Working Memory Impairment In Schizophrenia Research Articles

MK-801 impairs working memory on the Trial-Unique Nonmatch-to-Location test in mice, but this is not exclusively mediated by NMDA receptors on PV+ interneurons or forebrain pyramidal cells

NMDA receptors (NMDAr) are widely expressed throughout the brain on many cell types, and loss of function of these receptors (ie: NMDAr hypofunction) is a candidate mechanism explaining working memory impairment in schizophrenia. However, the cellular source driving the working memory deficits caused by NMDAr hypofunction has not been explored. The aim of this study was to assess the contribution of NMDAr on pyramidal cells and parvalbumin (PV+) interneurons to impairments in working memory induced by NMDAr hypofunction. We excised GluN1 - the gene encoding the obligatory subunit of the NMDAr - from PV + interneurons or CaMKIIα+ pyramidal cells using Cre-lox technology. Adult male PV GluN1 KO (n = 10) and CaMKIIα GluN1 KO mice (n = 9) and WT controls (n = 10 and n = 13) were trained to perform the Trial-Unique Nonmatching-to-Location (TUNL) task of working memory. Once trained, mice received the NMDAr antagonist MK-801 (0.1 and 0.3 mg/kg ip), and working memory assessed. Neither task acquisition nor working memory differed between the two transgenic lines and WT littermates. MK-801 dose-dependently decreased working memory accuracy in all strains (p < 0.001). PV GluN1 KO mice were sensitised to the impairing effects of MK-801 (p = 0.04), whereas CaMKIIα GluN1 KO mice showed equivalent working memory deficits as WT. Developmental NMDAr hypofunction at either PV+ interneurons or forebrain pyramidal cells is not sufficient to impair working memory, and neither of these cell types exclusively mediates working memory impairment caused by NMDAr antagonism. Reduced NMDAr signalling at PV+ interneurons could predispose circuits to NMDAr hypofunction magnifying deficits in working memory.

Simulation of the capacity and precision of working memory in the hypodopaminergic state: Relevance to schizophrenia

Working memory (WM) impairment has received attention as a behavioral characteristic of schizophrenia. Neurobiological studies have led to the hypothesis that a deficit in dopamine transmission through D1 receptors in the prefrontal cortex (PFC) is associated with WM impairment in schizophrenia. However, empirical approaches that aim to clarify the nature of the impairment and its underlying mechanism are difficult to enact, especially in unmedicated patients. By contrast, computational approaches using biologically plausible models have formed a powerful theoretical framework for the study of WM impairment in schizophrenia. This article attempts to directly connect neurobiological findings to the neuropsychological behaviors present in patients with schizophrenia. Using a biologically plausible prefrontal cortical circuit model, we simulated sustained activity during a simultaneous, multi-target WM task. We subsequently analyzed how dopaminergic modulation via D1 receptor activation alters the capacity and precision of WM and investigated the underlying mechanism. Hypodopaminergic modulation resulted in imprecision and a reduced capacity in WM primarily due to decreased N-methyl-d-aspartate (NMDA) conductance. Increasing NMDA conductance ameliorated both impairments. These results account for the mechanism that underlies WM impairments in schizophrenia and provide a theoretical basis for combination therapy with antipsychotic drugs and drugs that enhance NMDA receptor function, which is expected to be effective for the treatment of WM impairments in these patients.

Verbal working memory in schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) Study: The moderating role of smoking status and antipsychotic medications

ObjectivesWorking memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia. MethodsFrom 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter–number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order. ResultsSchizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment. ConclusionsResults confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke.

Failure to benefit from target novelty during encoding contributes to working memory deficits in schizophrenia

IntroductionAlthough working memory (WM) impairments are well documented in schizophrenic patients (PSZ), the underlying mechanisms are poorly understood. The aim of this study was to investigate the role of target salience during encoding to determine whether impaired visual attention in PSZ leads to poor WM.MethodsThirty-one PSZ and 28 demographically matched healthy controls (HC) performed a spatial delayed-response task. Attentional demands were manipulated during WM encoding by presenting high salient (novel) or low salient (familiar) targets. Participants also rated their level of response confidence at the end of each trial, allowing us to analyse different response types.ResultsWM was impaired in PSZ. Increasing target salience by increasing novelty improved WM performance in HC but not in PSZ. Poor WM performance in PSZ was largely due to an increase in the proportion of incorrect but high confident responses most likely reflecting a failure to encode the correct target.ConclusionsOur findings suggest that dysfunctions of non-mnemonic attentional processes during encoding contribute to WM impairments in schizophrenia and may represent an important target for cognitive remediation strategies.

The effects of perceptual encoding on the magnitude of object working memory impairment in schizophrenia

Deficits in the visual working memory (WM) system have been consistently reported in schizophrenia patients, but the relative contribution of initial perceptual encoding to these deficits remains unsettled. We assessed the role of visual perceptual encoding on performance on an object WM task. Schizophrenia patients (N=37) and nonpsychiatric control subjects (N=33) were tested on an object WM task involving three delay periods: 200ms, 3s, and 10s. Schizophrenia patients performed significantly less accurately than controls on all three conditions. However, after controlling for the effect of perceptual encoding (accuracy on the 200ms delay condition) on performance in the two memory load conditions, schizophrenia patients demonstrated intact WM in the 3s delay condition, and showed a weak trend for decreased accuracy on the 10s delay compared with controls. Analysis of individual differences in pattern of performance revealed that a distinct subgroup of poor encoder patients had a significantly greater reduction in accuracy at 3s than the other patient subgroups and controls. In contrast, among schizophrenia patients who performed poorly on the 10s delay, accuracy was equivalently reduced independent of encoding ability. WM deficits in controls were independent of encoding ability at both delay intervals. These results indicate that encoding ability titrates the magnitude of WM impairment in schizophrenia patients but not in controls, and that heterogeneity has to be taken into account to correctly estimate the effects of perceptual encoding on visual object WM deficits in schizophrenia.

Performance of schizophrenia and bipolar patients on verbal and figural working memory tasks.

Working memory (WM) was studied in 82 healthy volunteers, 43 schizophrenia patients, and 81 bipolar patients. Schizophrenia patients were impaired on verbal and figural WM tasks that possessed similar test discriminating power. Bipolar patients performed similarly to healthy volunteers. A mathematical model of WM performance revealed a primary role for reduced WM span in accounting for the impaired verbal WM of schizophrenia patients and a primary role for diminished attention in accounting for impaired figural WM. Although WM impairment in schizophrenia is due neither to the general effects of severe mental illness nor to the specific type of material studied, the microarchitecture of abnormal WM in schizophrenia may depend on the stimulus material presented.

Working memory for visual features and conjunctions in schizophrenia.

The visual working memory (WM) storage capacity of patients with schizophrenia was investigated using a change detection paradigm. Participants were presented with 2, 3, 4, or 6 colored bars with testing of both single feature (color, orientation) and feature conjunction conditions. Patients performed significantly worse than controls at all set sizes but demonstrated normal feature binding. Unlike controls, patient WM capacity declined at set size 6 relative to set size 4. Impairments with subcapacity arrays suggest a deficit in task set maintenance: Greater impairment for supercapacity set sizes suggests a deficit in the ability to selectively encode information for WM storage. Thus, the WM impairment in schizophrenia appears to be a consequence of attentional deficits rather than a reduction in storage capacity.