ERP Decoding Analysis of Visual Working Memory Processes in Schizophrenia

Our previous work suggests that 2 colors can be consolidated into visual short-term memory (VSTM) in parallel without a loss of memory precision, whereas consolidation of 2 orientations is performed in a strictly serial manner. Those experiments compared VSTM performance for simultaneously and sequentially presented stimuli. However, there is still controversy about whether the bandwidth for consolidation is determined by the type of information. To further investigate this issue, here we measured electroencephalography while participants attempted to consolidate 1, 2 or 4 simultaneously presented colors (Experiment 1) or orientations (Experiment 2) under limited presentation times. We used the contralateral delay activity (CDA) as an electrophysiological marker of the number of items that were consolidated. For colored stimuli, the CDA amplitude increased between set-size 1 and 2 but did not further increase for set size 4. By contrast, for orientation, the CDA amplitude remained at the set size 1 amplitude as set size increased to 2 or 4 items. Furthermore, in a long exposure duration (300 ms) condition that did not limit the consolidation process, the CDA amplitude pattern indicated that VSTM capacity is limited to about 3 colored items and about 2 orientation items in our paradigm. Thus, the CDA effects observed in the short presentation time was not limited by VSTM storage, but rather by consolidation. These results are consistent with our previous behavioral research and suggest that the bandwidth of VSTM consolidation is determined by the stimulus feature. (PsycINFO Database Record

Working memory (WM) is limited in capacity, but it is controversial whether these capacity limitations are domain-general or are generated independently within separate modality-specific memory systems. These alternative accounts were tested in bimodal visual/tactile WM tasks. In Experiment 1, participants memorized the locations of simultaneously presented task-relevant visual and tactile stimuli. Visual and tactile WM load was manipulated independently (one, two, or three items per modality), and one modality was unpredictably tested after each trial. To track the activation of visual and tactile WM representations during the retention interval, the visual contralateral delay activity (CDA) and tactile CDA (tCDA) were measured over visual and somatosensory cortex, respectively. CDA and tCDA amplitudes were selectively affected by WM load in the corresponding (tactile or visual) modality. The CDA parametrically increased when visual load increased from one to two and to three items. The tCDA was enhanced when tactile load increased from one to two items and showed no further enhancement for three tactile items. Critically, these load effects were strictly modality-specific, as substantiated by Bayesian statistics. Increasing tactile load did not affect the visual CDA, and increasing visual load did not modulate the tCDA. Task performance at memory test was also unaffected by WM load in the other (untested) modality. This was confirmed in a second behavioral experiment where tactile and visual loads were either two or four items, unimodal baseline conditions were included, and participants performed a color change detection task in the visual modality. These results show that WM capacity is not limited by a domain-general mechanism that operates across sensory modalities. They suggest instead that WM storage is mediated by distributed modality-specific control mechanisms that are activated independently and in parallel during multisensory WM.

Precision requirements do not affect the allocation of visual working memory capacity

This study examined the effects of test anxiety on working memory capacity. Studies have demonstrated that individuals with trait social anxiety disorder exhibit increased visual working memory capacity and that those with trait anxiety exhibit decreased working memory capacity. Test anxiety may also induce unique effects on individuals' working memory capacity, and we thus employed the change detection task to explore such effects. Participants were divided into high- and low-test anxiety groups. We used K score and contralateral delay activity (CDA) amplitude to measure working memory capacity, focusing on processing effectiveness and efficiency. The study results revealed that deficits in the working memory capacity of individuals in the high test anxiety group manifested in the CDA amplitude rather than in the K score. The CDA amplitude of the high test anxiety group did not increase after load 3, and that of the low test anxiety group did not increase after load 4. No difference was observed in the K scores of the two groups. The study concluded that test anxiety impairs processing efficiency but not processing effectiveness.

Visual short-term memory (VSTM) is a capacity limited resource, which is consistently estimated to hold about four visual items at a time. There is, however, debate in the literature about what constitutes an "item" and how resources are allocated within VSTM. Some research suggests information is stored in VSTM as discrete objects; however, there is also evidence suggesting that within-object features alter VSTM performance. The present study addresses the question of whether VSTM load effects reflect the number of discrete objects and/or the number of within-object features. An electrophysiological correlate of VSTM--the contralateral delay activity (CDA)--was measured while participants performed a lateralized change-detection task, in which to-be-remembered items varied in the number of features and locations. Each trial contained either a solitary simple feature (shape, color, or orientation) or one of two multifeature arrays: three features presented at three separate locations or three features bound at one location. While presenting multiple features--regardless of whether they are at discrete locations or bound within a single object--resulted in greater CDA amplitude relative to a solitary feature, there was a dissociation in the distribution of activity between the two multifeature conditions, such that the CDA at site P1/P2 was sensitive to the number of discrete objects, while activity at P7/P8 was most enhanced when multiple features were bound in one object. The findings demonstrate the inhomogeneity of the CDA and suggest this electrophysiological marker may reflect both discrete object individuation/separation and flexible feature-feature binding in VSTM.

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

This study examined the criterion and construct validity of a brief computerized cognitive test battery (CogState Schizophrenia Battery) compared to a conventional cognitive test battery recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus. The CogState and MATRICS batteries yielded comparable effect sizes in comparing patients with schizophrenia to healthy controls (Cohen's ds = −1.50 for both batteries). Moderate to large correlations were observed between CogState and MATRICS measures of processing speed, attention/vigilance, working memory, verbal and visual learning, reasoning/problem solving, and social cognition (rs = .56–.79). CogState and MATRICS composite scores also correlated strongly with scores on the University of California at San Diego (UCSD) Performance-Based Skills Assessment (UPSA; rs = .76 and .79, respectively) in patients with schizophrenia. Results of this study suggest that the CogState Schizophrenia Battery provides valid measurement of the cognitive domains nominated by the MATRICS consensus group as being important to consider in the context of pharmacological treatments for cognitive impairment in schizophrenia.

5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease.

Neurological soft signs (NSS) and cognitive impairment in chronic schizophrenia

Visual working memory temporarily represents a continuous stream of task-relevant objects as we move through our environment performing tasks. Previous work has identified candidate neural mechanisms of visual working memory storage; however, we do not know which of these mechanisms enable the storage of objects as we sequentially encounter them in our environment. Here, we measured the contralateral delay activity (CDA) and lateralized alpha oscillations as human subjects were shown a series of objects that they needed to remember. The amplitude of CDA increased following the presentation of each to-be-remembered object, reaching asymptote at about three to four objects. In contrast, the concurrently measured lateralized alpha power remained constant with each additional object. Our results suggest that the CDA indexes the storage of objects in visual working memory, whereas lateralized alpha suppression indexes the focusing of attention on the to-be-remembered objects.

Anticipatory processing increases attentional biases to disgust faces in socially anxious individuals: Evidence from the N2pc and CDA

Richard Keefe outlines the reasons for including cognitive impairment as one of the criteria for the diagnosis of schizophrenia in future diagnostic manuals (DSM-V and ICD-11). First, he convincingly argues that cognitive impairment has a major impact on the lives of almost all individuals who meet DSM-IV and ICD-10 criteria for schizophrenia. He reminds the reader that even patients who obtain normal or almost normal psychometric scores might still be cognitively impaired, compared to their potential as predicted by their parents’ intelligence and their socioeconomic context. Than he presents the advantages and stumbling blocks associated with adding cognitive impairment to future diagnostic criteria, and suggests solutions. The first advantage Keefe identifies is help in defining a point of rarity between schizophrenia and other diagnostic entities, to reduce diagnostic overlap. The second advantage is the encouragement of the clinical, academic, regulatory, and pharmaceutical communities to develop treatments targeting cognitive impairment. The main impediment he identifies is lack of assessment instruments which on the one hand are brief and simple and on the other are sufficiently detailed and comprehensive to capture developmental and current information in a valid and reliable manner. He voices the concern that non-psychologist clinicians, who are not sensitized and trained in the assessment of cognition, might be unwilling to carve out the necessary time from the already-limited patient-clinician encounter. Since, even for the most comprehensive scales, much of the variance is accounted for by only a few items, the solution he advocates is the use of brief scales which can be quickly learned and applied by clinicians. Keefe is correct to point out that cognitive impairment in schizophrenia differs from cognitive impairment in mood disorders, which is the main overlapping diagnostic group, in terms of prevalence, severity and course. However, the differences are neither large nor consistent, and it is unclear by how much the inclusion of cognitive impairment as a criterion would reduce the diagnostic overlap. Furthermore, cognitive impairment is present in almost all psychiatric diagnostic categories, some of which overlap with schizophrenia in manifestations other than cognitive impairment (e.g., severe personality disorders, drug abuse, obsessive-compulsive disorder). Moreover, there is considerable overlap between schizophrenia with severe cognitive impairment and mild mental retardation with unusual ideation, and the inclusion of cognitive impairment as a criterion for schizophrenia might only enhance the overlap. There is little doubt that the inclusion of cognitive impairment as a diagnostic criterion would increase awareness and focus on it the attention of all stakeholders. Whether this would hasten the development of treatments targeting cognitive impairment is less certain. Increased awareness might help divert budgets and other resources to education and rehabilitation programs focused on cognitive enchantment. Since education and rehabilitation activities have a incremental and cumulative effect, more budgets and resources might benefit cognition. However, the development of a pharmacological intervention targeting cognitive impairment is an endeavor waiting for a conceptual breakthrough, rather than the incremental assigning of more funds which would result from increased awareness. Cognitive impairment in schizophrenia may have more in common with cognitive impairment occurring in most other mental disorders than with schizophrenic psychosis per se 1,2. Cognitive attributes and predisposition to psychosis are partially inherited traits in schizophrenia patients. However, whether these traits co-segregate and follow common pathophysiologic pathways is far from certain. The lack of correlation between the severity of cognitive impairment and psychosis, and the fact that cognitive impairment appears before and persists after psychosis, are consistent with the idea that they are independent. Conceptually, therefore, it would take the same breakthrough to treat cognitive impairment in schizophrenia as it would take to improve cognitive functioning in any individuals, mentally ill or not, whose performance is 1.5 to 2.5 SDs below norms or expected performance. This major scientific endeavor could hardly benefit from the inclusion of cognitive impairment as a criterion for schizophrenia. I would not be too concerned with the willingness of those who treat schizophrenia (psychiatrists, nurses, social workers, and others) to learn and devote time to the assessment of cognition. The relentless efforts of researchers like Keefe and others over the past 15 years have already sensitized clinicians to the issue of cognitive impairment in schizophrenia patients. Once they are convinced of the benefit of diagnosing it and the potential of treating it, they are likely to adjust their priorities and fit cognitive assessment into the clinical encounter. In spite of the above reservations, I hope that Richard Keefe’s suggestion to include cognitive impairment as a criterion for schizophrenia is accepted. A diagnostic classification that leaves out an aspect which is so prevalent among the affected individuals and so central to their daily life would be deficient.

Purpose of the article Synaptic plasticity is known to play role in pathogenesis of schizophrenia. Cognitive impairment is one of the complications of schizophrenia, leading to poor quality of life. Matrix metalloprotease-9 (MMP-9) and neurotrophin-3 (NT-3) are markers of synaptic plasticity, widely investigated in neuropsychiatric disorders. The objective of the study was to investigate the levels of MMP-9 and NT-3 and their association with cognitive impairment in schizophrenia. Material and methods 124 schizophrenia patients and 124 controls were enrolled in the study. MMP-9 and NT-3 were estimated in both the groups using ELISA. Cognition was assessed using Addenbrooke cognitive examination-III (ACE-III) and disease severity was assessed using PANSS. Results MMP-9 (p = .003) and NT −3 (p < .001) were found to be elevated in schizophrenia cases compared to controls. There was significant association of MMP-9 with fluency (r = −0.195, p = .030), language (r = −0.196, p = .029) and total ACE-III scores (r = −0.197, p = .029). Also we observed that MMP-9 increases the risk of cognitive impairment in schizophrenia patients (OR = 2.509, CI= 1.215 − 5.18, p = .013). Conclusion MMP-9 and NT-3 are elevated in schizophrenia. MMP-9 was associated with fluency and language component of cognition and increases the risk of cognitive impairment in schizophrenia.

In Hybrid Search, observers search for any member of a set of targets held in memory. Current hybrid search models propose working memory (WM) serves to pass representations of attended items one at a time from early visual processes into long-term memory (LTM) for comparison to target representations (Drew, et al., 2015). Here, we sought to better understand the role of WM in hybrid search using an ERP component associated with WM load, the Contralateral Delay Activity (CDA). Participants (N=20) memorized setsizes (MSS) of 2 or 16 categorical targets (dogs, cats, tables, or dressers), counterbalanced across participants. Next, they passed a recognition memory test twice with >=80% accuracy. Then, for 700 trials (per MSS), participants were cued to attend to one lateralized search item and indicate if a target was present. The cued object was either a target (e.g., target cat), a non-target from the target category (e.g., non-target cat), a non-target from a similar category (e.g., dog), or a non-target from a dissimilar category (e.g., table). ERP waveforms were time-locked to search onset. Overall, CDA amplitude was larger for objects from the target category, which provides support for the idea that processing is terminated for irrelevant objects following initial object identification (Cunningham & Wolfe, 2014). For objects within the target category, CDA amplitude increased with MSS, suggesting LTM load-dependent WM involvement in hybrid search. Furthermore, N2pc amplitude increased as the non-targets became more similar to the object category, but only for MSS16. This suggests more non-targets with similar features were selected for further processing in memory at larger MSS. Together, these findings demonstrate WM plays a larger role in hybrid search than previously thought. Specifically, to identify objects within the target category, WM resources may be deployed to compare the target set held in LTM to the potential target.

Standardization, Integration, and Sharing—Leveraging Research Investments