones unguiculatus) were bred and reared either grouped under enriched environmental conditions or isolated under impoverished environmental conditions. The objective of the present study was to examine the influence of social environment on structural and functional ontogeny of the medial prefrontal cortex (mPFC). In this respect, we investigated the maturation of both prefrontal dopamine (DA) innervation and working memory. For that purpose, at the age of postnatal day 90, prefrontal DA fibers were stained immunocytochemically using an antibody against glutaraldehyde-conjugated DA and innervation density was determined by means of a computer controlled program for image analysis. In order to evaluate environmental effects on working memory, 90-day-old gerbils were tested for y-maze delayed alternation. It was found that, isolation produced a significant and severe restraint of the maturation of prefrontal DA innervation, leading to fiber densities which were 56% below those in group-reared gerbils. Isolation also induced a significant impairment of delayed alternation performance on the y-maze indicating that obvious deficits in working memory had developed under restricted rearing conditions. The present results are discussed with regard to activity-dependent postnatal maturation of the cortex and adaptive neuroplasticity.

Animals↗
PubMed2003

Working memory capacity and language processes in children with specific language impairment.

This study examined the interaction between working memory and language comprehension in children with specific language impairment (SLI), focusing on the function of the central executive component and its interaction with the phonological loop (A. D. Baddeley, 1986) in complex working memory tasks. Thirteen children with SLI and 13 age-matched (age range = 7;0 [years;months] to 10;0) children with typical language development participated. The tasks combined traditional nonword repetition tests and sentence comprehension by using sentences that differed in length and syntactic complexity. The children with SLI exhibited larger processing and attentional capacity limitations than their age-matched peers. Increased word length and syntactic complexity resulted in a large performance decrease in nonword repetition in both groups. There were some variations in the error pattern, which may indicate qualitative differences between the 2 groups. The performance of the children with SLI in nonword repetition, across the different tasks, indicated a limitation in simultaneous processing rather than difficulty in encoding and analyzing the phonological structure of the nonwords. Furthermore, syntactic complexity had a greater effect on performance accuracy than did sentence length.

Case-Control Studies↗