Impaired performance in a working memory binding task in patients with schizophrenia

This study investigated feature binding in a working memory task in patients with schizophrenia and in normal controls. Twenty-five patients and 25 controls participated. On each trial, three drawings of familiar objects were presented sequentially, each in a different cell of a 3 x 3 grid. In different blocks of trials, participants remembered either individual features (object and location conditions) or an object and its location (combination condition). The results showed that patients were slower and less accurate than controls under all conditions. Accuracy of both groups was reduced in the combination condition relative to the single-feature conditions, but patients showed disproportionately poorer performance in the combination condition than in the object and location conditions. Thus, patients with schizophrenia exhibit deficits in working memory, particularly when the task requires binding objects to their locations. This finding demonstrates that processes that establish coherent and temporary episodic representations in working memory are impaired in schizophrenia.     

Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia

Although there is considerable evidence that patients with schizophrenia fail to activate the dorsolateral prefrontal cortex (DLPFC) to the degree seen in normal comparison subjects when performing working memory or executive tasks, hypofrontality may be coupled with relatively increased activity in other brain regions. However, most imaging studies of working memory in schizophrenia have focused on DLPFC activity. The goal of this work is to review functional neuroimaging studies that contrasted patients with schizophrenia and healthy comparison subjects during a prototypical working memory task, the n-back paradigm, to highlight areas of hyper- and hypoactivation in schizophrenia. We utilize a quantitative meta-analysis method to review 12 imaging studies where patients with schizophrenia were contrasted with healthy comparison subjects while performing the n-back paradigm. Although we find clear support for hypofrontality, we also document consistently increased activation in anterior cingulate and left frontal pole regions in patients with schizophrenia compared to that in controls. These data suggest that whereas reduced DLPFC activation is reported consistently in patients with schizophrenia relative to healthy subjects, abnormal activation patterns are not restricted to this region, raising questions as to whether the pathophysiological dysfunction in schizophrenia is specific to the DLPFC and about the relationship between impaired performance and aberrant activation patterns. The complex pattern of hyper- and hypoactivation consistently found across studies implies that rather than focusing on DLPFC dysregulation, researchers should consider the entire network of regions involved in a given task when making inferences about the biological mechanisms of schizophrenia.     

Changes over time in frontotemporal activation during a working memory task in patients with schizophrenia

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including prefrontal and temporal cortex. Longitudinal studies have shown changes in prefrontal activation during treatment. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in healthy subjects and medicated patients with schizophrenia with an acute symptom exacerbation. Patients were scanned twice: within the first week after admission to the hospital and after 7-8 weeks of a multimodal treatment including atypical antipsychotic agents. There were no differences in activation of lateral prefrontal regions in patients relative to healthy controls neither at baseline nor after 7-8 weeks. Controls showed relatively more activation in parietal, striatal and cerebellar regions. In patients with schizophrenia, frontotemporal function was bilaterally enhanced after 7-8 weeks. This activation change was associated with improved accuracy in a verbal WM task, improved verbal WM-span and symptom reduction as measured by the BPRS global score and the BPRS factor for thought disturbance. Although we could not replicate findings of functional hypofrontality in the patients with schizophrenia, frontotemporal activation changed with treatment and was associated with verbal WM performance and significant reduction of psychopathology.     

Assessment of single and bound features in a working memory task in schizophrenia

If disturbance of binding in long term memory is well established in schizophrenia, data concerning working memory maintenance are less clear. Feature binding in working memory was investigated in 19 patients with schizophrenia and 19 healthy controls. Binding was assessed by comparing two conditions in which participants had to retain four letters and four spatial locations. These features were presented either bound or separate. Results showed that both groups had better performances for bound than separate features, despite the fact that patients performed significantly worse than controls. When maintenance for isolated features was assessed, patients were severely disturbed for spatial locations but not for letters. Such a result suggests that reduced working memory performance in patients with schizophrenia for bound features is probably a consequence of a spatial deficit rather than a specific deficit of the binding process. Thus, not all form of binding are disturbed in schizophrenia.     

Inefficient neural activity in patients with schizophrenia and nonpsychotic relatives of schizophrenic patients: Evidence from a working memory task

Studies of schizophrenia with functional MRI have shown hyper- and hypoactivations in various brain regions including the prefrontal cortex. Functional anomalies have also been reported in first-degree relatives of schizophrenic patients. The aim of this study was to examine working memory related brain functions in healthy subjects, schizophrenic patients and unaffected relatives and to determine the influence of psychopathology on these processes. A parametric n-back working memory task and functional MRI were used to examine 61 patients with schizophrenia, 11 nonpsychotic relatives of schizophrenic patients and a comparison group of 61 healthy subjects. The results indicated increased as well as decreased brain functions in schizophrenic patients compared to the control group depending on the task difficulty and the performance: during the attention task (0-back), which served as control condition, behavioral responses of patients and healthy subjects hardly differed but BOLD responses were considerably enhanced in schizophrenic patients. With increasing task difficulty differences between groups in BOLD responses diminished whereas behavioral deficits of patients increased. The examination of attention-independent working memory-functions (2- vs. 0-back) produced hypoactivations in patients, especially in frontal, temporal and subcortical brain regions. Furthermore, positive symptoms were associated with parietal dysfunctions. Behavioral performance and neural responses of unaffected relatives of schizophrenic patients were intermediate between schizophrenic patients and controls indicating slight brain dysfunctions. In addition, compensatory strategies were demonstrated. These findings suggest that the genetic risk for schizophrenia is accompanied by neural inefficiency which is associated with cognitive deficits, especially in difficult tasks.     

Clinical utility of the N-back task in functional neuroimaging studies of working memory

Introduction: N-back tasks are commonly used in functional neuroimaging studies to identify the neural mechanisms supporting working memory (WM). Despite widespread use, the clinical utility of these tasks is not well specified. This study compared N-back performance during functional magnetic resonance imaging (fMRI) with task data acquired outside of the scanner as a measure of reliability across environment. N-back task validity was examined in relation to performance and rater-based measures used clinically to assess working memory. Method: Forty-three healthy adults completed verbal and object N-back tasks during fMRI scanning and outside the scanner. Task difficulty was varied parametrically (0, 1, and 2-back conditions). Order of N-back task completion was stratified by modality (verbal/object) and environment. Participants completed the Digit Span (DS) and provided self-ratings using the Behavior Rating Inventory of Executive Function (BRIEF-WM). Results: Mean verbal and object N-back accuracy was above 95% across load conditions; task difficulty was effectively manipulated across load conditions. Performance accuracy did not significantly differ by environment. N-back reaction time was slower during fMRI (F = 6.52, p = .01, η_p² = .13); participants were faster when initially completing tasks outside the scanner (η_p² = .10–.15). Verbal 2-back accuracy was significantly related to DS performance (r = .36, p = .02). N-back performance was not related to BRIEF-WM. Conclusions: Our results provide evidence for reliability of N-back accuracy during fMRI scanning; however, reliability of reaction time data is affected by order of task presentation. Data regarding construct validity are inconsistent and emphasize the need to consider clinical utility of behavioral measures in the design and interpretation of functional neuroimaging studies.     

The association between antisaccade task and working memory task performance in schizophrenia and bipolar disorder

To date, the research literature has yielded conflicting reports regarding the specificity of antisaccade deficits to schizophrenia. We sought to examine antisaccade and working memory task performance in schizophrenia patients and bipolar patients, as well as to examine the relationship between the two tasks in both patient populations. Thirty-four schizophrenia patients, 20 bipolar patients, and 30 nonpatient controls were administered saccadic inhibition (antisaccade), working memory, and sensorimotor tasks. Compared with the controls, the schizophrenia patients displayed both antisaccade deficits and working memory deficits. In contrast, the bipolar patients produced significantly more errors on the antisaccade task than the controls, though the bipolar group performed similarly to the control group on the working memory task. Mediational analyses demonstrated that working memory partially mediates the relationship between patients' diagnostic group status and antisaccade task performance; working memory performance contributed uniquely to the prediction of antisaccade task performance in the two patient groups. Antisaccade deficits do not appear specific to schizophrenia. The results suggest that in schizophrenia, working memory and antisaccade tasks are tapping similar cognitive processes, whereas in bipolar patients the processes underlying antisaccade and working memory performance are disparate.     

Antipsychotic drugs exacerbate impairment on a working memory task in first-episode schizophrenia.

BACKGROUND: This study sought to replicate previous findings of worsened performance on a translational spatial working memory task among antipsychotic-na?ve first-episode schizophrenia patients after antipsychotic treatment and to extend these findings by examining whether changes in the allocation of covert attention contribute to this effect. METHODS: Fourteen antipsychotic-na?ve schizophrenia patients performed an oculomotor delayed response task before and 6 weeks after antipsychotic treatment (risperidone n = 11; olanzapine n = 3). Fifteen matched healthy individuals were studied in parallel. RESULTS: Patients' pretreatment deficit in accurately remembering spatial locations was exacerbated by antipsychotic treatment, consistent with previous findings; however, this occurred only when covert attention was directed away from remembered locations during delay periods. CONCLUSIONS: Disruption in the allocation of covert attention might contribute to patients' decline in spatial working memory after antipsychotic treatment. Alterations in prefrontal dopaminergic systems or reduced thalamocortical drive might account for this apparent adverse cognitive effect of antipsychotic treatment.     

Alterations in functional activation in euthymic bipolar disorder and schizophrenia during a working memory task

Dysfunctions in prefrontal cortical networks are thought to underlie working memory (WM) impairments consistently observed in both subjects with bipolar disorder and schizophrenia. It remains unclear, however, whether patterns of WM‐related hemodynamic responses are similar in bipolar and schizophrenia subjects compared to controls. We used fMRI to investigate differences in blood oxygen level dependent activation during a WM task in 21 patients with euthymic bipolar I, 20 patients with schizophrenia, and 38 healthy controls. Subjects were presented with four stimuli (abstract designs) followed by a fifth stimulus and required to recall whether the last stimulus was among the four presented previously. Task‐related brain activity was compared within and across groups. All groups activated prefrontal cortex (PFC), primary and supplementary motor cortex, and visual cortex during the WM task. There were no significant differences in PFC activation between controls and euthymic bipolar subjects, but controls exhibited significantly increased activation (cluster‐corrected P < 0.05) compared to patients with schizophrenia in prefrontal regions including dorsolateral prefrontal cortex (DLPFC). Although the bipolar group exhibited intermediate percent signal change in a functionally defined DLPFC region of interest with respect to the schizophrenia and control groups, effects remained significant only between patients with schizophrenia and controls. Schizophrenia and bipolar disorder may share some behavioral, diagnostic, and genetic features. Differences in the patterns of WM‐related brain activity across groups, however, suggest some diagnostic specificity. Both patient groups showed some regional task‐related hypoactivation compared to controls across the brain. Within DLPFC specifically, patients with schizophrenia exhibited more severe WM‐related dysfunction than bipolar subjects. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task

OBJECTIVE: The evidence for verbal working memory deficits in schizophrenia has been inconsistent. Few studies have evaluated verbal working memory in the first-degree relatives of schizophrenia patients, who likely share the genetic diathesis for schizophrenia but not the potential confounds associated with chronic mental illness. METHOD: The Wechsler Digit Span Task was used to investigate verbal working memory in 52 schizophrenia patients, 56 of their first-degree relatives, and 73 nonpsychiatric comparison subjects. RESULTS: The nonpsychotic relatives showed no impairment on the forward digit span task, a measure of general attention, but did show impairment on the backward digit span task, a measure of verbal working memory. Schizophrenia patients showed impairment on both the forward and backward digit span tasks. CONCLUSIONS: These results indicate that the forward and backward digit span tasks tap different cognitive abilities that are differentially associated with the diathesis for schizophrenia. Working memory deficits associated with schizophrenia appear to be generalized and not limited to the spatial modality.     

精神分裂症患者的工作记忆损伤研究

目的 探讨精神分裂症患者和正常人之间空间、语音及面孔工作记忆的差异.方法 分别对44名精神分裂症患者和40名健康成年人进行空间、语音及面孔工作记忆测试,比较两组任务成绩及反应时间的差异.结果 患者在进行空间工作记忆和面孔工作记忆任务时,准确率明显低于对照组,空间工作记忆(患者组:86.12+12.4%,对照组:91.63+6.18%,P1=0.014),面孔工作记忆(患者组:63.01+9.04%,对照组:69.14+9.24%,P2=0.003),而进行语音工作记忆任务时,两组准确率无统计学差异(P=0.42)患者在进行三项工作记忆测试时,耗时均较对照组长(P<0.05).结论 患者工作记忆损伤存在不均衡性,可能与精神分裂症损伤的脑区不同有关.     

Prefrontal hyperactivation during a working memory task in early-onset schizophrenia spectrum disorders: An fMRI study

Working memory (WM) dysfunction is increasingly recognized as a core feature of schizophrenia, but few studies have investigated prefrontal activation during WM tasks in early-onset schizophrenia spectrum disorder (EOS). Our aim was to explore prefrontal activation during a WM-task in EOS patients compared to healthy controls using functional magnetic resonance imaging (fMRI). Fifteen patients with EOS and 15 matched healthy controls performed a 0-back and a 2-back task while fMRI data were acquired. Results indicated that even though performance between patients and controls was comparable on both tasks, there was a hyperactivation in patients' ventrolateral prefrontal cortex (VLPFC) during the 2-back task compared to healthy controls. This pattern of activation suggests that, in patients with EOS, the VLPFC compensated in order to match performance of the controls. The activations in the EOS group may reflect the use of a compensatory, cognitive strategy while solving WM-tasks.     

Spatial working memory deficits in schizophrenia: relationship with tardive dyskinesia and negative symptoms

OBJECTIVE: This study examined the interrelationship between negative symptoms, orofacial tardive dyskinesia, and specific neurocognitive processes, particularly those involved in memory and executive function, in patients with schizophrenia. METHOD: A set of computerized neurocognitive tasks, the Cambridge Neuropsychological Test Automated Battery, was used to assess executive and memory function in 54 hospitalized patients with chronic schizophrenia. Analysis of covariance was used to examine differences between groups with or without the topographical syndromes of orofacial tardive dyskinesia and between groups with high or low negative symptom scores. Principal-components and path analyses were used to examine further the influence of negative symptoms and orofacial tardive dyskinesia on performance on tests of memory and executive function. RESULTS: Both orofacial tardive dyskinesia and negative symptoms were significantly and independently associated with deficits on measures of spatial working memory span derived from principal-components analysis, but only orofacial tardive dyskinesia was associated with deficits on measures of spatial working memory strategy. Both were also associated with impairment on the delayed-matching-to-sample task, a test of memory. These associations were not explained by deficits in global intellectual function. Path analysis suggested that the relationships between the clinical symptoms and performance on the delayed-matching-to-sample task were mediated entirely through their relationship with the spatial working memory measures. CONCLUSIONS: In schizophrenia, orofacial tardive dyskinesia and evident negative symptoms are relatively independent markers of compromise of the cerebral systems that mediate spatial working memory. Candidate neural circuits include the frontal-striatal-thalamic systems, particularly those involving the dorsolateral prefrontal cortex.     

Baseline brain perfusion and working memory capacity: a neuroimaging study

Early studies of rest cerebral metabolism and perfusion reported no association with intellectual capacity. We revisit this issue using a larger sample (N=146) and a continuous arterial spin labeling technique to measure perfusion, and working memory capacity as a measure of intellectual capacity. In the cortex, working memory capacity correlated diffusely and negatively with perfusion. This negative association was more marked in the prefrontal and temporal cortex of the left hemisphere. However, there were also weak positive correlations in the auditory areas, accompanied by analogous correlations in all other areas associated with sensory modalities, with a preference for right lateralization. These findings are discussed in terms of the cortical and vascular organization of the brain.     

Language comprehension and working memory language comprehension and working memory deficits in patients with schizophrenia

The present study examined the hypothesis that patients with schizophrenia have deficits in language comprehension compared to normal controls, and that these deficits are associated with disturbances in working memory (WM). In addition, we hypothesized that language comprehension deficits would be associated with the severity of specific symptoms in the patients (formal thought disorder and hallucinations). Participants were 27 stable outpatients with schizophrenia and 28 demographically similar controls. Language comprehension was measured by presenting sentences auditorily that varied in length and syntactic complexity, followed by two or three comprehension questions. We measured working memory by administering a reading span task. Results indicated that, as predicted, language comprehension deficits were significantly greater in patients with schizophrenia than controls. Also as predicted, working memory was strongly correlated with language comprehension performance in both patients with schizophrenia and controls. Contrary to our predictions, language comprehension and working memory deficits were not associated with either formal thought disorder or hallucinations.     

Inhibitory control and spatial working memory: a saccadic eye movement study of negative symptoms in schizophrenia

The negative symptoms of schizophrenia are perhaps the most unremitting and burdensome features of the disorder. Negative symptoms have been associated with distinct motor, cognitive and neuropathological impairments, possibly stemming from prefrontal dysfunction. Eye movement paradigms can be used to investigate basic sensorimotor functions, as well as higher order cognitive aspects of motor control such as inhibition and spatial working memory - functions subserved by the prefrontal cortex. This study investigated inhibitory control and spatial working memory in the saccadic system of 21 patients with schizophrenia (10 with high negative symptoms scores and 11 with low negative symptom scores) and 14 healthy controls. Tasks explored suppression of reflexive saccades during qualitatively different tasks, the generation of express and anticipatory saccades, and the ability to respond to occasional, unpredictable ("oddball") targets that occurred during a sequence of well-learned, reciprocating saccades between horizontal targets. Spatial working memory was assessed using a single and a two-step memory-guided task (involving a visually-guided saccade during the delay period). Results indicated significant increases in response suppression errors, as well as increased response selection impairments, during the oddball task, in schizophrenia patients with prominent negative symptoms. The variability of memory-guided saccade accuracy was also increased in patients with prominent negative symptom scores. Collectively, these findings provide further support for the proposed association between prefrontal dysfunction and negative symptoms.     

Visuo-perceptual organization and working memory in patients with schizophrenia

We explore the mechanisms sub-tending the re-organization and memorization of visual information by studying how these mechanisms fail in patients with schizophrenia. Several studies have suggested that patients have difficulties in organizing information in perception and memory. We explore to what extent prompting patients to group items influences memory performance. We distinguish automatic grouping from top-down grouping processes, which are especially involved in re-organizing information. The main task was to memorize pairs of figures. Following manipulation of proximity, pairs of figures were part of the same perceptual group (within-group pair, formed on the basis of automatic grouping) or belonged to different groups (between-group pairs, re-grouped through top-down processes). Prior to the memory task, subjects ran a perception task prompting them to prioritize either within-group or between-group pairs. Unlike patients, controls globally benefited from grouping by proximity in the memory task. In addition, the results showed that prioritizing between-group pairs had a deleterious effect in patients, but with a large decrement in memory performance in the case of within-group rather than between-group figures. This occurred despite preserved focalization on within-group figures, as shown by eye-movement recordings. The suggestion is that when patients are prompted to re-group separate items, they can do so, but the benefit derived from automatic grouping is then not only lost but also reversed. This suggests re-organizing visual information not only involves re-grouping separate items but also integrating these new groups in a unified representation, which is impaired in patients with schizophrenia.     

Macaque monkeys exhibit behavioral signs of metamemory in an oculomotor working memory task

The ability to monitor one's own memory processes is an important feature of human cognition and is referred to as metamemory. Although several human neuropsychological and neuroimaging studies have been conducted on metamemory, the neural mechanism that underlies this cognitive function is still unknown due to a lack of neurobiological research using nonhuman animals. In the present study, we trained four macaque monkeys to perform an oculomotor working memory task that was designed to be suitable for various neurobiological approaches to metamemory. In this task, the monkeys were sometimes allowed to choose to either take or escape from a spatial working memory test (Choice condition) and sometimes forced to take the test (Test condition). The difficulty of the task was manipulated by varying the number of distractors. We used two criteria to determine whether the monkeys showed metamnemonic ability: (1) there should be a negative correlation between memory performance in the Test condition and the escape rate in the Choice condition, and (2) memory performance should be better in the Choice condition than in the Test condition. Three of the four monkeys fulfilled these criteria. In addition, the response times of one of these three monkeys provided additional evidence that it used metamnemonic ability. These results suggest that the present task can be a useful tool for investigating the neural mechanism of metamemory in monkeys. Neurobiological research on metamemory using primate models is necessary to understand human cognition, and our study contributes to progress in this research area.     

精神分裂症患者的工作记忆及决策功能特点的研究

目的:研究精神分裂症患者的工作记忆及决策功能特点。方法:收集年龄在18~55岁之间符合《中国精神障碍分类与诊断标准》第3版(CCMD-3)精神分裂症诊断标准的患者40例作为研究组,选择40例健康者作为对照组。两组分别予数字广度测验及爱荷华赌博任务(IGT),将两组结果加以比较。结果:与对照组比较,研究组的数字广度总分、正序分及逆序分均较低,差异有统计学意义(t=2.885,t=3.771,t=3.477;P=0.007,P=0.001,P=0.002);IGT的净得分总分比较,研究组(-1.45±3.67)分低于对照组(5.98±4.63)分,差异有统计学意义(t=7.954,P=0.000);IGT各Block的净得分比较,重复测量方差分析结果显示组别主效应显著(F=7.676,P=0.008),研究组Block 4、Block5的净得分低于对照组,差异有统计学意义(t=4.145,t=2.753;P=0.000,P=0.022)。结论:精神分裂症患者存在明显的工作记忆及决策功能缺陷。     

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

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