Publications by authors named "James M Gold"

228 Publications

Reliability and Replicability of Implicit and Explicit Reinforcement Learning Paradigms in People With Psychotic Disorders.

Schizophr Bull 2021 04;47(3):731-739

Department of Psychology, University of Minnesota, Minneapolis, MN.

Background: Motivational deficits in people with psychosis may be a result of impairments in reinforcement learning (RL). Therefore, behavioral paradigms that can accurately measure these impairments and their change over time are essential.

Methods: We examined the reliability and replicability of 2 RL paradigms (1 implicit and 1 explicit, each with positive and negative reinforcement components) given at 2 time points to healthy controls (n = 75), and people with bipolar disorder (n = 62), schizoaffective disorder (n = 60), and schizophrenia (n = 68).

Results: Internal consistency was acceptable (mean α = 0.78 ± 0.15), but test-retest reliability was fair to low (mean intraclass correlation = 0.33 ± 0.25) for both implicit and explicit RL. There were no clear effects of practice for these tasks. Largely, performance on these tasks shows intact implicit and impaired explicit RL in psychosis. Symptom presentation did not relate to performance in any robust way.

Conclusions: Our findings replicate previous literature showing spared implicit RL and impaired explicit reinforcement in psychosis. This suggests typical basal ganglia dopamine release, but atypical recruitment of the orbitofrontal and dorsolateral prefrontal cortices. However, we found that these tasks have only fair to low test-retest reliability and thus may not be useful for assessing change over time in clinical trials.
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http://dx.doi.org/10.1093/schbul/sbaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084427PMC
April 2021

Using Computational Modelling to Capture Schizophrenia-Specific Reinforcement Learning Differences and Their Implications on Patient Classification.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Apr 17. Epub 2021 Apr 17.

Background: Psychiatric diagnosis and treatment have historically taken a symptom-based approach, with less attention on identifying underlying symptom-producing mechanisms. Recent efforts have illuminated the extent to which different underlying circuitry can produce phenotypically similar symptomatology (e.g. psychosis in bipolar disorder vs schizophrenia). Computational modelling makes it possible to identify and mathematically differentiate behaviorally-unobservable, specific reinforcement-learning (RL) differences in schizophrenia (SZ) patients versus other disorders, likely due to a higher reliance on prediction-error(PE)-driven learning associated with basal ganglia, and under-reliance on explicit value representations associated with OFC.

Methods: We use a well-established probabilistic-RL task to replicate those findings in individuals with schizophrenia both on (N=120) and off (N=44) anti-psychotic medications, and include a patient comparison group of bipolar patients with psychosis (N=60) and healthy controls (n=72).

Results: Using accuracy, there was a main effect of group (F(3,279)=7.87, p<0.001, such that all patients groups were less accurate than controls. Using computationally derived parameters, both medicated and unmediated individuals with SZ, but not bipolar patients, demonstrated a reduced "mixing" parameter (F(3,295)=13.91,p<0.001), indicating less dependence on learning explicit value representations, as well as greater learning decay between training and test (F(1,289)=12.81, p<0.001). Unmedicated SZ also showed greater decision noise (F(3,295)=2.67, p=0.04).

Conclusions: Both medicated and unmedicated patients show overreliance on PE-driven learning, as well as significantly higher noise and value-related memory decay, compared to the healthy controls and the bipolar patients. Additionally, the computational model parameters capturing these processes can significantly improve patient/control classification, potentially providing useful diagnosis insight.
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http://dx.doi.org/10.1016/j.bpsc.2021.03.017DOI Listing
April 2021

Combined Oxytocin and Cognitive Behavioral Social Skills Training for Social Function in People With Schizophrenia.

J Clin Psychopharmacol 2021 May-Jun 01;41(3):236-243

Veterans Affairs San Diego Healthcare System; Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, CA.

Background: A significant proportion of people with schizophrenia are characterized by impaired ability to socially engage with others. The development of effective interventions for social functioning remains a central therapeutic challenge. Cognitive-behavioral social skills training (CBSST) has been found to improve social functioning in schizophrenia, but with only medium effect sizes. Intranasal oxytocin also has prosocial effects, but also only with modest effect sizes. This study assessed whether the addition of intranasal oxytocin to CBSST can strengthen their impact on social function.

Methods: Participants (N = 62) with schizophrenia or schizoaffective disorder entered a 24-week, double-blind, placebo-controlled, randomized clinical trial with a 3-month follow-up evaluation at 2 sites: Maryland and San Diego. Participants were randomized to either intranasal oxytocin 36 IU (3 sprays) twice a day (n = 31) or intranasal placebo-oxytocin (3 sprays) twice a day (n = 31). All participants received CBSST plus a social cognition skills training module (48 total sessions).

Results: There were no significant treatment group differences in social functioning, positive symptoms, negative symptoms, defeatist beliefs, or asocial beliefs. The interpretation of treatment effects was complicated by site effects, whereby participants in San Diego began the trial with greater severity of impairments and subsequently showed greater improvements compared with participants in Maryland.

Conclusions: The results did not support the utility of add-on intranasal oxytocin to psychosocial rehabilitation interventions like CBSST for improvement in social function (ClinicalTrials.gov trial number: NCT01752712).
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http://dx.doi.org/10.1097/JCP.0000000000001397DOI Listing
March 2021

Social Cognitive Networks and Social Cognitive Performance Across Individuals With Schizophrenia Spectrum Disorders and Healthy Control Participants.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Dec 5. Epub 2020 Dec 5.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Schizophrenia spectrum disorders (SSDs) feature social cognitive deficits, although their neural basis remains unclear. Social cognitive performance may relate to neural circuit activation patterns more than to diagnosis, which would have important prognostic and therapeutic implications. The current study aimed to determine how functional connectivity within and between social cognitive networks relates to social cognitive performance across individuals with SSDs and healthy control participants.

Methods: Participants with SSDs (n = 164) and healthy control participants (n = 117) completed the Empathic Accuracy task during functional magnetic resonance imaging as well as lower-level (e.g., emotion recognition) and higher-level (e.g., theory of mind) social cognitive measures outside the scanner. Functional connectivity during the Empathic Accuracy task was analyzed using background connectivity and graph theory. Data-driven social cognitive networks were identified across participants. Regression analyses were used to examine network connectivity-performance relationships across individuals. Positive and negative within- and between-network connectivity strengths were also compared in poor versus good social cognitive performers and in SSD versus control groups.

Results: Three social cognitive networks were identified: motor resonance, affect sharing, and mentalizing. Regression and group-based analyses demonstrated reduced between-network negative connectivity, or segregation, and greater within- and between-network positive connectivity in worse social cognitive performers. There were no significant effects of diagnostic group on within- or between-network connectivity.

Conclusions: These findings suggest that the neural circuitry of social cognitive performance may exist dimensionally. Across participants, better social cognitive performance was associated with greater segregation between social cognitive networks, whereas poor versus good performers may compensate via hyperconnectivity within and between social cognitive networks.
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http://dx.doi.org/10.1016/j.bpsc.2020.11.014DOI Listing
December 2020

All or nothing belief updating in patients with schizophrenia reduces precision and flexibility of beliefs.

Brain 2021 Apr;144(3):1013-1029

Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence RI 02912-1821, USA.

Schizophrenia is characterized by abnormal perceptions and beliefs, but the computational mechanisms through which these abnormalities emerge remain unclear. One prominent hypothesis asserts that such abnormalities result from overly precise representations of prior knowledge, which in turn lead beliefs to become insensitive to feedback. In contrast, another prominent hypothesis asserts that such abnormalities result from a tendency to interpret prediction errors as indicating meaningful change, leading to the assignment of aberrant salience to noisy or misleading information. Here we examine behaviour of patients and control subjects in a behavioural paradigm capable of adjudicating between these competing hypotheses and characterizing belief updates directly on individual trials. We show that patients are more prone to completely ignoring new information and perseverating on previous responses, but when they do update, tend to do so completely. This updating strategy limits the integration of information over time, reducing both the flexibility and precision of beliefs and provides a potential explanation for how patients could simultaneously show over-sensitivity and under-sensitivity to feedback in different paradigms.
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http://dx.doi.org/10.1093/brain/awaa453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041039PMC
April 2021

Temporal-thalamic and cingulo-opercular connectivity in people with schizophrenia.

Neuroimage Clin 2021 11;29:102531. Epub 2020 Dec 11.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, School of Medicine, United States.

A growing body of research has suggested that people with schizophrenia (SZ) exhibit altered patterns of functional and anatomical brain connectivity. For example, many previous resting state functional connectivity (rsFC) studies have shown that, compared to healthy controls (HC), people with SZ demonstrate hyperconnectivity between subregions of the thalamus and sensory cortices, as well as hypoconnectivity between subregions of the thalamus and prefrontal cortex. In addition to thalamic findings, hypoconnectivity between cingulo-opercular brain regions thought to be involved in salience detection has also been commonly reported in people with SZ. However, previous studies have largely relied on seed-based analyses. Seed-based approaches require researchers to define a single a priori brain region, which is then used to create a rsFC map across the entire brain. While useful for testing specific hypotheses, these analyses are limited in that only a subset of connections across the brain are explored. In the current manuscript, we leverage novel network statistical techniques in order to detect latent functional connectivity networks with organized topology that successfully differentiate people with SZ from HCs. Importantly, these techniques do not require a priori seed selection and allow for whole brain investigation, representing a comprehensive, data-driven approach to determining differential connectivity between diagnostic groups. Across two samples, (Sample 1: 35 SZ, 44 HC; Sample 2: 65 SZ, 79 HC), we found evidence for differential rsFC within a network including temporal and thalamic regions. Connectivity in this network was greater for people with SZ compared to HCs. In the second sample, we also found evidence for hypoconnectivity within a cingulo-opercular network of brain regions in people with SZ compared to HCs. In summary, our results replicate and extend previous studies suggesting hyperconnectivity between the thalamus and sensory cortices and hypoconnectivity between cingulo-opercular regions in people with SZ using data-driven statistical and graph theoretical techniques.
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http://dx.doi.org/10.1016/j.nicl.2020.102531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750447PMC
December 2020

Predicting Attention-Shaping Response in People With Schizophrenia.

J Nerv Ment Dis 2021 03;209(3):203-207

Rutgers University, Behavioral Health Care, Piscataway Township, New Jersey.

Abstract: People with schizophrenia often experience attentional impairments that hinder learning during psychological interventions. Attention shaping is a behavioral technique that improves attentiveness in this population. Because reinforcement learning (RL) is thought to be the mechanism by which attention shaping operates, we investigated if preshaping RL performance predicted level of response to attention shaping in people with schizophrenia. Contrary to hypotheses, a steeper attentiveness growth curve was predicted by less intact pretreatment RL ability and lower baseline attentiveness, accounting for 59% of the variance. Moreover, baseline attentiveness accounted for over 13 times more variance in response to attention shaping than did RL ability. Results suggest attention shaping is most effective for lower-functioning patients, and those high in RL ability may already be close to ceiling in terms of their response to reinforcers. Attention shaping may not be a primarily RL-driven intervention, and other mechanisms of its effects should be considered.
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http://dx.doi.org/10.1097/NMD.0000000000001286DOI Listing
March 2021

Increased repulsion of working memory representations in schizophrenia.

J Abnorm Psychol 2020 Nov 3;129(8):845-857. Epub 2020 Sep 3.

Center for Mind and Brain and Department of Psychology, University of California, Davis.

Computational neuroscience models propose that working memory (WM) involves recurrent excitatory feedback loops that maintain firing over time along with lateral inhibition that prevents the spreading of activity to other feature values. In behavioral paradigms, this lateral inhibition appears to cause a repulsion of WM representations away from each other and from other strong sources of input. Recent computational models of schizophrenia have proposed that reduction in the strength of inhibition relative to strength of excitation may underlie impaired cognition, and this leads to the prediction that repulsion effects should be reduced in people with schizophrenia spectrum disorders (PSZ) relative to healthy control subjects (HCS). We tested this hypothesis in 2 experiments measuring WM repulsion effects. In Experiment 1, 45 PSZ and 32 HCS remembered the location of a single object relative to a centrally presented visual landmark and reported this location after a short delay. The reported location was repelled away from the landmark in both groups, but this repulsion effect was increased rather than decreased in PSZ relative to HCS. In Experiment 2, 41 PSZ and 34 HCS remembered 2 sequentially presented orientations and reported each orientation after a short delay. The reported orientations were biased away from each other in both groups, and this repulsion effect was again more pronounced in PSZ than in HCS. Contrary to the widespread hypothesis of reduced inhibition in schizophrenia, we provide robust evidence from 2 experiments showing that the behavioral performance of PSZ exhibited an exaggeration rather than a reduction of competitive inhibition. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606631PMC
November 2020

A Randomized Clinical Trial of Oxytocin or Galantamine in Schizophrenia: Assessing the Impact on Behavioral, Lexical, and Self-Report Indicators of Social Affiliation.

Schizophr Bull Open 2020 Jan 3;1(1):sgaa001. Epub 2020 Aug 3.

Department of Psychology, University of Maryland College Park, Biology/Psychology Building, College Park, MD.

Prior studies examining the impact of oxytocin on negative symptoms in schizophrenia have yielded mixed results. The current study explored whether oxytocin can improve more proximal indicators of social affiliation as indicated by changes in behavior, language and subjective indices of social affiliation among individuals with schizophrenia spectrum disorders during a role-play designed to elicit affiliative responses. We tested the hypothesis that daily intranasal oxytocin administered for 6 weeks would improve social affiliation as manifested by increased social skill ratings, use of positive, affiliative, and social words, and subjective responses from a previously published randomized controlled trial. Forty outpatients with schizophrenia or schizoaffective disorder were randomized to the oxytocin, galantamine, or placebo group and completed affiliative role-plays and self-report questionnaires of affect, reactions to the affiliative confederate, and willingness to interact at baseline and post-treatment. Results demonstrated that oxytocin was not effective at improving behavioral or subjective indicators of social affiliation. This study adds to a growing literature that the prosocial effects of oxytocin in schizophrenia are limited or null.
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http://dx.doi.org/10.1093/schizbullopen/sgaa001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418868PMC
January 2020

Both unmedicated and medicated individuals with schizophrenia show impairments across a wide array of cognitive and reinforcement learning tasks.

Psychol Med 2020 Aug 17:1-11. Epub 2020 Aug 17.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

Background: Schizophrenia is a disorder characterized by pervasive deficits in cognitive functioning. However, few well-powered studies have examined the degree to which cognitive performance is impaired even among individuals with schizophrenia not currently on antipsychotic medications using a wide range of cognitive and reinforcement learning measures derived from cognitive neuroscience. Such research is particularly needed in the domain of reinforcement learning, given the central role of dopamine in reinforcement learning, and the potential impact of antipsychotic medications on dopamine function.

Methods: The present study sought to fill this gap by examining healthy controls (N = 75), unmedicated (N = 48) and medicated (N = 148) individuals with schizophrenia. Participants were recruited across five sites as part of the CNTRaCS Consortium to complete tasks assessing processing speed, cognitive control, working memory, verbal learning, relational encoding and retrieval, visual integration and reinforcement learning.

Results: Individuals with schizophrenia who were not taking antipsychotic medications, as well as those taking antipsychotic medications, showed pervasive deficits across cognitive domains including reinforcement learning, processing speed, cognitive control, working memory, verbal learning and relational encoding and retrieval. Further, we found that chlorpromazine equivalency rates were significantly related to processing speed and working memory, while there were no significant relationships between anticholinergic load and performance on other tasks.

Conclusions: These findings add to a body of literature suggesting that cognitive deficits are an enduring aspect of schizophrenia, present in those off antipsychotic medications as well as those taking antipsychotic medications.
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http://dx.doi.org/10.1017/S003329172000286XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095353PMC
August 2020

Anti-inflammatory Combination Therapy for the Treatment of Schizophrenia.

J Clin Psychopharmacol 2020 Sep/Oct;40(5):444-450

From the Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.

Background: Despite adequate antipsychotic treatment, most people with schizophrenia continue to exhibit persistent positive and negative symptoms and cognitive impairments. The current study was designed to examine the efficacy and safety of adjunctive anti-inflammatory combination therapy for these illness manifestations.

Methods: Thirty-nine people with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, schizophrenia or schizoaffective disorder were entered into a 12-week double-blind, 2-arm, triple-dummy, placebo-controlled, randomized clinical trial: 19 were randomized to anti-inflammatory combination therapy and 20 were randomized to placebo. The Brief Psychiatric Rating Scale positive symptom item total score was used to assess positive symptom change, the Scale for the Assessment of Negative Symptoms total score was used to assess negative symptom change, the Calgary Depression Scale total score was used to assess depressive symptom change, and the MATRICS Consensus Cognitive Battery was used to assess neuropsychological test performance.

Results: There was a significant time effect for Brief Psychiatric Rating Scale positive symptom item score (t226 = -2.66, P = 0.008), but the treatment (t54=1.52, P = 0.13) and treatment × time (t223 = 0.47, P = 0.64) effects were not significant. There were no significant time (t144 = 0.53, P = 0.72), treatment (t58=0.48, P = 0.63), or treatment × time (t143 = -0.20, P = 0.84) effects for the Scale for the Assessment of Negative Symptoms total score; or for any of the other symptom measures. There were no significant group differences in the change in the MATRICS Consensus Cognitive Battery composite score over the course of the study (F1,26=2.20, P = 0.15).

Conclusions: The study results suggest that there is no significant benefit of combined anti-inflammatory treatment for persistent positive symptoms or negative symptoms or cognitive impairments (clinicaltrials.gov trial number: NCT01514682).
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http://dx.doi.org/10.1097/JCP.0000000000001253DOI Listing
August 2020

Antisaccade Deficits in Schizophrenia Can Be Driven by Attentional Relevance of the Stimuli.

Schizophr Bull 2021 03;47(2):363-372

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Catonsville, MD.

The antisaccade task is considered a test of cognitive control because it creates a conflict between the strong bottom-up signal produced by the cue and the top-down goal of shifting gaze to the opposite side of the display. Antisaccade deficits in schizophrenia are thought to reflect impaired top-down inhibition of the prepotent bottom-up response to the cue. However, the cue is also a highly task-relevant stimulus that must be covertly attended to determine where to shift gaze. We tested the hypothesis that difficulty in overcoming the attentional relevance of the cue, rather than its bottom-up salience, is key in producing impaired performance in people with schizophrenia (PSZ). We implemented 3 versions of the antisaccade task in which we varied the bottom-up salience of the cue while holding its attentional relevance constant. We found that difficulty in performing a given antisaccade task-relative to a prosaccade version using the same stimuli-was largely independent of the cue's bottom-up salience. The magnitude of impairment in PSZ relative to control subjects was also independent of bottom-up salience. The greatest impairment was observed in a version where the cue lacked bottom-up salience advantage over other locations. These results indicate that the antisaccade deficit in PSZ does not reflect an impairment in overcoming bottom-up salience of the cue, but PSZ are instead impaired at overcoming its attentional relevance. This deficit may still indicate an underlying inhibitory control impairment but could also reflect a hyperfocusing of attentional resources on the cue.
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http://dx.doi.org/10.1093/schbul/sbaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965078PMC
March 2021

Refining the Empirical Constraints on Computational Models of Spatial Working Memory in Schizophrenia.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 09 19;5(9):913-922. Epub 2020 May 19.

Center for Mind & Brain and Department of Psychology, University of California, Davis, Davis, California.

Background: Impairments in spatial working memory (sWM) have been well documented in schizophrenia. Here we provide a comprehensive test of a microcircuit model of WM performance in schizophrenia that predicts enhanced effects of increasing delay duration and distractors based on a hypothesized imbalance of excitatory and inhibitory processes.

Methods: Model predictions were tested in 41 people with schizophrenia (PSZ) and 32 healthy control subjects (HCS) performing an sWM task. In one condition, a single target location was followed by delays of 0, 2, 4, or 8 seconds. In a second condition, distractors were presented during the 4-second delay interval at 20°, 30°, 40°, 50°, or 90° from the original target location.

Results: PSZ showed less precise sWM representations than HCS, and the rate of memory drift over time was greater in PSZ than in HCS. Relative to HCS, the spatial recall responses of PSZ were more repelled by distractors presented close to the target location and more attracted by distractors presented far from the target location. The degree of attraction to distant distractors was correlated with the rate of memory drift in the absence of distractors.

Conclusions: Consistent with the microcircuit model, PSZ exhibited both a greater rate of drift and greater attraction to distant distractors relative to HCS. These two effects were correlated, consistent with the proposal that they arise from a single underlying mechanism. However, the repulsion effects produced by nearby distractors were not predicted by the model and thus require an updated modeling framework.
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http://dx.doi.org/10.1016/j.bpsc.2020.05.003DOI Listing
September 2020

Retention of Value Representations Across Time in People With Schizophrenia and Healthy Control Subjects.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Apr 2;6(4):420-428. Epub 2020 Jun 2.

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, School of Medicine, Baltimore, Maryland.

Background: The current study aimed to further etiological understanding of the psychological mechanisms underlying negative symptoms in people with schizophrenia. Specifically, we tested whether negative symptom severity is associated with reduced retention of reward-related information over time and thus a degraded ability to utilize such information to guide future action selection.

Methods: Forty-four patients with a diagnosis of schizophrenia or schizoaffective disorder and 28 healthy control volunteers performed a probabilistic reinforcement-learning task involving stimulus pairs in which choices resulted in reward or in loss avoidance. Following training, participants indicated their valuation of learned stimuli in a test/transfer phase. The test/transfer phase was administered immediately following training and 1 week later. Percent retention was defined as accuracy at week-long delay divided by accuracy at immediate delay.

Results: Healthy control subjects and people with schizophrenia showed similarly robust retention of reinforcement learning over a 1-week delay interval. However, in the schizophrenia group, negative symptom severity was associated with reduced retention of information regarding the value of actions across a week-long interval. This pattern was particularly notable for stimuli associated with reward compared with loss avoidance.

Conclusions: Our results show that although individuals with schizophrenia may initially learn about rewarding aspects of their environment, such learning decays at a more rapid rate in patients with severe negative symptoms. Thus, previously learned reward-related information may be more difficult to access to guide future decision making and to motivate action selection.
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http://dx.doi.org/10.1016/j.bpsc.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708393PMC
April 2021

Enhancing Psychosis Risk Prediction Through Computational Cognitive Neuroscience.

Schizophr Bull 2020 12;46(6):1346-1352

Departments of Psychology, Psychiatry, Medical Social Sciences, Institutes for Policy Research (IPR) and Innovations in Developmental Sciences (DevSci), Evanston and Chicago, IL.

Research suggests that early identification and intervention with individuals at clinical high risk (CHR) for psychosis may be able to improve the course of illness. The first generation of studies suggested that the identification of CHR through the use of specialized interviews evaluating attenuated psychosis symptoms is a promising strategy for exploring mechanisms associated with illness progression, etiology, and identifying new treatment targets. The next generation of research on psychosis risk must address two major limitations: (1) interview methods have limited specificity, as recent estimates indicate that only 15%-30% of individuals identified as CHR convert to psychosis and (2) the expertise needed to make CHR diagnosis is only accessible in a handful of academic centers. Here, we introduce a new approach to CHR assessment that has the potential to increase accessibility and positive predictive value. Recent advances in clinical and computational cognitive neuroscience have generated new behavioral measures that assay the cognitive mechanisms and neural systems that underlie the positive, negative, and disorganization symptoms that are characteristic of psychotic disorders. We hypothesize that measures tied to symptom generation will lead to enhanced sensitivity and specificity relative to interview methods and the cognitive intermediate phenotype measures that have been studied to date that are typically indicators of trait vulnerability and, therefore, have a high false positive rate for conversion to psychosis. These new behavioral measures have the potential to be implemented on the internet and at minimal expense, thereby increasing accessibility of assessments.
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http://dx.doi.org/10.1093/schbul/sbaa091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707066PMC
December 2020

Modeling perception and behavior in individuals at clinical high risk for psychosis: Support for the predictive processing framework.

Schizophr Res 2020 12 24;226:167-175. Epub 2020 Jun 24.

Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, United States of America. Electronic address:

Early intervention in psychotic spectrum disorders is critical for maximizing key clinical outcomes. While there is some evidence for the utility of intervention during the prodromal phase of the illness, efficacy of interventions is difficult to assess without appropriate risk stratification. This will require biomarkers that robustly help to identify risk level and are also relatively easy to obtain. Recent work highlights the utility of computer-based behavioral tasks for understanding the pathophysiology of psychotic symptoms. Computational modeling of performance on such tasks may be particularly useful because they explicitly and formally link performance and symptom expression. Several recent studies have successfully applied principles of Bayesian inference to understanding the computational underpinnings of hallucinations. Within this framework, hallucinations are seen as arising from an over-weighting of prior beliefs relative to sensory evidence. This view is supported by recently-published data from two tasks: the Conditioned Hallucinations (CH) task, which determines the degree to which participants use expectations in detecting a target tone; and a Sine-Vocoded Speech (SVS) task, in which participants can use prior exposure to speech samples to inform their understanding of degraded speech stimuli. We administered both of these tasks to two samples of participants at clinical high risk for psychosis (CHR; N = 19) and healthy controls (HC; N = 17). CHR participants reported both more conditioned hallucinations and more pre-training SVS detection. In addition, relationships were found between participants' performance on both tasks. On computational modeling of behavior on the CH task, CHR participants demonstrate significantly poorer recognition of task volatility as well as a trend toward higher weighting of priors. A relationship was found between this latter effect and performance on both tasks. Taken together, these results support the assertion that these two tasks may be driven by similar latent factors in perceptual inference, and highlight the potential utility of computationally-based tasks in identifying risk.
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http://dx.doi.org/10.1016/j.schres.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774587PMC
December 2020

Heterogeneity of emotional experience in schizophrenia: Trait affect profiles predict clinical presentation and functional outcome.

J Abnorm Psychol 2020 Oct 25;129(7):760-767. Epub 2020 Jun 25.

Department of Psychology.

The current study examined whether subgroups of individuals with schizophrenia could be identified based on their profiles of trait positive and negative emotional experience, and whether those subgroups differed in their symptom presentation and functional outcome. Participants included 192 outpatients diagnosed with schizophrenia or schizoaffective disorder (SZ) and 149 demographically matched healthy controls who completed the trait version of the Positive and Negative Affect Scale, as well as symptom and functional outcome assessments. Cluster analysis determined whether patients could be separated into meaningful subgroups based on their trait emotional experience profiles, and discriminant function analysis determined whether these groups were valid and adequately separated. Forty-two percent of the patients fell into an affectively normal cluster, whereas 28% and 30% fell into low positive affect (PA) and high negative affect (NA) clusters, respectively. These subgroups differed significantly on positive symptoms, negative symptoms, diagnoses, and functional outcomes. Trait emotional experience is heterogeneous in outpatients with psychotic disorders, and meaningful subgroups of patients with different profiles of PA and NA can be identified. These subgroups show meaningful differences in clinical presentation, which may necessitate different treatment approaches. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541640PMC
October 2020

Cortical hyperactivation at low working memory load: A primary processing abnormality in people with schizophrenia?

Neuroimage Clin 2020 25;26:102270. Epub 2020 Apr 25.

University of Maryland School of Medicine, Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228, United States.

A frequent finding when studying substrates of working memory (WM) deficits in people with schizophrenia (PSZ) is task-induced hyperactivation relative to healthy control subjects (HCS) when WM load is low. Hyperactivation accompanying similar performance is commonly attributed to cognitive deficits rendering relatively easy operations more resource-consuming. To test if hyperactivation at low load really is secondary to cognitive impairment in PSZ, we re-analyzed functional MRI data showing left posterior parietal cortex (PPC) hyperactivation in PSZ when holding a single color-item in WM. In subgroups matched for the number of items successfully stored in WM (K) by excluding the highest-performing HCS and lowest-performing PSZ, performance was almost identical across all set sizes (1-7). While BOLD activation at the larger set sizes did not differ between groups, PSZ still robustly hyperactivated left PPC when a single item had to be maintained. The same pattern was observed in subgroups matched for model-based estimates of WM capacity or attentional lapse rate. Given that in the K-matched subsamples PSZ performed as well as HCS even in the most challenging load conditions and that no BOLD signal difference was seen at high loads, it is implausible that PSZ over-recruited WM-related neural structures because they were more challenged by maintaining a single item in WM. Instead, the findings are consistent with a primary schizophrenia-related processing abnormality as proposed by the hyperfocusing hypothesis, which suggests that an abnormally narrow but intense focusing of processing resources is central to many aspects of impaired cognition in PSZ.
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http://dx.doi.org/10.1016/j.nicl.2020.102270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210598PMC
February 2021

Increased influence of a previously attended feature in people with schizophrenia.

J Abnorm Psychol 2020 Apr;129(3):305-311

Center for Mind and Brain and Department of Psychology, University of California, Davis.

Everyday functioning requires the appropriate allocation of visual attention, which is achieved through multiple mechanisms of attentional guidance. Traditional theories have focused on top-down and bottom-up factors, but implicit learning from recent experience ("selection history") also has a substantial impact on attentional allocation. The present experiment examined the influence of intertrial priming on attentional guidance in people with schizophrenia and matched control subjects. Participants searched for a color pop-out target, which switched randomly between a red target among blue distractors and a blue target among red distractors. We found that performance on the current trial was more influenced by the previous-trial target color in people with schizophrenia than in control subjects. Moreover, this implicit priming effect was greater in individuals with lower working memory capacity (as measured in a separate task). These results suggest that intertrial priming has an exaggerated impact on attentional guidance in people with schizophrenia and that this is associated with other aspects of impaired cognition. Overall, these results are consistent with the hyperfocusing hypothesis, which proposes that a single underlying attentional abnormality may explain a range of atypical effects across perception, attention, and cognition in schizophrenia. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112152PMC
April 2020

Assessing the information content of ERP signals in schizophrenia using multivariate decoding methods.

Neuroimage Clin 2020 14;25:102179. Epub 2020 Jan 14.

Center for Mind & Brain and Department of Psychology, University of California - Davis, USA.

Multivariate pattern classification (decoding) methods are commonly employed to study mechanisms of neurocognitive processing in typical individuals, where they can be used to quantify the information that is present in single-participant neural signals. These decoding methods are also potentially valuable in determining how the representation of information differs between psychiatric and non-psychiatric populations. Here, we examined ERPs from people with schizophrenia (PSZ) and healthy control subjects (HCS) in a working memory task that involved remembering 1, 3, or 5 items from one side of the display and ignoring the other side. We used the spatial pattern of ERPs to decode which side of the display was being held in working memory. One might expect that decoding accuracy would be inevitably lower in PSZ as a result of increased noise (i.e., greater trial-to-trial variability). However, we found that decoding accuracy was greater in PSZ than in HCS at memory load 1, consistent with previous research in which memory-related ERP signals were larger in PSZ than in HCS at memory load 1. We also observed that decoding accuracy was strongly related to the ratio of the memory-related ERP activity and the noise level. In addition, we found similar noise levels in PSZ and HCS, counter to the expectation that PSZ would exhibit greater trial-to-trial variability. Together, these results demonstrate that multivariate decoding methods can be validly applied at the individual-participant level to understand the nature of impaired cognitive function in a psychiatric population.
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http://dx.doi.org/10.1016/j.nicl.2020.102179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965722PMC
January 2021

Differential Effects of Psychotic Illness on Directed and Random Exploration.

Comput Psychiatr 2020 1;4:18-39. Epub 2020 Aug 1.

Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Schizophrenia is associated with a number of deficits in decision-making, but the scope, nature, and cause of these deficits are not completely understood. Here we focus on a particular type of decision, known as the dilemma, in which people must choose between exploiting options that yield relatively known rewards and exploring more ambiguous options of uncertain reward probability or magnitude. Previous work has shown that healthy people use two distinct strategies to decide when to explore: directed exploration, which involves choosing options that would reduce uncertainty about the reward values (information seeking), and random exploration (exploring by chance), which describes behavioral variability that is not goal directed. We administered a recently developed gambling task designed to quantify both directed and random exploration to 108 patients with schizophrenia (PSZ) and 33 healthy volunteers (HVs). We found that PSZ patients show reduced directed exploration relative to HVs, but no difference in random exploration. Moreover, patients' directed exploration behavior clusters into two qualitatively different behavioral phenotypes. In the first phenotype, which accounts for the majority of the patients (79%) and is consistent with previously reported behavior, directed exploration is only marginally (but significantly) reduced, suggesting that these patients can use directed exploration, but at a slightly lower level than community controls. In contrast, the second phenotype, comprising 21% of patients, exhibit a form of "extreme ambiguity aversion," in which they almost never choose more informative options, even when they are clearly of higher value. Moreover, in PSZ, deficits in directed exploration were related to measures of intellectual function, whereas random exploration was related to positive symptoms. Taken together, our results suggest that schizophrenia has differential effects on directed and random exploration and that investigating the explore/exploit dilemma in psychosis patients may reveal subgroups of patients with qualitatively different patterns of exploration.
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http://dx.doi.org/10.1162/cpsy_a_00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990386PMC
August 2020

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

Schizophr Res Cogn 2020 Mar 31;19:100161. Epub 2019 Oct 31.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States of America.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests.
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http://dx.doi.org/10.1016/j.scog.2019.100161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889798PMC
March 2020

Dynamic reorganization of the frontal parietal network during cognitive control and episodic memory.

Cogn Affect Behav Neurosci 2020 02;20(1):76-90

Imaging Research Center, University of California at Davis, Sacramento, CA, USA.

Higher cognitive functioning is supported by adaptive reconfiguration of large-scale functional brain networks. Cognitive control (CC), which plays a vital role in flexibly guiding cognition and behavior in accordance with our goals, supports a range of executive functions via distributed brain networks. These networks process information dynamically and can be represented as functional connectivity changes between network elements. Using graph theory, we explored context-dependent network reorganization in 56 healthy adults performing fMRI tasks from two cognitive domains that varied in CC and episodic-memory demands. We examined whole-brain modular structure during the DPX task, which engages proactive CC in the frontal-parietal cognitive-control network (FPN), and the RiSE task, which manipulates CC demands at encoding and retrieval during episodic-memory processing, and engages FPN, the medial-temporal lobe and other memory-related networks in a context dependent manner. Analyses revealed different levels of network integration and segregation. Modularity analyses revealed greater brain-wide integration across tasks in high CC conditions compared to low CC conditions. Greater network reorganization occurred in the RiSE memory task, which is thought to require coordination across multiple brain networks, than in the DPX cognitive-control task. Finally, FPN, ventral attention, and visual systems showed within network connectivity effects of cognitive control; however, these cognitive systems displayed varying levels of network reorganization. These findings provide insight into how brain networks reorganize to support differing task contexts, suggesting that the FPN flexibly segregates during focused proactive control and integrates to support control in other domains such as episodic memory.
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http://dx.doi.org/10.3758/s13415-019-00753-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018593PMC
February 2020

The Critical Need for Help-Seeking Controls in Clinical High-Risk Research.

Clin Psychol Sci 2019 Nov 23;7(6):1171-1189. Epub 2019 Sep 23.

Department of Psychology, University of Maryland, Baltimore County.

Despite rapidly growing knowledge of the clinical high-risk (CHR) state for psychosis, the vast majority of case-control studies have relied on healthy volunteers as a reference point for drawing inferences about the CHR construct. Researchers have long recognized that results generated from this design are limited by significant interpretive concerns, yet little attention has been given to how these concerns affect the growing field of CHR research. We argue that overreliance on healthy controls in CHR research threatens the validity of inferences concerning group differences, hinders advances in understanding the development of psychosis, and limits clinical progress. We suggest that the combined use of healthy and help-seeking (i.e., psychiatric) controls is a necessary step for the next generation of CHR research. We then evaluate methods for help-seeking control studies, identify the available CHR studies that have used such designs, discuss select findings in this literature, and offer recommendations for research.
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http://dx.doi.org/10.1177/2167702619855660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891463PMC
November 2019

The latent structure of depressive symptoms across clinical high risk and chronic phases of psychotic illness.

Transl Psychiatry 2019 09 16;9(1):229. Epub 2019 Sep 16.

Northwestern University Department of Psychology, Department of Psychiatry, Department of Medical Social Sciences, Institute for Policy Research, and Institute for Innovations in Developmental Sciences, Evanston, IL, 60208, USA.

Depressive symptoms are highly prevalent in psychotic populations and result in significant functional impairment. Limited knowledge of whether depressive symptoms are invariant across stages of illness curtails our ability to understand how these relate to illness progression. Clarifying the latent structure of depressive symptoms across stages of illness progression would aid etiological conceptualizations and preventive models. In the present study, one-factor (including all items) and two-factor (depression/hopelessness and guilt/self-depreciation) solutions were specified through confirmatory factor analysis (CFA). Measurement invariance analyses were undertaken across schizophrenia (SCZ; n = 312) and clinical high-risk (CHR; n = 175) groups to estimate whether the same construct is being measured across groups. Clinical correlates of the factors were examined. Results indicated that CHR individuals had a greater proportion of mood disorder diagnoses. Metric invariance held for the one-factor solution, and scalar invariance held for the two-factor solution. Notably, negative symptoms did not correlate with depressive symptoms in the SCZ group, though strong correlations were observed in CHR individuals. Positive symptoms were comparably associated with depressive symptoms in both groups. Results suggest depressive symptoms are more prevalent in CHR individuals. Targeting these symptoms may aid future efforts to identify risk of conversion. Further, some depressive symptoms may be systematically more endorsed in CHR individuals. Separating into depression/hopelessness and guilt/self-depreciation scores may aid comparability across stages of illness progression, though this issue deserves careful attention and future study.
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http://dx.doi.org/10.1038/s41398-019-0563-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746855PMC
September 2019

Detecting motor slowing in clinical high risk for psychosis in a computerized finger tapping model.

Eur Arch Psychiatry Clin Neurosci 2020 Apr 20;270(3):393-397. Epub 2019 Aug 20.

Department of Psychology, Northwestern University, 2029 Sheridan Rd, Evanston, IL, 60208, USA.

Finger tapping is sensitive to motor slowing and emerging symptoms in individuals at clinical high risk for psychosis (CHR). A sensitive, computerized finger tapping task would be beneficial in early psychosis screening batteries. The study included 41 CHR and 32 healthy volunteers, who completed a computerized finger tapping task and clinical interviews. This computerized finger tapping task was sensitive to slowing in the CHR group compared to healthy volunteers, and as expected negative but not positive symptoms related to motor slowing. Computerized finger tapping tasks may be an easily dispersible tool for early symptom detection battery relevant to emerging negative symptoms.
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http://dx.doi.org/10.1007/s00406-019-01059-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031007PMC
April 2020

The Hyperfocusing Hypothesis: A New Account of Cognitive Dysfunction in Schizophrenia.

Schizophr Bull 2019 09;45(5):991-1000

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD.

Impairments in basic cognitive processes such as attention and working memory are commonly observed in people with schizophrenia and are predictive of long-term outcome. In this review, we describe a new theory-the hyperfocusing hypothesis-which provides a unified account of many aspects of impaired cognition in schizophrenia. This hypothesis proposes that schizophrenia involves an abnormally narrow but intense focusing of processing resources. This hyperfocusing impairs the ability of people with schizophrenia to distribute attention among multiple locations, decreases the number of representations that can simultaneously be maintained in working memory, and causes attention to be abnormally captured by irrelevant inputs that share features with active representations. Evidence supporting the hyperfocusing hypothesis comes from a variety of laboratory tasks and from both behavioral and electrophysiological measures of processing. In many of these tasks, people with schizophrenia exhibit supranormal effects of task manipulations, which cannot be explained by a generalized cognitive deficit or by nonspecific factors such as reduced motivation or poor task comprehension. In addition, the degree of hyperfocusing in these tasks is often correlated with the degree of impairment in measures of broad cognitive function, which are known to be related to long-term outcome. Thus, the mechanisms underlying hyperfocusing may be a good target for new treatments targeting cognitive deficits in schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbz063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737469PMC
September 2019

Is Attentional Filtering Impaired in Schizophrenia?

Schizophr Bull 2019 09;45(5):1001-1011

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD.

Recent evidence suggests that schizophrenia involves hyperfocusing, an unusually narrow but intense focusing of processing resources. This appears to contradict the classic idea that schizophrenia involves an impairment in the ability to focus on relevant information and filter irrelevant information. Here, we review one set of studies suggesting that attentional filtering is impaired in people with schizophrenia and another set of studies suggesting that attentional filtering is unimpaired or even enhanced in these individuals. Considerable evidence supports both conclusions, and we propose 3 potential ways of reconciling the conflicting evidence. First, impaired attentional filtering may occur primarily during periods of active psychosis, with hyperfocusing being a part of the broad pattern of cognitive impairment that persists independent of the level of positive symptoms. Second, schizophrenia may involve hyperfocusing in the visual modality and impaired attentional filtering in the auditory modality. Third, attention may be directed toward irrelevant inputs as a result of impaired executive control, and hyperfocusing on those inputs may be functionally equivalent to a failure of attentional filtering. Given the widespread clinical observations and first-person reports of impaired attentional filtering in schizophrenia, it will be important for future research to test these possibilities.
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http://dx.doi.org/10.1093/schbul/sbz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737485PMC
September 2019

Failures in top-down control in schizophrenia revealed by patterns of saccadic eye movements.

J Abnorm Psychol 2019 Jul 13;128(5):415-422. Epub 2019 Jun 13.

Maryland Psychiatric Research Center.

Successful execution of many behavioral goals relies on well-organized patterns of saccadic eye movements, and in complex tasks, these patterns can reveal the component processes underlying task performance. The present study examined the pattern of eye movements in a visual search task to provide evidence of attentional control impairments in people with schizophrenia (PSZ). We tested PSZ( = 38) and nonpsychiatric control subjects (NCS, = 35) in a task that was designed to stress top-down control by pitting task goals against bottom-up salience. Participants searched for either a low-contrast (nonsalient) or a high-contrast (salient) target among low- and high-contrast distractors. By examining fixations of the low- and high-contrast items, we evaluated the ability of PSZ and NCS to focus on low-salience targets and filter out high-salience distractors (or vice versa). When participants searched for a salient target, both groups successfully focused on relevant, high-contrast stimuli and filtered out target-mismatched, low-contrast stimuli. However, when searching for a nonsalient target, PSZ were impaired at efficiently suppressing high-contrast (salient) distractors. Specifically, PSZ were more likely than NCS to fixate and revisit salient distractors, and they dwelled on these items longer than did NCS. The results provide direct evidence that PSZ are impaired in their ability to utilize top-down goals to overcome the prepotent tendency to focus attention on irrelevant but highly salient information. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640840PMC
July 2019