Working Memory Dysfunction In Schizophrenia Research Articles

The Visual Word Form Area compensates for auditory working memory dysfunction in schizophrenia

Auditory working memory impairments feature prominently in schizophrenia. However, the existence of altered and perhaps compensatory neural dynamics, sub-serving auditory working memory, remains largely unexplored. We compared the dynamics of induced high gamma power (iHGP) across cortex in humans during speech-sound working memory in individuals with schizophrenia (SZ) and healthy comparison subjects (HC) using magnetoencephalography (MEG). SZ showed similar task performance to HC while utilizing different brain regions. During encoding of speech sounds, SZ lacked the correlation of iHGP with task performance in posterior superior temporal gyrus (STGp) that was observed in healthy subjects. Instead, SZ recruited the visual word form area (VWFA) during both stimulus encoding and response preparation. Importantly, VWFA activity during encoding correlated with the magnitude of SZ hallucinations, task performance and an independent measure of verbal working memory. These findings suggest that VWFA plasticity is harnessed to compensate for STGp dysfunction in schizophrenia patients with hallucinations.

3.63 Developmental Trajectories of Gaba Receptor Subunits in Layer 3 Pyramidal and Gaba Neurons in Monkey Visual and Prefrontal Cortices

Visuospatial working memory (WM) requires information transfer among cortical regions, including visual and prefrontal cortices, via layer 3 pyramidal neurons whose activity is regulated by GABAergic parvalbumin (PV) neurons. In primates, WM performance improves through adolescence and certain measures mature earlier in the visual cortex (V2) than the prefrontal cortex (PFC). GABA neurotransmission undergoes protracted postnatal maturation, with a progressive shift from a2 (GABRA2) to a1 (GABRA1) subunit containing GABA receptors, which is important for WM function. Evidence suggests that schizophrenia is a disorder of cognitive neurodevelopment, with impairments in WM and in layer 3 neurons. Thus, studying the maturation of key molecular components in layer 3 cortical circuitry is crucial for understanding the molecular pathogenesis of WM dysfunction in schizophrenia. Therefore, we examined the postnatal developmental trajectories of GABRA1 and GABRA2 messenger RNA (mRNA) in layer 3 pyramidal and PV neurons from a caudal (V2) and rostral region (PFC) in the WM network in rhesus monkeys.

18.3 DISTURBED AND INTACT ATTENTIONAL PROCESSES DURING WORKING MEMORY ENCODING IN SCHIZOPHRENIA: CONVERGING BEHAVIORAL AND IMAGING GENETICS EVIDENCE

BackgroundWorking memory and attention are fundamental and closely linked cognitive domains. This close link is exemplified by the crucial role of selective attention for the selection of information to be encoded into working memory. Patients with schizophrenia are markedly impaired in many aspects of both domains. However, the interplay between these cognitive deficits on both the cognitive and neurophysiological level remains poorly understood. Based on our previous findings regarding the central role of impaired working memory encoding to working memory dysfunction in schizophrenia, we hypothesize, that impaired attentional processes contribute to working memory dysfunction specifically during the encoding stage. This hypothesis was tested in both a behavioral experiment and in an fMRI imaging genetics study.MethodsFor the behavioral study, we investigated 35 patients with schizophrenia and 35 matched healthy controls. In a change detection task, participants were simultaneously presented with both highly salient and non-salient spatial information. They were instructed to encode either the highly salient or the non-salient information. In half of the conditions, they were aided by a cue pointing them towards the relevant information. Our goal was to test, whether patients with schizophrenia were biased toward a particular type of information and whether a top-down cue would influence such a bias. In the imaging genetics study, we investigated 100 right-handed individuals without personal or family history of psychiatric disorders, who performed a visuospatial change detection task. The fMRI data were preprocessed and analyzed using Brain Voyager QX 20. For genotyping we used a custom Illumina HumanCoreExome-24 BeadChip array. We calculated polygenic scores (PGS) for schizophrenia based on 108 loci associated with schizophrenia in a recent mega-analysis of the Psychiatric Genetic Consortium (PGC2). We computed whole brain correlations between BOLD activation and PGS to elucidate the relationship between genetic risk for schizophrenia and abnormal brain function.ResultsIn the behavioral study, patients were significantly more impaired when required to encode non-salient compared to salient information. However, this impairment was specific to conditions without a top-down cue. This demonstrates, that patients could use top-down attention to overcome a bottom-up bias towards highly salient information during working memory encoding. In the fMRI data, we observed a significant negative correlation between BOLD activation in the right temporo-parietal junction (TPJ) during working memory encoding and PGS for schizophrenia. Across all subjects, this area showed robust deactivation during encoding. The TPJ is a crucial region of the ventral attention network and is closely involved in bottom-up attentional processes. Previous fMRI studies observed stronger deactivation of the TPJ during working memory encoding with increasing cognitive demand. Therefore, our results indicate that participants with a higher genetic risk for schizophrenia had to commit more cognitive resources by downregulating their ventral attention network.DiscussionTaken together, the results of both studies point toward specific disturbance of bottom-up attention during working memory encoding, which might be linked to genetic risk for schizophrenia. Conversely, top-down attention appears to be relatively spared. These findings provide new constraints for cognitive and neurophysiological models of impaired working memory encoding in schizophrenia.

FV 2 Reduced spatial variability in cortical working memory networks after macro-anatomical alignment – Converging evidence from multiple fMRI studies

Introduction Reducing the spatial variability in group analyses is an important issue in functional neuroimaging studies. Commonly volume-based whole-brain alignment procedures are used to provide a common analysis space and to align brains across subjects. Inter-individual differences in the cortical folding pattern are an important source of spatial variability. However, volume based alignment methods do not take this factor into account. By contrast, surface based alignment procedures have been shown to significantly improve macro-anatomical alignment and increase the overlap of functional activation. However, this has primarily been demonstrated for sensory and motor paradigms, but not for higher cognitive functions such as working memory. However, working memory is particularly relevant for investigating the neurophysiological and genetic mechanisms of neuropsychiatric disorders such as schizophrenia. Methods We applied the same high-resolution, multiscale curvature driven cortex based alignment procedure to three separate fMRI data sets using Brain Voyager QX 2.8. Anatomical scans were segmented along the white–gray matter boundary. Cortical hemispheres were reconstructed and morphed into spherical representations. Each cortical folding pattern was aligned to a dynamically updated group average through iterative morphing following a coarse-to-fine matching strategy. In a spatial working memory study with 32 healthy participants (study 1), we studied the impact of this macroanatomical alignment procedure on spatial variability of functional activation in the working memory network. In a separate spatial working memory imaging genetics study with 112 healthy participants (study 2), we examined a panel of SNPs previously reported in imaging genetics studies, and investigated whether macroanatomical alignment increased the likelihood of detecting effects of these SNPs on activation of the cortical working memory network. In a study of visual working memory dysfunction in schizophrenia with 17 patients with schizophrenia and 17 matched controls (study 3), we investigated, whether macroanatomical alignment differentially affects patients with schizophrenia, which are characterized by increased interindividual cortical anatomical variability. Results In study 1 we observed a reduction of spatial variability of functional activation by roughly 30% in key frontal and parietal areas of the working memory network and a small but robust increase in activation strength after macroanatomical alignment. In study 2 we observed, that macroanatomical alignment increased the likelihood to detect significant effects of individual SNPs on working memory related brain activation. In study 3 spatial variability of functional activation decreased in both groups, but this effect was more pronounced in patients. Conclusions Cortex based alignment substantially reduces the spatial variability of functional activation during working memory. This also improves the effect sizes of imaging genetics studies. Furthermore, our method appears to correct the increased interindividual cortical anatomical variability found in schizophrenia to a considerable degree, addressing an important confound in neuroimaging studies of this disorder. We conclude that the benefits of cortex based alignment warrant its more frequent use in fMRI studies of higher cognitive processes in healthy and patient populations.

Early Sensory Contributions to Contextual Encoding Deficits in Schizophrenia

The AX version of the visual continuous performance task (AX-CPT) is widely used for investigating visual working memory dysfunction in schizophrenia. Event-related potentials (ERP) provide an objective index of brain function and can be used to evaluate brain substrates underlying impaired cognition in schizophrenia. To assess the mechanisms that underlie visual working memory dysfunction in schizophrenia relative to impairment of early visual processing. Case-control study. Inpatient and outpatient facilities associated with the Nathan Kline Institute for Psychiatric Research. A total of 30 individuals with schizophrenia and 17 healthy comparison subjects. Three versions of the AX-CPT, with parametric variations in the proportions of trial types, were used to test performance and underlying neural activity during differential challenge situations. Contrast sensitivity measures were obtained from most subjects. Behavioral performance was assessed using d' context scores. Integrity of stimulus- and task-related cortical activation to both cue and probe stimuli was assessed using sensory (C1, P1, N1) and cognitive (N2, contingent negative variation [CNV]) ERP components. Early magnocellular/parvocellular function was assessed using contrast sensitivity. Linear regression and path analyses were used to assess relations between physiological and behavioral parameters. Patients showed reduced amplitude of both early sensory (P1, N1) and later cognitive (N2, CNV) ERP components. Deficits in sensory (N1) and cognitive (N2) component activation to cue stimuli contributed independently to impaired behavioral performance. In addition, sensory deficits predicted impaired cognitive ERP generation. Finally, deficits in performance correlated with impairments in contrast sensitivity to low, but not high, spatial frequency stimuli. Working memory deficits in schizophrenia have increasingly been attributed to impairments in stimulus encoding rather than to failures in memory retention. This study provides objective physiological support for encoding hypotheses. Further, deficits in sensory processing contribute significantly to impaired working memory performance, consistent with generalized neurochemical models of schizophrenia.

Contribution of Impaired Early-Stage Visual Processing to Working Memory Dysfunction in Adolescents With Schizophrenia

Working memory (WM) deficits in patients with schizophrenia have mainly been associated with prefrontal dysfunction. However, the contribution of perceptual deficits and abnormalities in sensory areas has not been explored. The present study closes this important gap in our understanding of WM dysfunction in schizophrenia by monitoring neural activity during WM encoding and retrieval with event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). To investigate the neurophysiological changes that contribute to WM impairment in early-onset schizophrenia at perceptual and cognitive stages using the ERP components P1, P3a, P370, and P570 and fMRI data from extrastriate visual areas. We conducted the study between June 1, 2003, and December 20, 2006. Electroencephalographic and fMRI data were acquired separately during a visual delayed discrimination task. Participants encoded up to 3 abstract shapes that were presented sequentially for 600 milliseconds each and decided after a 12-second delay whether a probe matched 1 of the sample stimuli. Between-group study at an inpatient psychiatric hospital and outpatient psychiatric facilities. Seventeen adolescents with early-onset schizophrenia according to DSM-IV criteria and 17 matched controls participated in the study. Amplitude of the ERP components P1, P3a, P370, and P570 and the fMRI signal from extrastriate visual areas. The P1 amplitude was reduced in patients during encoding and retrieval. The P1 amplitude increased with WM load during encoding only in controls. In this group, a stronger P1 amplitude increase predicted better WM performance. The P1 reduction was mirrored by reduced activation of visual areas in patients in fMRI. The P370 amplitude during encoding and retrieval was also reduced in patients. The P1 amplitude reduction indicates an early visual deficit in adolescents with schizophrenia. Our findings suggest that P1 is of particular relevance for successful WM encoding. Early visual deficits contribute to impaired WM in schizophrenia in addition to deficits in later memory-related processes.

Working memory capacity in schizophrenia: a parametric fMRI study

Impaired working memory (WM) function in schizophrenia has been associated with abnormal activation of the dorsolateral prefrontal cortex (DLPFC). It is, however, not clear whether abnormal activation is a sign of DLPFC pathology, or a correlate of poor performance. We address this question by examining activity in the WM brain system at different levels of task difficulty. A parametric fMRI paradigm is used to examine how the WM system responds to increasing load. A parametric fMRI design with four levels of a spatial N-back task was used to examine the relationships between working memory load, functional output (performance) and brain activity in 10 schizophrenic patients on atypical antipsychotic medication and to compare these to 10 healthy controls. In spite of increasingly poor performance in schizophrenic patients, activity increased normally in DLPFC and inferior parietal cortex bilaterally and in anterior cingulate, with increasing load. At 3-back, activity dropped in DLPFC in comparison with controls, but not in the other regions. The results indicate that peak activation of the WM-system is reached at a lower processing load in schizophrenic patients than in healthy controls. As a decline of DLPFC activity at high processing loads in itself is not abnormal, WM dysfunction in schizophrenia appears to be the result of an impaired functional output of the whole WM system, causing elevation of the effective burden imposed by WM tasks.

Functional hypofrontality and working memory dysfunction in schizophrenia.

Hypofrontality is a common but not invariable finding in schizophrenia. Inconsistencies in the literature may reflect, in part, the fact that abnormal physiological responses in the prefrontal cortex are best identified under conditions that place well-specified functional demands on this region. The authors studied eight patients with schizophrenia and eight matched comparison subjects using [(15)O]H2O positron emission tomography and the "N-back" task, which activates the prefrontal cortex as a function of working memory load in normal subjects. Under low-working-memory-load conditions, the accuracy of both groups in the N-back task was equal, but when the memory load increased, the patients' performance deteriorated more than did that of the comparison subjects. The regional cerebral blood flow response to increased working memory load was significantly reduced in the patients' right dorsolateral prefrontal cortex. These results confirm the importance of using tasks that tap specific cognitive functions, linked to specific neural systems, in studies of brain-behavior relationships in schizophrenia. Hypofrontality is reliably demonstrated in schizophrenia during tasks that engage working memory functions of the prefrontal cortex.

526. - Mechanisms of auditory working memory dysfunction in schizophrenia

526. - Mechanisms of auditory working memory dysfunction in schizophrenia

Hypofrontality and working memory dysfunction in schizophrenia

Hypofrontality and working memory dysfunction in schizophrenia

Verbal working memory dysfunction in schizophrenia: use of a Brown-Peterson paradigm

Recent studies of schizophrenia have implicated deficits in processes related to working memory, but the cognitive features of these deficits have been incompletely characterized. We used a modified Brown-Peterson paradigm to compare working memory in patients with schizophrenia and in normal control subjects. Distractor conditions differed in processing demand, increasing in complexity from no distractor to counting backwards (serial threes). We found significant effects of group, of distractor condition, and of a group × distractor condition interaction. The significant interaction was the result of a more rapid decline in the performance of schizophrenic patients with concurrent articulation. In addition, the schizophrenic group also made significantly more intrusion errors. The study suggests that schizophrenic patients exhibit dysfunction of the verbal working memory system due to a diminution in its overall processing resources.