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Deficits of spatial working memory in chronic schizophrenia.

This study tests the hypothesis that deficits of spatial working memory are an inherent trait in schizophrenic patients, regardless of their clinical status. The participants were 22 chronic schizophrenic patients, 11 schizophrenic patients in remission, and 22 normal adults. All participants were asked to track the outlines of a square presented on a computer screen in a clockwise direction while moving their eyes at their preferred rate and then to reproduce the square on a blank computer screen (Task A). Thereafter, the computer only displayed the four corners of the same square. The corners were displayed sequentially in a clockwise direction, one at a time at equal intervals. They were asked first to track the four corners of the square and then to reproduce the square on a blank computer screen (Task B). Chronic schizophrenic patients reproduced tasks A and B with significantly greater distortions than normal controls. The extent of their distortions was significantly greater during the reproduction of Task A than Task B. By contrast, schizophrenic patients in remission reproduced both Tasks A and B with the same accuracy as normal controls. On the basis of these findings it is concluded that the chronic schizophrenic patients have a significant deficit of spatial working memory, but that this deficit can be ameliorated by cognitive interventions and is therefore not an immutable trait in schizophrenia.

Adult↗

Differences between auditory evoked responses recorded during spatial and nonspatial working memory tasks.

Results from several recent studies suggest that neuronal processing of sound content and its spatial location may be dissociated. The use of modern neuroimaging techniques has allowed for the determination that different brain structures may be specifically activated during working memory processing of pitch and location of sound. The time course of these task-related differences, however, remains uncertain. In the present study, we performed simultaneous whole-head electroencephalogram and magnetoencephalogram recordings, using a new behavioral paradigm, to investigate the dynamics of differences between "what" and "where" evoked responses in the auditory system as a function of memory load. In the location task the latency of the N1m was shorter and its generator was situated more inferiorly than in the pitch task. Working memory processing of the tonal frequency enhanced the amplitude of the N2 component, as well as the negative-going deflection at a latency around 400 ms. A memory-load-dependent task-related difference was found in the positive slow wave which was higher during the location than pitch task at the low load. Late slow waves were affected by memory load but not type of task. These results suggest that separate neuronal networks are involved in the attribute-specific analysis of auditory stimuli and their encoding into working memory, whereas the maintenance of auditory information is accomplished by a common, nonspecific neuronal network.

Acoustic Stimulation↗

Working-memory capacity and phonological processing in deafened adults and individuals with a severe hearing impairment.

The purpose of the present article is to review a number of studies conducted in our own laboratory with respect to working memory capacity and phonological processing in deafened adults and individuals with a severe hearing impairment, and how these two cognitive components relate to speech processing. The results demonstrate that one specific component in the phonological processing system (i.e., the phonological representation system) is deteriorating, whereas other parts are preserved intact. The characteristic of the individual's phonological representation is further correlated with success in speech reading and speech understanding with some cochlear implant systems. Working memory capacity is a capacity that remains intact despite a long duration of deafness/severe hearing loss. The size of the working memory is related to skill in speech reading and level of speech understanding with cochlear implants and perceived effort in a noisy environment.

Adult↗

Brain imaging of the central executive component of working memory.

This review presents neuroimaging studies which have explored the cerebral substrates of the central executive component of the working memory model proposed by Baddeley and Hitch [Working memory (1986); Recent advances in learning and motivation (1974)]. These studies have demonstrated that different executive functions (manipulating and updating of information, dual-task coordination, inhibition and shifting processes) not only recruit various frontal areas, but also depend upon posterior (mainly parietal) regions. Such results are in agreement with the hypothesis that executive functions rely on a distributed cerebral network not restricted to anterior cerebral areas. Moreover, the intervention of similar prefrontal regions in a large number of executive tasks suggests that the central executive functioning must be understood in terms of different interactions between a network of regions rather than in terms of a specific association between one region and one higher-level cognitive process.

Brain↗

Selective working memory impairments following intradentate injection of colchicine: attenuation of the behavioral but not the neuropathological effects by gangliosides GM1 and AGF2.

Bilateral injection of 3.5 micrograms of colchicine into the dentate gyrus produced specific learning and memory impairments together with a selective pattern of neuropathology. Animals injected with colchicine exhibited a significant impairment in their ability to perform the working memory, but not the reference memory, component of a multiple component T-maze task. These deficits were transient and over time all animals were able to reaquire the task to preoperative levels of performance. Histological analyses revealed that intradentate injection of colchicine produced 1) a significant decrease in the width of both the superior and inferior blades of the dentate gyrus reflecting the extensive loss of granule cells, 2) a related decrease in the size of the dentate molecular layer, and 3) a decrease in the number of cholinergic neurons in the medial septum. The second phase of the experiment demonstrated that gangliosides GM1 and AGF2 did not prevent the initial impairments in working memory performance induced by colchicine but rather accelerated the rate at which it recovered. The gangliosides did not decrease the extent of neuronal damage; there was no sparing of granule cells in the dentate gyrus or cholinergic neurons in the medial septum. These data further support a role for the hippocampus in working memory processes and they also indicate that gangliosides GM1 and AGF2 might be useful for treating the behavioral deficits induced by hippocampal damage.

Animals↗

Individual and developmental differences in working memory across the life span.

The effects of secondary tasks on verbal and spatial working memory were examined in multiple child, young adult, and older adult samples. Although memory span increased with age in the child samples and decreased with age in the adult samples, there was little evidence of systematic change in the magnitude of interference effects. Surprisingly, individuals who had larger memory spans when there was no secondary task showed greater interference effects than their age-mates. These findings are inconsistent with the hypothesis that age and individual differences in working memory are due to differences in the ability to inhibit irrelevant information, at least as this hypothesis is currently formulated. Moreover, our results suggest that different mechanisms underlie developmental and individual differences in susceptibility to interference across the life span. A model is proposed in which memory span and processing speed both increase with development but are relatively independent abilities within age groups.

Adult↗

Role of hippocampal M2 muscarinic receptors in the estrogen-induced enhancement of working memory.

We have previously demonstrated that acetylcholine, acting at M2 muscarinic receptors, mediates the estradiol-induced increase in hippocampal N-methyl-d-aspartate receptor binding and the associated enhancement in working memory. The goal of present experiment was to investigate the role of hippocampal M2 receptors in the behavioral aspects of these effects. Ovariectomized rats were trained to locate a hidden escape platform on a matching-to-place version of the water maze in which the platform was moved to a new location for each session of four daily trials. Following 18 days of training, rats were randomly assigned to receive one of the following treatments: 1) injections of oil vehicle delivered 72 and 48 h before testing and continuous delivery of vehicle into the dorsal hippocampus via bilateral cannulae implants connected to osmotic minipumps; 2) injections of estradiol benzoate (EB) delivered 72 and 48 h before testing and continuous delivery of vehicle into the hippocampus; 3) injections of EB delivered 72 and 48 h before testing and continuous delivery of the M2 muscarinic receptor antagonist, AFDX 116, into the hippocampus; and 4) injections of EB delivered 72 and 48 h before testing and continuous delivery of AFDX 116 into a control site in the cortex. Chronic administration of AFDX 116 into the hippocampus, but not the cortex, significantly attenuated an estrogen-induced enhancement in performance on a working memory task in the water maze as indicated by increased latency and increased path length to locate an escape platform during a test trial when a 90 min delay was imposed between the first and second trials. These results indicate that acetylcholine acts at M2 muscarinic receptors located in the hippocampus to mediate the positive effects exerted by estrogen on working memory.

Acetylcholine↗

Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers.

RATIONALE: Dopamine (DA) D(2) receptor antagonists have been shown to produce similar impairments to those seen in Parkinson's disease. These include working memory and set-shifting deficits. Theories of DA function have predicted that distraction or impaired switching may be important determinants of such deficits. OBJECTIVES: In order to test these hypotheses, we have followed up our previous findings with more refined tests (1) that allow measurement of spatial working memory (SWM) and distraction, (2) that allow separation of executive and mnemonic components of SWM and (3) that allow isolation of set-shifting from learning deficits. METHODS: Thirty-six young healthy male volunteers were tested on two occasions after oral administration of either 400 mg sulpiride or placebo. All participants performed the delayed response task. Sixteen participants received task-irrelevant distractors during this task, and were also given a self-ordered SWM test. The remaining participants were given delayed response tasks with task-relevant distractors, and tests of attentional and task set-shifting. RESULTS: Sulpiride impaired performance of the delayed-response task both without distraction and with task-relevant distraction. By contrast, the drug protected against deficits from task-irrelevant distraction seen in the placebo group. Task set-switching was also impaired by sulpiride, with participants being slower to respond on switch trials compared with non-switch trials. There was also a trend for attentional set-shifting to be impaired following sulpiride. In contrast, self-ordered SWM performance was enhanced by sulpiride on the second test session only. CONCLUSIONS: These results support models of central DA function that postulate a role in switching behaviour, and in certain aspects of working memory.

Adult↗

Blockade of hippocampal M1 muscarinic receptors impairs working memory performance of rats.

In order to clarify the roles of hippocampal M1 and M2 muscarinic receptors in working and reference memory performance of rats, the effects of intrahippocampal injections of selective antagonists at both receptors on this behavior were examined with a three-panel runway task. In the working memory task, the M1 muscarinic receptor antagonist pirenzepine, injected bilaterally at 0.32 and 1.0 microgram/side into the dorsal hippocampus, significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points). This effect of intrahippocampal pirenzepine (1.0 microgram/side) on working memory was attenuated by concurrent injection of 10 micrograms/side AF102B, the selective M1 muscarinic receptor agonist. Intrahippocampal injection of the M2 muscarinic receptor antagonist methoctramine at doses up to 1.0 microgram/side had no significant effect on the number of working memory errors. Intrahippocampal methoctramine injection at 3.2 micrograms/side produced a significant increase in working memory errors, an effect that was reversed by concurrent injection of 10 micrograms/side AF102B. Concurrent injection of 0.32 microgram/side methoctramine significantly reduced the increase in working memory errors induced by intrahippocampal pirenzepine (1.0 microgram/side). In the reference memory task, neither pirenzepine nor methoctramine affected the number of errors when injected into the hippocampus at doses up to 1.0 and 3.2 micrograms/side, respectively. These results suggest that processes mediated by M1 muscarinic receptors in the hippocampus are involved in working memory, but not in reference memory, and that blockade of hippocampal M2 muscarinic receptors ameliorates working memory deficits produced by M1 muscarinic blockade, possibly by increasing acetylcholine release.

Animals↗

Stimulus duration in working memory is represented by neuronal activity in the monkey prefrontal cortex.

Humans are capable of memorizing several attributes of a presented stimulus as well as its duration of presentation. However, the neuronal representation of stimulus duration in memory remains unknown. This study investigated activities of single neurons in the prefrontal cortex of monkeys while they were performing a behavioral task in which working memory for stimulus duration was needed. Here we describe specific neurons whose discharge rates reflect encoding or retention of the duration of the presentation of stimuli to be remembered. We also describe other specific neurons whose activities reflect encoding or retention of fixed duration, similar but unrelated to the stimulus duration presented in each trial. Some of these specific neurons showed the same duration-related discharges even while the monkeys were performing a different task, in which working memory for stimulus duration was no longer needed. From these results, we suggest that neurons in the prefrontal cortex play roles in encoding and retention of temporal information in working memory and that some of those neurons are dedicated to representation of temporal information attributed to stimuli even when the temporal information is unnecessary for correct performance.

Action Potentials↗

Frontal theta event-related synchronization: comparison of directed attention and working memory load effects.

Early studies showed that long-term encoding and retrieval of new information is associated with modulation of the theta rhythm. More recently, changes in theta power amplitude over frontal electrode sites were reported during working memory, yet their relative significance in regard to attentional and memory processes remains unclear. Event-related synchronisation responses in the 4-7.5 Hz theta EEG frequency band was studied in 12 normal subjects performing four different tasks: two working memory tasks in which load varied from one (1-back task) to two (2-back task) items, an oddball detection (attention) task and a passive fixation task. A phasic theta increase was observed following stimulus apparition on all electrode sites within each task, with longer culmination peak and maximal amplitude over frontal electrodes. Frontal theta event-related synchronization (ERS) was of higher amplitude in the 1-back, 2-back and detection tasks as compared to the passive fixation task. Additionally, the detection task elicited a larger frontal and central theta ERS than the 2-back task. By analyzing theta ERS characteristics in various experimental conditions, the present study reveals that early phasic theta response over frontal regions primarily reflects the activation of neural networks involved in allocation of attention related to target stimuli rather than working memory processes.

Adult↗

Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys.

This study demonstrates that dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impairs working memory of conscious behaving monkeys. In addition, acute and chronic MK-801 produces different effects on D(1) and D(2) receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D(1) (D(1)R) and D(2) (D(2)R) binding were assayed by [(11)C]NNC112 and [(11)C]FLB457, respectively, using high-specific radioactivity and a specially designed monkey positron emission tomograph (PET). Acute single dose (0.03, 0.1, and 0.3 mg/kg) i.v. administration of MK-801 resulted in dose-related impairment of working memory performance of an oculomotor delayed response (ODR) task. There was no impairment of performance of a visually guided saccade (VGS) task with low doses of 0.03 and 0.1, but it was depressed with 0.3 mg/kg. Chronic daily MK-801 (0.03 mg/kg, i.m., b.i.d. for 13 days) induced impaired ODR task performance with no effect on the VGS task. Although acute single doses of MK-801 caused no significant changes in [(11)C]NNC112 binding to PFC D(1)R, chronic daily treatment increased binding about 14% (P<.05). Acute MK-801 dose-dependently decreased [(11)C]FLB457 binding about 35% (P<.01) to PFC D(2)R; chronic treatment had no significant effect. Microdialysis analyses demonstrated that acute single doses of MK-801 (0.03 and 0.1 mg/kg) increased extracellular glutamate and dopamine (DA) levels in PFC. Chronic MK-801 gradually lowered glutamate and DA levels in PFC. The results demonstrate in conscious, unanesthetized primates that MK-801 induces impairment of PFC function, as measured by working memory performance. Furthermore, in response to lowered levels of DA in PFC, D(1)R binding is increased, whereas D(2)R binding is not.

Animals↗

Effects of excitotoxic median raphe lesions on scopolamine-induced working memory deficits in inhibitory avoidance.

The aim of the present study was to investigate the effects of excitotoxic damage of the serotonergic cell bodies in the median raphe nucleus (MRN) on the scopolamine-induced working memory deficits in a single-trial light/dark inhibitory avoidance task. Rats were given 1 mg/kg of scopolamine hydrobromide (intraperitonal, i.p.) or saline before the inhibitory avoidance training, in which initial preference to the dark compartment (escape latency) was used to measure nonmnemonic behaviors, and response latency to enter the dark compartment immediately after the shock was used to measure working memory. It was found that scopolamine significantly reduced escape latencies in sham-lesioned rats, whereas it had no effect in the rats with MRN lesions. Although MRN lesion per se did not alter response latency, it prevented scopolamine-induced decrease in this parameter. These results suggest that the antagonistic interactive processes between serotonergic projections of the MRN and the muscarinic cholinergic system modulate nonmnemonic attentional component of working memory formation in the inhibitory avoidance.

Alzheimer Disease↗

Object-based attention and object working memory: overlapping processes revealed by selective interference effects in humans.

Human observers can discriminate two attributes from the same object more efficiently than attributes from two different objects even if the retinal locations of the attributes are the same in the single and dual object cases. The single object advantage challenges the spatial spotlight view of attention and suggests that attentional selection can be object based. We report that the single object advantage is reliably reduced when an object working memory task is performed concurrently, whereas concurrent verbal and spatial working memory tasks have no effect. This selective interference effect provides support for the existence of object-based attentional processes that also contribute to the short-term retention of objects in working memory. These results are consistent with the hypothesis that both attentional and memory subsystems are organized along domain-specific lines, and suggest the importance of attention in rehearsal operations. The contributions of inferior temporal and parietal mechanisms that have been implicated in attending to and remembering objects are considered.

Animals↗

Event-related alpha and theta responses in a visuo-spatial working memory task.

OBJECTIVE: To explore the reactivity of the theta and alpha rhythms during visuo-spatial working memory. METHODS: One hundred and seventy-four subjects performed a delayed response task. They had to remember the spatial location of a target stimulus on a computer screen for a 1 or a 4s retention interval. The target either remained visible throughout the entire interval (sensory trials) or disappeared after 150ms (memory trials). Changes in induced band power (IBP) in the electroencephalogram (EEG) were analyzed in 4 narrow, individually adjusted frequency bands between 4 and 12Hz. RESULTS: After presentation of the target stimulus, a phasic power increase was found, irrespective of condition and delay interval, in the lower (roughly, 4-8Hz) frequency bands, with a posterior maximum. During the retention interval, sustained occipital-parietal alpha power increase and frontal theta power decrease were found. Most importantly, the memory trials showed larger IBP decreases in the theta band over frontal electrodes than the sensory trials. CONCLUSIONS: The phasic power increase following target onset is interpreted to reflect encoding of the target location. The sustained theta decrease, which is larger for memory trials, is tentatively interpreted to reflect visuo-spatial working memory processes.

Adult↗

Intraseptal injection of the 5-HT1A/5-HT7 agonist 8-OH-DPAT and working memory in rats.

RATIONALE: In rats, 5-HT(1A) receptors are present in the septal region, e.g. on cholinergic neurons of the medial septum, where they might be a substrate for cognitively relevant interactions between cholinergic and serotonergic systems. OBJECTIVE: The present experiment assessed the effects of the stimulation of septal 5-HT(1A) receptors on spatial working memory. METHODS: Stimulation of septal 5-HT(1A) receptors was carried out by infusions targetting the medial septum of the 5-HT(1A)/5-HT(7) receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT; 0.5 or 4 microg). Spatial memory was assessed in a water maze using a protocol placing emphasis on spatial working memory. The location of the hidden platform was changed every day and performance was assessed on two consecutive trials each day. RESULTS: In comparison to vehicle injections, the intraseptal infusion of 4 microg 8-OH-DPAT impaired performance significantly: rats treated with 8-OH-DPAT exhibited increased distances to reach the hidden platform on both trials 1 and 2. Rats infused with 0.5 microg showed similar changes that failed to be significant. Such effects were not observed when the platform was visible. CONCLUSIONS: These results extend those of a previous experiment which showed that intraseptal injections of 8-OH-DPAT impaired spatial reference memory. Based on the characteristics of the observed deficits, it is suggested that the 8-OH-DPAT-induced impairment, rather than being only the result of a true alteration of working memory, might reflect a more global cognitive deficiency in which alteration of general memory capacities may be biased by disrupted search strategies/exploration and/or dysfunctions of attention.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys.

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.

Animals↗

Effects of ethanol on nonspatial working memory and attention in rats.

Investigation into the neural basis for ethanol-induced cognitive dysfunction requires the use of valid animal models. An operant signal detection procedure was developed to assess simultaneously the processes of sustained attention and working memory in rats, and to determine the effects of ethanol on these cognitive functions. Ethanol, at 0.75 g/kg ip, produced delay- and stimulus length-dependent decreases in choice accuracy, effects that are consistent with deficits in both working memory and sustained attention. Local infusion of ethanol directly into the medial septal area resulted in a selective loss of choice accuracy at the long delay. The impairment by intraseptal ethanol did not interact with stimulus length. Thus, the working memory impairment, but not the decrement in sustained attention, was mimicked by intraseptal ethanol. The current model provides a foundation for studying the neural basis of ethanol's cognitive effects.

Animals↗