Abnormal cortical neural synchrony during working memory in schizophrenia

Objective

To better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information.

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.     

Verbal working memory impairments in individuals with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia

Working memory (WM) impairment is a promising candidate endophenotype for schizophrenia that could facilitate the identification of susceptibility genes for this disorder. The validity of this putative endophenotype was assessed by determining whether 149 probands with schizophrenia and 337 of their first-degree relatives demonstrated WM impairment as compared to 190 unaffected community comparison subjects. Subjects were participants in the Consortium on the Genetics of Schizophrenia (COGS) project, a seven-site research network that was established to investigate the genetic architecture of endophenotypes for schizophrenia. Participants received comprehensive clinical assessments and completed two verbal WM tasks, one requiring transient on-line storage and another requiring maintenance plus complex manipulation of information by reordering the stimuli. Schizophrenia probands performed worse than the other groups on both tasks, with larger deficits found for the more challenging reordering WM task. The probands' relatives performed more poorly than community comparison subjects on both tasks, but the difference was significant only for the more challenging maintenance plus complex manipulation WM task. This WM impairment was not attributable to diagnoses of schizophrenia spectrum disorder, mood disorders, or substance use disorders in the relatives. In conjunction with evidence that WM abilities are substantially heritable, the current results support the validity and usefulness of verbal WM impairments in manipulation of information as endophenotypes for schizophrenia in large-scale genetic linkage and association studies.     

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.     

Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study.

BACKGROUND: First-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness and show deficits on high-load information processing tasks. We used functional magnetic resonance imaging (fMRI) to test whether nonpsychotic relatives show altered functional activation in the prefrontal cortex (PFC), thalamus, hippocampus, and anterior cingulate during a working memory task requiring interference resolution. METHODS: Twelve nonpsychotic relatives of persons with schizophrenia and 12 healthy control subjects were administered an auditory, verbal working memory version of the Continuous Performance Test during fMRI. An asymmetric, spin-echo, T2*-weighted sequence (15 contiguous, 7-mm axial slices) was acquired on a full-body MR scanner. Data were analyzed by Statistical Parametric Mapping (SPM). RESULTS: Compared with control subjects, relatives showed greater task-elicited activation in the PFC and the anterior and dorsomedial thalamus. When task performance was controlled, relatives showed significantly greater activation in the anterior cingulate. When effects of other potentially confounding variables were controlled, relatives generally showed significantly greater activation in the dorsomedial thalamus and anterior cingulate. CONCLUSIONS: This pilot study suggests that relatives of persons with schizophrenia have subtle differences in brain function in the absence of psychosis. These differences add to the growing literature identifying neurobiological vulnerabilities to schizophrenia.     

Automatization and working memory capacity in schizophrenia

Working memory (WM) dysfunction in schizophrenia is characterized by inefficient WM recruitment and reduced capacity, but it is not yet clear how these relate to one another. In controls practice of certain cognitive tasks induces automatization, which is associated with reduced WM recruitment and increased capacity of concurrent task performance. We therefore investigated whether inefficient function and reduced capacity in schizophrenia was associated with a failure in automatization. FMRI data was acquired with a verbal WM task with novel and practiced stimuli in 18 schizophrenia patients and 18 controls. Participants performed a dual-task outside the scanner to test WM capacity. Patients showed intact performance on the WM task, which was paralleled by excessive WM activity. Practice improved performance and reduced WM activity in both groups. The difference in WM activity after practice predicted performance cost in controls but not in patients. In addition, patients showed disproportionately poor dual-task performance compared to controls, especially when processing information that required continuous adjustment in WM. Our findings support the notion of inefficient WM function and reduced capacity in schizophrenia. This was not related to a failure in automatization, but was evident when processing continuously changing information. This suggests that inefficient WM function and reduced capacity may be related to an inability to process information requiring frequent updating.     

Impairment on a self-ordered working memory task in patients with early-acquired hippocampal atrophy

One of the features of both adult-onset and developmental forms of amnesia resulting from bilateral medial temporal lobe damage, or even from relatively selective damage to the hippocampus, is the sparing of working memory. Recently, however, a number of studies have reported deficits on working memory tasks in patients with damage to the hippocampus and in macaque monkeys with neonatal hippocampal lesions. These studies suggest that successful performance on working memory tasks with high memory load require the contribution of the hippocampus. Here we compared performance on a working memory task (the Self-ordered Pointing Task), between patients with early onset hippocampal damage and a group of healthy controls. Consistent with the findings in the monkeys with neonatal lesions, we found that the patients were impaired on the task, but only on blocks of trials with intermediate memory load. Importantly, only intermediate to high memory load blocks yielded significant correlations between task performance and hippocampal volume. Additionally, we found no evidence of proactive interference in either group, and no evidence of an effect of time since injury on performance. We discuss the role of the hippocampus and its interactions with the prefrontal cortex in serving working memory.     

Control of working memory content in schizophrenia

People with schizophrenia (PSZ) exhibit signs of reduced working memory (WM) capacity. However, this may reflect an impairment in managing its content, e.g. preventing irrelevant information from taking up available storage space, rather than a true capacity reduction. We tested the ability to eliminate and update WM content in 38 PSZ and 30 healthy control subjects (HCS). Images of real-world objects were presented consecutively, and a tone cued the item most likely to be tested for memory. On half the trials, randomly intermixed, a second tone occurred. Participants were informed that the item cued by the second tone was now the most likely to be tested, and the item cued by the first tone now the least likely, providing incentive to eliminate the first cued item from WM. Both HCS and PSZ displayed a robust performance advantage for cued items. Unexpectedly, PSZ more efficiently removed the no-longer-essential item from WM than HCS. The magnitude of the WM clearance of this first cued item correlated with memory performance for the newly prioritized second cued item in PSZ, indicating that it was adaptive. However, WM clearance was not associated with WM capacity, ruling out the need to budget limited resources as an explanation for greater clearance in PSZ. A robust correlation between WM clearance and poverty of speech in PSZ instead suggests that the propensity to rapidly clear non-essential information and minimize the number of items in WM may be the reflection of a negative symptom trait. This finding may reflect a more general tendency of PSZ to focus processing more narrowly than HCS.     

Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings

Working memory (WM) deficits are a persistent, disabling and relatively treatment-resistant feature of schizophrenia that may underlie many cognitive deficits and symptoms. They are associated with prefrontal cortex dysfunction. While most neuroimaging studies of WM demonstrate “task-related hypofrontality” in schizophrenic relative to healthy subjects, several recent studies have reported equal or increased prefrontal activity. These findings challenge central assumptions regarding cognitive deficits and prefrontal cortex dysfunction in schizophrenia. The goal of this review is to reconcile these seemingly discrepant findings. Methodological factors addressed include the use of intersubject averaging, WM task parameters and the reliability of the measures. Factors intrinsic to schizophrenia and their relevance to the selection of experimental methods and the interpretation of group data are also discussed. Both hypo- and hyperfrontality are hypothesized to be valid and informative reflections of prefrontal cortex dysfunction in schizophrenia. Due to the heterogeneity and variability of both performance and regional recruitment in schizophrenia, whether individual data is considered, the level and type of WM demands and the composition of the sample with regard to performance deficits all influence study outcome and contribute to discrepancies. Although the prefrontal cortex is consistently implicated in WM deficits, the basis of its dysfunction and its exact contribution remain unclear. Future work might focus on delineating the exact WM processes, domains and components that are deficient. In addition, variability in behavior and activation might best be regarded as intrinsic to schizophrenia and having a neural basis that requires explanation. In combination with other techniques, neuroimaging can identify the neural circuitry responsible for WM deficits and elucidate the contribution of each anatomical component.     

The influence of emotional distraction on verbal working memory: an fMRI investigation comparing individuals with schizophrenia and healthy adults

The ability to maintain information over short periods of time (i.e., working memory) is critically important in a variety of cognitive functions including language, planning, and decision-making. Recent functional Magnetic Resonance Imaging (fMRI) research with healthy adults has shown that brain activations evoked during the delay interval of working memory tasks can be reduced by the presentation of distracting emotional events, suggesting that emotional events may take working-memory processes momentarily offline. Both executive function and emotional processing are disrupted in schizophrenia, and here we sought to elucidate the effect of emotional distraction upon brain activity in schizophrenic and healthy adults performing a verbal working memory task. During the delay period between the memoranda and memory probe items, emotional and neutral distractors differentially influenced brain activity in these groups. In healthy adults, the hemodynamic response from posterior cingulate, orbital frontal cortex, and the parietal lobe strongly differentiated emotional from neutral distractors. In striking contrast, schizophrenic adults showed no significant differences in brain activation when processing emotional and neutral distractors. Moreover, the influence of emotional distractors extended into the memory probe period in healthy, but not schizophrenic, adults. The results suggest that although emotional items are highly salient for healthy adults, emotional items are no more distracting than neutral ones to individuals with schizophrenia.     

Examining encoding imprecision in spatial working memory in schizophrenia

BACKGROUND: Visuospatial working memory is not a unitary sketch pad but comprises independent dimensions of target distance and direction and at least two levels of detail (fine-grained and category level). The aim of this study was to examine these multiple aspects of encoding in patients with schizophrenia using a modified delayed response task. METHOD: 42 patients with schizophrenia and 48 healthy controls pointed, as accurately as possible from a fixed starting position, to the visual location of target stimuli presented to a touch-sensitive screen. An adaptive staircase procedure was used to equate stimulus duration for each individual. Encoding accuracy and maintenance of distance (mm) and direction ( degrees ) information was examined following a 0-second (immediate) or 4-second (unfilled) delay. Analyses utilized both absolute (unsigned) and signed data. RESULTS: The results showed that the average duration required to detect a target was significantly longer in patients than controls. When stimulus duration was equated, (a) the absolute accuracy of distance and direction responses was not significantly different between groups at 0-second delay but was significantly reduced at 4-second delay in patients with schizophrenia, and (b) signed direction errors at 4-second delay were significantly different between groups at stimulus angles greater than 90 degrees . CONCLUSIONS: The findings challenge previous suggestions of deficits in fine-grained encoding of spatial information in schizophrenia but confirm a difficulty maintaining both direction and distance details in working memory. Imprecision in spatial memory in schizophrenia also introduced greater bias from category level (prior) representations, especially in left hemi-space.     

Inefficiently increased anterior cingulate modulation of cortical systems during working memory in young offspring of schizophrenia patients

Background

Children and adolescent offspring of schizophrenia patients are at increased risk for schizophrenia and are also characterized by impairments in brain structure and function. To date, few studies have investigated whether functional interactions between brain regions are intact or altered. Using an established verbal working memory paradigm with variable levels of memory load, we investigated the modulatory effect of activity in cognitive control regions of the brain (specifically the dorsal anterior cingulate cortex) on activity in core working memory regions, in particular the dorsal prefrontal cortex and the parietal lobe.

Methods

Forty four subjects participated. An n-back task with two levels of working memory load (1- and 2-back) was employed during fMRI (4 T Bruker MedSpec system). Data were processed with SPM5 and the modulatory effects of the anterior cingulate were investigated using psycho-physiological interaction (PPI).

Results

In spite of only subtle activation differences, and no significant differences in performance accuracy, a significant group x memory load interaction in the parietal lobe, indicated aberrantly increased modulatory inputs to this region under conditions of high working memory load in schizophrenia offspring.

Discussion

Increased modulatory inputs from a central control region like the anterior cingulate presumably reflect relative inefficiency in intra-cortical interactions in the vulnerable brain. This inefficiency may reflect a developmentally mediated impairment in functional brain interactions in this important vulnerable population. It is highly plausible that the resultant effect of these altered interactions is an increased vulnerability to impaired brain development, and therefore to psychiatric disorders including schizophrenia.     

The psychopathology,neuropsychology, and neurobiology of associative and working memory in schizophrenia

Summary A large number of psycholinguistic findings on how human beings store lexical information suggest the existence of associative memory, which may be characterized by a large capacity and a long duration. Its anatomical basis supposedly is, at least in part, the frontal lobes, and some of its functional characteristics have been tentatively linked to dopamine release. Working memory has a limited capacity, lasts only for seconds and is relevant for goal-directed behavior. Its anatomical basis in the frontal cortex is established and strong evidence suggests the involvement of dopaminergic pathways. Experimental evidence using several lexical decision tasks and a delayed response task is provided to demonstrate that some characteristic features of schizophrenic thinking — in particular the rapid shift of associations, the indirect relationship of associations, the overly abstract or overly concrete use of concepts, the lack of context-sensitivity and of general integrative function and intellectual capacity — can be explained in terms of an activation or disinhibition of associative memory, and of a dysfunctional working memory. The findings serve as an example of schizophrenia reserarch in a cognitive neuroscience framework.     

Examining an emotion enhancement effect in working memory: Evidence from age-related differences

The aim of the present study was to examine age-related differences between young, young–old and old–old adults in an affective version of the classical Working Memory Operation Span Test. The affective version of the Working Memory Operation Span Test included neutral words (as in the classical version) as well as negative and positive ones. Results showed that while young adults performed better than the young–old and old–old with neutral words, age-related differences between young and young–old with positive words were no longer significant, and age-related differences were nullified with negative ones. Altogether, results indicate that emotional words can reduce age-related decline when maintenance and manipulation of information in working memory in older adults are required.     

A study of visual and auditory verbal working memory in schizophrenic patients compared to healthy subjects

Impaired working memory (WM) performance is considered as a central feature of schizophrenia. Divided into two components, verbal and spatial, WM has been shown to involve frontal and parietal regions. Verbal WM can be tested either visually or aurally. The present study aimed to test schizophrenic patients in both visual and auditory verbal WM in order to assess a possible distinct pattern of alteration of these two modalities. Twenty-four schizophrenic patients and 24 healthy controls were compared with 2-back continuous visual and auditory verbal WM testing. Both groups were also tested on a neuropsychological battery including Wisconsin Card Sorting Test (WCST). Schizophrenic patients were less efficient in both verbal WM tests. When taking age and educational level as covariates and both WM modalities as dependent variables, there was no differential effect of modalities across groups. In further exploratory analyses, partial correlations brought association between verbal WM and psychosocial adaptation, WCST and length of illness. These results suggest a similar pattern of alteration of both modalities of verbal WM in schizophrenic patients. The implications of this finding are discussed. Received: 16 February 1999 / Accepted: 20 December 1999     

Decreased processing speed might account for working memory span deficit in schizophrenia,and might mediate the associations between working memory span and clinical symptoms

ObjectiveVerbal working memory span is decreased in patients with schizophrenia, and this might contribute to impairment in higher cognitive functions as well as to the formation of certain clinical symptoms. Processing speed has been identified as a crucial factor in cognitive efficiency in this population. We tested the hypothesis that decreased processing speed underlies the verbal working memory deficit in patients and mediates the associations between working memory span and clinical symptoms.MethodForty-nine schizophrenia inpatients recruited from units for chronic and acute patients, and forty-five healthy participants, were involved in the study. Verbal working memory span was assessed by means of the letter-number span. The Digit Copy test was used to assess motor speed, and the Digit Symbol Substitution Test to assess cognitive speed.ResultsThe working memory span was significantly impaired in patients (F(1,90) = 4.6, P < 0.05). However, the group difference was eliminated when either the motor or the cognitive speed measure was controlled (F(1,89) = 0.03, P = 0.86, and F(1,89) = 0.03, P = 0.88). In the patient group, working memory span was significantly correlated with negative symptoms (r = –0.52, P < 0.0001) and thought disorganisation (r = –0.34, P < 0.025) scores. Regression analyses showed that the association with negative symptoms was no longer significant when the motor speed measure was controlled (β = –0.12, P = 0.20), while the association with thought disorganisation was no longer significant when the cognitive speed measure was controlled (β = –0.10, P = 0.26).ConclusionsDecrement in motor and cognitive speed plays a significant role in both the verbal working memory impairment observed in patients and the associations between verbal working memory impairment and clinical symptoms.     

Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis.

BACKGROUND: In nonpsychotic parents and siblings of schizophrenic patients, the recurrence risk ratios of sustained attention deficits, as measured by the continuous performance test (CPT), were examined with a series of cut-off points. METHODS: Among 116 parents and 95 siblings of 91 schizophrenic probands in northern Taiwan, both undegraded and degraded sessions of the CPT were administered. Subjects' signal detection sensitivity of CPT performance (d') was standardized against a community sample without (unadjusted z score) or with (adjusted z score) adjustment for age, gender, and educational level. RESULTS: Differences in the risk ratios between the parents and siblings that were based on the unadjusted z scores of CPT d' diminished markedly if the adjusted z scores were used. As the cut-off point in the adjusted z score decreased from -2.5 to -3.0, the risk ratio increased continually for both the undegraded (10.1-18.8 for parents, 10.0-16.7 for siblings) and degraded (12.4-102.7 for parents, 8.6-72.0 for siblings) test. CONCLUSIONS: Stringent cut-off criteria of CPT deficits with adjustment for demographic features leads to recurrence risk ratios greater than those based on schizophrenia alone in both parents and siblings of schizophrenic patients.     

Spatial working memory span,delayed response and executive function in schizophrenia

This study investigated the spatial working memory span (SWMS) as well as the immediate memory span of schizophrenic patients, and examined the contribution of each span to the patients’ executive function deficit in the visuospatial domain. SWMS measured the visuospatial working memory capacity that simultaneously processes and stores visuospatial information. Immediate memory span was measured with the spatial span (SS), a variant of Corsi's block-tapping test. A total of 16 patients diagnosed with schizophrenia and 16 normal control subjects participated in the study. SWMS, as well as the forward and backward SS, was significantly reduced in schizophrenia. The SWMS deficit observed in this study and previous findings of deficit in verbal working memory spans suggest that impairment in working memory capacity in schizophrenia is general, and not limited to the verbal domain. Executive function as assessed with the self-ordered pointing task (SOPT) was also impaired in the patients, which is consistent with clinical observations of self-monitoring impairment in schizophrenia. SWMS was able to account for the performance on the SOPT, but its contribution in the patients’ impairment did not reach statistical significance. Backward span deficit explained this executive function impairment. SWMS was effective in explaining schizophrenic patients’ impaired performance on the spatial delayed response, a prefrontal function task. Implications of the relations observed between the spans and the prefrontal function tasks are discussed.     

The effects of working memory demands on the neural correlates of prospective memory

Event-related brain potentials (ERPs) were used to examine the reciprocal costs of working and prospective memory loads on the neural correlates of the realization of delayed intentions and the detection of target stimuli. The electrophysiological data revealed several interesting results: (1) distinct modulations of the ERPs were elicited by working memory targets and prospective memory cues, (2) working memory load modulated the amplitude of the N300 elicited by prospective memory cues, (3) prospective memory load was associated with a broadly distributed sustained modulation that began shortly after stimulus onset, and (4) brain-behavior correlations between the neural correlates of prospective memory and working memory varied with the working memory demands of the ongoing activity. These findings appear to indicate that attentional processes associated with the detection of prospective memory cues are sensitive to the working memory demands of the ongoing activity and that different processes may support prospective memory depending on the working memory demands of the ongoing activity.     

Backward inhibition in a task of switching attention within verbal working memory

Three experiments were conducted to examine the backward inhibition effect in attention switching within verbal working memory. Experiment one showed significant backward inhibition effect in a "tri-count task". Experiment two suggested that the effect was not due to a perceptual inhibition on the previously presented figure. Experiment three excluded the sequential expectancy explanation for this inhibition effect. Our results suggest that attention switching between working memory items is accompanied by inhibition of the previously attended working memory item. The findings are discussed in respect to the account of the executive function.