Schizophrenics show spatial working memory deficits.

The present study demonstrates that schizophrenics are impaired on spatial delayed-response tasks, analogous to those that have been used to assess the working memory function of the dorsolateral prefrontal cortex in rhesus monkeys. Schizophrenic patients and two control groups, normal subjects and bipolar psychiatric patients, were tested on the oculomotor version of the memory task, a haptic version of the same task, and two control tasks: a sensory task that did not require working memory and a digit span test. The schizophrenic patients showed marked deficits relative to the two control groups in both the oculomotor and haptic delayed-response tasks. They were not, however, impaired on the digit span test, which taps verbal working memory as well as voluntary attention, and on the sensory control task, in which their responses were guided by external cues rather than by spatial working memory. These findings provide direct evidence that schizophrenics suffer a loss in representational processing and that this deficit is modality independent. These data on spatial working memory add to the growing evidence for involvement of the dorsolateral prefrontal cortex in schizophrenic disease.     

Visuospatial working memory deficits in adolescent onset schizophrenia

This study determines that visuospatial working memory (VSWM) deficits are evident in adolescent-onset schizophrenia, while the spatial strategy and spatial span components of VSWM are spared. These findings imply that frontal-striatal-parietal neural networks are dysfunctional in adolescent-onset schizophrenia, while mid-dorsolateral and ventrolateral PFC functions remain intact: the current conceptualisation of schizophrenia as a progressive neurodevelopmental disorder is consistent with these results.     

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.     

Reduced prefrontal-parietal effective connectivity and working memory deficits in schizophrenia

The neural mechanisms behind cognitive deficits in schizophrenia still remain unclear. Functional neuroimaging studies on working memory (WM) yielded inconsistent results, suggesting task performance as a moderating variable of prefrontal activation. Beyond regional specific activation, disordered integration of brain regions was supposed as a critical pathophysiological mechanism of cognitive deficits in schizophrenia. Here, we first hypothesized that prefrontal activation implicated in WM depends primarily on task performance and therefore stratified participants into performance subgroups. Second, in line with the dysconnectivity hypothesis, we asked whether connectivity in the prefrontal-parietal network underlying WM is altered in all patients. We used functional magnetic resonance imaging in human subjects (41 schizophrenia patients, 42 healthy controls) and dynamic causal modeling to examine effective connectivity during a WM task. In line with our first hypothesis, we found that prefrontal activation was differentially modulated by task performance: there was a significant task by group by performance interaction revealing an increase of activation with performance in patients and a decrease with performance in controls. Beyond that, we show for the first time that WM-dependent effective connectivity from prefrontal to parietal cortex is reduced in all schizophrenia patients. This finding was independent of performance. In conclusion, our results are in line with the highly influential hypothesis that the relationship between WM performance and prefrontal activation follows an inverted U-shaped function. Moreover, this study in a large sample of patients reveals a mechanism underlying prefrontal inefficiency and cognitive deficits in schizophrenia, thereby providing direct experimental evidence for the dysconnectivity hypothesis.     

A computational model for spatial working memory deficits in schizophrenia

Cognitive deficits in schizophrenia have been hypothesized to be caused by altered synaptic transmission in circuits of the prefrontal cortex. 2 main hypotheses have been put forward: reduced inhibition and hypofunctional NMDA receptors. Recently, Lee et al. (2008) found that spatial working memory deficits in schizophrenic patients include a disproportionately high incidence of high-confidence error responses. Here, we have studied what synaptic dysfunction can generate this specific behavioral deficit using a computational network model of spatial working memory. We developed quantitative behavioral readout from our network simulations, which reflected the qualitative properties of underlying neural dynamics. We then analyzed the behavioral effect of the GABAergic and glutamatergic hypotheses on our network simulations. We found that reduction in inhibitory transmission in the network caused a reduction in performance through an increase of high-confidence errors, as in the experimental data. In contrast, a concerted reduction in NMDA-receptor-dependent transmission reduced performance via increased low-confidence errors. Only when NMDA receptors were specifically depleted in interneurons did the behavioral read-out of our network mimic the behavioral results for schizophrenic patients. Thus, dynamics in our model network support a role of both global inhibition reduction and hypofunctional NMDA receptors in interneurons in generating the behavioral deficits of simple spatial working memory tasks in schizophrenia.     

Event-related theta oscillations during working memory tasks in patients with schizophrenia and healthy controls

Altered frontal lobe activity and executive control associated with working memory (WM) dysfunction are recognized as core deficits in schizophrenia. These impairments have been discussed as being associated with deficits in self-regulated action monitoring and anticipatory action plan generation. To study electrophysiological correlates of executive control -- specifically action monitoring and action rule switching -- under varying WM load, we used a paradigm derived from classic N-back (WM) tasks and requiring monitoring of simple actions. We focused on event-related changes in post-stimulus theta oscillatory activity during varying cognitive and WM demand in healthy controls and schizophrenia patients. The results show significant WM load and rule-switching-related increases of post-stimulus theta amplitude at fronto-central locations in controls. In patients with schizophrenia, there was no such modulation, but -- apart from an increased early theta at left temporal locations -- generally reduced late theta responses in all tasks and at all locations. Furthermore, the patients with schizophrenia showed significant differences in their error patterns, which imply differences in automation and anticipation of actions between controls and patients. These findings suggest that theta oscillations are involved in mediating frontal lobe activity and functions related to enhanced executive control. We conclude that the patients with schizophrenia showed deficits in acquiring a mental task set which appear to be associated with impairments in action monitoring and task-specific regulation of executive control.     

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.     

Verbal and visuospatial working memory development and deficits in children and adolescents with schizophrenia

Aim: Deficits in working memory are considered a core feature of schizophrenia and are present early in the course of the illness. Because working memory continues to mature through childhood and into early adulthood, it was the aim of this study to assess developmental trajectories of verbal and visuospatial working memory performance in children and adolescents with schizophrenia. Differences in the developmental trajectories in patients compared with controls may reflect differential effects within specific neural networks involved in working memory performance. Methods: Twenty-six children and adolescents with schizophrenia (age range of 8–19 years) and 37 controls matched on age and gender participated in the study. Modified versions of both a verbal and visuospatial Sternberg Item Recognition Paradigm were administered. Results: In the three age groups studied, patients performed significantly worse than controls on the verbal working memory tasks. There were significant effects of diagnosis and load on the verbal Sternberg, with patients performing worse than controls. However, there was no diagnosis by load interactions. Similar findings were present for the visuospatial Sternberg, except for the youngest age group. The 8- to 12-year-old patients had a disproportionately lower performance on the verbal working memory task than on the visuospatial task. Conclusions: Our findings support disruptions in shared verbal and visuospatial working memory networks, such as those supporting encoding processes, in children and adolescents with schizophrenia. We also found specific deficits in non-shared verbal working memory performance in childhood-onset schizophrenia.     

Prose memory deficits associated with schizophrenia

Memory of contextual information is essential to one's quality of living. This study investigated if the different components of prose memory, across three recall conditions: first learning trial immediate recall, fifth learning trial immediate recall, and 30-min delayed recall, are differentially impaired in people with schizophrenia, relative to healthy controls. A total of 39 patients with schizophrenia and 39 matched healthy controls were recruited. Their prose memory, in terms of recall accuracy, temporal sequence, recognition accuracy and false positives, commission of distortions, and rates of learning, forgetting, and retention were tested and compared. After controlling for the level of intelligence and depression, the patients with schizophrenia were found to commit more distortions. Furthermore, they performed poorer on recall accuracy and temporal sequence accuracy only during the first initial immediate recall. On the other hand, the rates of forgetting/retention and recognition accuracy were comparable between the two groups. These findings suggest that people with schizophrenia could be benefited by repeated exposure to the materials to be remembered. These results may have important implications for rehabilitation of verbal declarative memory deficits in schizophrenia.     

Spatial working memory deficits in adolescents at clinical high risk for schizophrenia

Identifying endophenotypic markers is crucial to schizophrenia research for finding appropriate preventive strategies. Working memory (WM) deficit has been suggested as a marker for schizophrenia but its presence in adolescents at high risk is understudied. We piloted a test of spatial WM function in adolescents at clinical high risk (CHR) for schizophrenia and in age- and IQ-matched low-risk control subjects. CHR adolescents showed deficits in spatial WM compared with controls but showed intact performance on a non-WM-demanding spatial control task. Although based on a small pilot study, the results strongly suggest that WM deficit may be a risk factor for psychosis.     

Face and object visual working memory deficits in first-episode schizophrenia correlate with multiple neurocognitive performances

BackgroundWorking memory (WM) deficit is considered a core feature and cognitive biomarker in patients with schizophrenia. Several studies have reported prominent object WM deficits in patients with schizophrenia, suggesting that visual WM in these patients extends to non-spatial domains. However, whether non-spatial WM is similarly affected remains unclear.AimThis study primarily aimed to identify the processing of visual object WM in patients with first-episode schizophrenia.MethodsThe study included 36 patients with first-episode schizophrenia and 35 healthy controls. Visual object WM capacity, including face and house WM capacity, was assessed by means of delayed matching-to-sample visual WM tasks, in which participants must distribute memory so that they can discriminate a target sample. We specifically examined their anhedonia experience by the Temporal Experience of Pleasure Scale and the Snaith-Hamilton Pleasure Scale. Cognitive performance was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).ResultsBoth face and house WM capacity was significantly impaired in patients with schizophrenia. For both tasks, the performance of all the subjects was worse under the high-load condition than under the low-load condition. We found that WM capacity was highly positively correlated with the performance on RBANS total scores (r=−0.528, p=0.005), RBANS delayed memory scores (r=−0.470, p=0.013), RBANS attention scores (r=−0.584, p=0.001), RBANS language scores (r=−0.448, p=0.019), Trail-Making Test: Part A raw scores (r=0.465, p=0.015) and simple IQ total scores (r=−0.538, p=0.005), and correlated with scores of the vocabulary test (r=−0.490, p=0.011) and scores of the Block Diagram Test (r=−0.426, p=0.027) in schizophrenia. No significant correlations were observed between WM capacity and Positive and Negative Syndrome Scale symptoms.ConclusionsOur research found that visual object WM capacity is dramatically impaired in patients with schizophrenia and is strongly correlated with other measures of cognition, suggesting a mechanism that is critical in explaining a portion of the broad cognitive deficits observed in schizophrenia.     

Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia.

BACKGROUND: Schizophrenic patients show deficits in working memory (WM) and inhibition of prepotent responses. We examined brain activity while subjects performed tasks that placed demands on WM and overriding prepotent response tendencies, testing predictions that both processes engage overlapping prefrontal cortical (PFC) regions and that schizophrenic patients show reduced PFC activity and performance deficits reflecting both processes. METHODS: Functional magnetic resonance imaging data were acquired while 16 schizophrenic and 15 healthy subjects performed the N-Back task that varied WM load and a version of the AX-CPT that required overriding a prepotent response tendency. RESULTS: Both tasks engaged overlapping cortical networks (e.g., bilateral dorsolateral PFC, Broca's area, parietal cortex). Increased WM load monotonically increased activity; preparation to override a prepotent response produced greater and more enduring activity. Group differences on each task emerged in a right dorsolateral PFC region: schizophrenic subjects showed lesser magnitude increases under conditions of high WM and prepotent response override demands, with concomitant performance impairments. CONCLUSIONS: Schizophrenic patients exhibit PFC-mediated deficits in WM and preparation to override prepotent responses. Findings are consistent with the operation of a single underlying PFC-mediated cognitive control mechanism and with physiologic dysfunction of the dorsolateral PFC in schizophrenic patients reflecting impairments in this mechanism.     

Abnormal medial temporal activity for bound information during working memory maintenance in patients with schizophrenia

Alterations of binding in long‐term memory in schizophrenia are well established and occur as a result of aberrant activity in the medial temporal lobe (MTL). In working memory (WM), such a deficit is less clear and the pathophysiological bases remain unstudied. Seventeen patients with schizophrenia and 17 matched healthy controls performed a WM binding task while undergoing functional magnetic resonance imaging. Binding was assessed by contrasting two conditions comprising an equal amount of verbal and spatial information (i.e., three letters and three spatial locations), but differing in the absence or presence of a link between them. In healthy controls, MTL activation was observed for encoding and maintenance of bound information but not for its retrieval. Between‐group comparisons revealed that patients with schizophrenia showed MTL hypoactivation during the maintenance phase only. In addition, BOLD signals correlated with behavioral performance in controls but not in patients with schizophrenia. Our results confirm the major role that the MTL plays in the pathophysiology of schizophrenia. Short‐term and long‐term relational memory deficits in schizophrenia may share common cognitive and functional pathological bases. Our results provide additional information about the episodic buffer that represents an integrative interface between WM and long‐term memory. © 2009 Wiley‐Liss, Inc.     

fMRI study of maintenance and manipulation processes within working memory in first-episode schizophrenia

OBJECTIVE: Working memory, a critical cognitive capacity that is affected in schizophrenia, can be divided into maintenance and manipulation processes. Previous behavioral research suggested that manipulation is more affected than maintenance in patients with chronic schizophrenia. In this study of first-episode schizophrenia patients, the authors evaluated the extent to which the two working memory processes are affected early in the course of schizophrenia. METHOD: Study subjects were 11 first-episode schizophrenia patients and 11 matched healthy comparison subjects. Each group performed two verbal working memory tasks while undergoing functional magnetic resonance imaging. One task required maintenance of information; the other required manipulation of information in addition to maintenance. RESULTS: Under behaviorally matched conditions, both groups activated a predominantly left-sided frontal-parietal network. The manipulation plus maintenance task elicited activation of greater magnitude and spatial extent. With both tasks, patients showed less bilateral dorsolateral prefrontal cortex activation and greater ventrolateral prefrontal cortex activation, relative to the comparison subjects. A group-by-task interaction was observed for activation at the left dorsolateral and ventrolateral prefrontal cortex. The increase in activation when patients engaged in the manipulation plus maintenance task was disproportionately less in the dorsolateral prefrontal cortex and greater in the ventrolateral prefrontal cortex. CONCLUSIONS: These functional neuroanatomical findings add support to earlier suggestions that manipulation of information is selectively more affected than maintenance of information in persons with schizophrenia. They also suggest the presence of interacting regions of dysfunctional and compensatory prefrontal responses in the dorsolateral and ventrolateral prefrontal cortex, respectively, that are more prominent when information is manipulated. This disrupted prefrontal network is present relatively early in the course of schizophrenia.     

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.     

Neural correlates of verbal and nonverbal working memory deficits in individuals with schizophrenia and their high-risk siblings

Impaired working memory and functional brain activation deficits within prefrontal cortex (PFC) may be associated with vulnerability to schizophrenia. This study compared working memory and PFC activation in individuals with schizophrenia, their unaffected siblings and healthy comparison participants. We administered a "2back" version of the "nback" task. Functional MRI (fMRI) was used to measure brain activity. Nineteen individuals with DSM-IV schizophrenia, 18 of their siblings, and 72 healthy comparison participants underwent fMRI scans while performing word and face "nback" working memory tasks. Repeated trials (items whose prior presentation was not in the correct nback position) allowed us to assess group differences in the ability to code the temporal order of items. Individuals with schizophrenia and their siblings performed worse than controls on repeated lure trials, suggesting an association between schizophrenia and impairments in the coding of temporal order within working memory. Both individuals with schizophrenia and their siblings also demonstrated abnormal brain activation in PFC, such that both groups had hyperactivation in response to word stimuli and hypoactivation in response to face stimuli. These results provide further evidence that individuals with schizophrenia and their siblings are impaired in their ability to encode the temporal order of items within working memory and that disturbances in working memory and PFC activation may be genetic markers of the vulnerability to schizophrenia.     

Nonverbal working memory deficits in schizophrenia patients: evidence of a supramodal executive processing deficit

BACKGROUND: Although there have been several investigations of spatial working memory performance in schizophrenia patients, there have been considerably fewer studies of object working memory. The purpose of the present investigation was to evaluate the domain specificity of nonverbal working memory impairment in schizophrenia patients. METHODS: Delayed match-to-sample tasks involving spatial, identity and affective information were administered to schizophrenia and schizophrenia-spectrum patients (n=36) and normal controls (n=29). RESULTS: Using visual stimuli that can be considered prototypical of object vision, namely, faces we observed that schizophrenia patients perform poorly on working memory tasks that are based on the identity and/or features of the stimulus (i.e., object-based working memory tasks) as well as on a working memory task based on the spatial location of the stimulus. We observed significant associations between global ratings of negative symptoms and working memory performance. CONCLUSIONS: These data demonstrate that the working memory deficit displayed by schizophrenia and schizophrenia-spectrum patients extends to nonspatial visual domains.     

Dorsolateral prefrontal cortex activity during maintenance and manipulation of information in working memory in patients with schizophrenia

CONTEXT: It remains unclear whether altered regional brain physiological activity in patients with schizophrenia during working memory tasks relates to maintenance-related processes, manipulation-related (ie, executive) processes, or both. OBJECTIVE: To examine regional functional activations of the brain during maintenance- and manipulation-related working memory processing in patients with schizophrenia and in healthy comparison subjects. DESIGN: Functional images of the brain were acquired in 11 schizophrenic patients and 12 healthy control subjects (matched for age, sex, handedness, and parental education) during 2 spatial working memory paradigms, one contrasting maintenance-only processing with maintenance and manipulation processing and the other contrasting parametrically varying maintenance demands. RESULTS: Patients and controls showed activation of a large, spatially distributed network of cortical and subcortical regions during spatial working memory processing. When task demands required explicit manipulation of information held in memory, controls recruited right dorsolateral prefrontal cortex (Brodmann areas 45 and 46) to a significantly greater extent than patients. A similar effect was observed for the larger memory set sizes of the memory set size task. No other brain regions showed activation differences between groups for either task. These differences persisted when comparing activation maps for memory set sizes in which the 2 groups were equivalent in behavioral accuracy and when comparing subgroups of patients and controls matched for behavioral accuracy on either task. CONCLUSIONS: Physiological disturbances in the dorsolateral prefrontal cortex contribute differentially to patients' difficulties with maintaining spatial information across a brief delay, as well as with manipulating the maintained representation. These differences persisted when comparing conditions in which the 2 groups were equivalent in behavioral accuracy.     

Visuospatial memory deficits in adolescent onset schizophrenia

Visuospatial memory encoding deficits have been reported in adults with schizophrenia, while adolescents with schizophrenia have not been specifically investigated with visuospatial memory encoding and retrieval paradigms. A cross sectional study of delayed matching-to-sample performance in 19 right handed, male, anti-psychotic medication na?ve adolescents with undifferentiated schizophrenia and 28 age, gender, IQ and handedness matched healthy participants was completed. The adolescent-onset schizophrenia group demonstrated significant impairment in visuospatial memory, independent of the degree of delay, consistent with an encoding impairment. The impaired encoding phase of visuospatial memory in the adolescent-onset schizophrenia group is consistent with findings in adult onset schizophrenia samples, suggesting a developmental stage-independent deficit.