A computational neuroimaging study of reinforcement learning and goal-directed exploration in schizophrenia spectrum disorders.

BACKGROUND: Prior evidence indicates that negative symptom severity and cognitive deficits, in people with schizophrenia (PSZ), relate to measures of reward-seeking and loss-avoidance behavior (implicating the ventral striatum/VS), as well as uncertainty-driven exploration (reliant on rostrolateral prefrontal cortex/rlPFC). While neural correlates of reward-seeking and loss-avoidance have been examined in PSZ, neural correlates of uncertainty-driven exploration have not. Understanding neural correlates of uncertainty-driven exploration is an important next step that could reveal insights to how this mechanism of cognitive and negative symptoms manifest at a neural level. METHODS: We acquired fMRI data from 29 PSZ and 36 controls performing the Temporal Utility Integration decision-making task. Computational analyses estimated parameters corresponding to learning rates for both positive and negative reward prediction errors (RPEs) and the degree to which participates relied on representations of relative uncertainty. Trial-wise estimates of expected value, certainty, and RPEs were generated to model fMRI data. RESULTS: Behaviorally, PSZ demonstrated reduced reward-seeking behavior compared to controls, and negative symptoms were positively correlated with loss-avoidance behavior. This finding of a bias toward loss avoidance learning in PSZ is consistent with previous work. Surprisingly, neither behavioral measures of exploration nor neural correlates of uncertainty in the rlPFC differed significantly between groups. However, we showed that trial-wise estimates of relative uncertainty in the rlPFC distinguished participants who engaged in exploratory behavior from those who did not. rlPFC activation was positively associated with intellectual function. CONCLUSIONS: These results further elucidate the nature of reinforcement learning and decision-making in PSZ and healthy volunteers.

Motivational deficits in schizophrenia relate to abnormalities in cortical learning rate signals.

Individuals from across the psychosis spectrum display impairments in reinforcement learning. In some individuals, these deficits may result from aberrations in reward prediction error (RPE) signaling, conveyed by dopaminergic projections to the ventral striatum (VS). However, there is mounting evidence that VS RPE signals are relatively intact in medicated people with schizophrenia (PSZ). We hypothesized that, in PSZ, reinforcement learning deficits often are not related to RPE signaling per se but rather their impact on learning and behavior (i.e., learning rate modulation), due to dysfunction in anterior cingulate and dorsomedial prefrontal cortex (dmPFC). Twenty-six PSZ and 23 healthy volunteers completed a probabilistic reinforcement learning paradigm with occasional, sudden, shifts in contingencies. Using computational modeling, we found evidence of an impairment in trial-wise learning rate modulation (α) in PSZ before and after a reinforcement contingency shift, expressed most in PSZ with more severe motivational deficits. In a subsample of 22 PSZ and 22 healthy volunteers, we found little evidence for between-group differences in VS RPE and dmPFC learning rate signals, as measured with fMRI. However, a follow-up psychophysiological interaction analysis revealed decreased dmPFC-VS connectivity concurrent with learning rate modulation, most prominently in individuals with the most severe motivational deficits. These findings point to an impairment in learning rate modulation in PSZ, leading to a reduced ability to adjust task behavior in response to unexpected outcomes. At the level of the brain, learning rate modulation deficits may be associated with decreased involvement of the dmPFC within a greater RL network.

Latent structure of cognition in schizophrenia: a confirmatory factor analysis of the MATRICS Consensus Cognitive Battery (MCCB).

BACKGROUND: The number of separable cognitive dimensions in schizophrenia has been debated. Guided by the extant factor analytic literature, the NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative selected seven cognitive domains relevant to treatment studies in schizophrenia: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. These domains are assessed in the MATRICS Consensus Cognitive Battery (MCCB). The aim of this study was to conduct a confirmatory factor analysis (CFA) of the beta battery of the MCCB to compare the fit of the MATRICS consensus seven-domain model to other models in the current literature on cognition in schizophrenia. METHOD: Using data from 281 schizophrenia outpatients, we compared the seven correlated factors model with alternative models. Specifically, we compared the 7-factor model to (a) a single-factor model, (b) a three correlated factors model including speed of processing, working memory, and general cognition, and (c) a hierarchical model in which seven first-order factors loaded onto a second-order general cognitive factor. RESULTS: Multiple fit indices indicated the seven correlated factors model was the best fit for the data and provided significant improvement in model fit beyond the comparison models. CONCLUSIONS: These results support the assessment of these seven cognitive dimensions in clinical trials of interventions to improve cognition in schizophrenia. Because these cognitive factors are separable to some degree, it is plausible that specific interventions may have differential effects on the domains.

Cognition in schizophrenia and schizo-affective disorder: impairments that are more similar than different.

BACKGROUND: Cognition is increasingly being recognized as an important aspect of psychotic disorders and a key contributor to functional outcome. In the past, comparative studies have been performed in schizophrenia and schizo-affective disorder with regard to cognitive performance, but the results have been mixed and the cognitive measures used have not always assessed the cognitive deficits found to be specific to psychosis. A set of optimized cognitive paradigms designed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium to assess deficits specific to schizophrenia was used to measure cognition in a large group of individuals with schizophrenia and schizo-affective disorder. METHOD: A total of 519 participants (188 with schizophrenia, 63 with schizo-affective disorder and 268 controls) were administered three cognitive paradigms assessing the domains of goal maintenance in working memory, relational encoding and retrieval in episodic memory and visual integration. RESULTS: Across the three domains, the results showed no major quantitative differences between patient groups, with both groups uniformly performing worse than healthy subjects. CONCLUSIONS: The findings of this study suggests that, with regard to deficits in cognition, considered a major aspect of psychotic disorder, schizophrenia and schizo-affective disorder do not demonstrate major significant distinctions. These results have important implications for our understanding of the nosological structure of major psychopathology, providing evidence consistent with the hypothesis that there is no natural distinction between cognitive functioning in schizophrenia and schizo-affective disorder.

Deriving behavioural receptive fields for visually completed contours.

The visual system is constantly faced with the problem of identifying partially occluded objects from incomplete images cast on the retinae. Phenomenologically, the visual system seems to fill in missing information by interpolating illusory and occluded contours at points of occlusion, so that we perceive complete objects. Previous behavioural [1] [2] [3] [4] [5] [6] [7] and physiological [8] [9] [10] [11] [12] studies suggest that the visual system treats illusory and occluded contours like luminance-defined contours in many respects. None of these studies has, however, directly shown that illusory and occluded contours are actually used to perform perceptual tasks. Here, we use a response-classification technique [13] [14] [15] [16] [17] [18] [19] [20] to answer this question directly. This technique provides pictorial representations - 'classification images' - that show which parts of a stimulus observers use to make perceptual decisions, effectively deriving behavioural receptive fields. Here we show that illusory and occluded contours appear in observers' classification images, providing the first direct evidence that observers use perceptually interpolated contours to recognize objects. These results offer a compelling demonstration of how visual processing acts on completed representations, and illustrate a powerful new technique for constraining models of visual completion.

Cognitive deficits and the neurobiology of schizophrenia.

Recent research in schizophrenia has demonstrated widespread abnormalities in patients' brain structure, cognitive function, and physiology. These abnormalities are most probably developmental in origin and involve a network of connected frontal-temporal-limbic structures.

Configurable NOR gate arrays from Belousov-Zhabotinsky micro-droplets.

We investigate the Belousov-Zhabotinsky (BZ) reaction in an attempt to establish a basis for computation using chemical oscillators coupled via inhibition. The system consists of BZ droplets suspended in oil. Interdrop coupling is governed by the non-polar communicator of inhibition, Br2. We consider a linear arrangement of three droplets to be a NOR gate, where the center droplet is the output and the other two are inputs. Oxidation spikes in the inputs, which we define to be TRUE, cause a delay in the next spike of the output, which we read to be FALSE. Conversely, when the inputs do not spike (FALSE) there is no delay in the output (TRUE), thus producing the behavior of a NOR gate. We are able to reliably produce NOR gates with this behavior in microfluidic experiment.

Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia.

BACKGROUND: Impaired Wisconsin Card Sorting Test (WCST) performance has been one critical piece of evidence suggesting frontal lobe dysfunction in schizophrenia. However, the specific cognitive processes underlying impaired performance have not been identified. Impaired WCST performance in schizophrenia might in part reflect a fundamental working memory deficit. METHODS: We examined the performance of 30 normal subjects and 36 patients with schizophrenia on a neuropsychological battery including a novel measure of working memory-letter-number (LN) span. RESULTS: Patients with schizophrenia were impaired on LN span performance, which was also highly correlated with WCST performance (r = 0.74). Between-group WCST differences were eliminated when we covaried LN span. Regression analyses suggested that LN span performance predicted the WCST category achieved score, whereas measures of set shifting, verbal fluency, and attention were predictive of perseveration. CONCLUSION: Working memory may be a critical determinant of one aspect of WCST performance in schizophrenia.

Schizophrenia and temporal lobe epilepsy. A neuropsychological analysis.

BACKGROUND: Recent neuroimaging studies have reported structural abnormalities of mesial temporal lobe structures in schizophrenia. This study compared the neuropsychological performance of patients with schizophrenia with patients with either left or right temporal lobe epilepsy to determine if lateralized, developmental temporal lobe dysfunction provides a model of the cognitive impairments observed in schizophrenia. METHODS: A total 66 patients with schizophrenia and 101 patients with medically intractable focal temporal lobe epilepsy (48 left temporal, 53 right temporal) received a comprehensive neuropsychological battery. RESULTS: The three groups did not differ on age, years of education, or Full-Scale IQ. However, clear differences were noted in performance profiles. Patients with schizophrenia scored significantly higher than either epilepsy group on a measure of word reading thought to reflect premorbid competence. Patients with schizophrenia demonstrated greater attentional impairment and motor slowing than either epilepsy group. The patients with schizophrenia had superior semantic knowledge and verbal memory compared with the left temporal lobe group. On the Wisconsin Card Sorting Test the patients with schizophrenia obtained significantly fewer categories than either temporal lobe group, but were not significantly more perseverative. CONCLUSIONS: Data suggest lateralized temporal lobe dysfunction does not provide an adequate model of the cognitive impairments seen in schizophrenia. The disorders seem to follow different developmental paths: In early-onset epilepsy, the acquisition of cognitive skills and academic knowledge is compromised, while in schizophrenia cognitive functions are lost. Extratemporal pathologic features, most likely of the frontal lobe, are implicated in the cognitive dysfunction of schizophrenia.

Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect.

BACKGROUND: Although intellectual and neurocognitive deficits accompany schizophrenia, there are inconsistencies in the literature concerning issues of intellectual decline, premorbid deficits, a modal deficit pattern, and preserved abilities. METHODS: A battery of neuropsychological tests was administered once to 117 consecutively admitted patients with chronic schizophrenia and a group of 27 healthy control subjects to examine patterns of premorbid and current intellect (measured by means of reading scores and IQ, respectively) and the attendant cognitive profiles in schizophrenia using classification methods based on clinically derived (IQ levels) and atheoretical (cluster) techniques. RESULTS: Sixty patients (51%) with schizophrenia who displayed a general intellectual decline of 10 points or greater from estimated premorbid levels also exhibited deficits of executive function, memory, and attention. Twenty-eight patients (23%) with consistently low estimated premorbid intellect and current intellectual levels who displayed no evidence of IQ decline exhibited language and visual processing deficits in addition to deficits present in the intellectually declining group. The remaining 29 patients (25%) who displayed average estimated premorbid intellectual levels did not show IQ decline and exhibited a cognitive profile similar to normal, with the exception of executive function and attention impairment. Atheoretical analyses support the findings from clinically derived subgroups. CONCLUSIONS: These results suggest that IQ decline, although modal in schizophrenia, is not universally characteristic and that executive function and attention deficits may be core features of schizophrenia, independent of IQ variations.

Decisional capacity for informed consent in schizophrenia research.

BACKGROUND: The adequacy of subjects' informed consent to research is the focus of an important public and professional debate. The potential impairment of decisional capacity in persons with schizophrenia is central to the discussions. This study ascertains the decisional capacity for informed consent in schizophrenic research subjects, to determine if reduced capacity relates to specific aspects of psychopathologic features and to test the hypothesis that reduced capacity can be remediated with an educational informed consent process. METHODS: Decisional capacity was assessed for 30 research subjects with schizophrenia and 24 nonill (normal) comparison subjects. Measures of psychopathologic features and cognition were obtained for the subjects with schizophrenia. Subjects who performed poorly on the decisional capacity measure received an educational intervention designed to improve their ability to provide informed consent and were then retested. RESULTS: The patient group did not perform as well as the controls on initial decisional capacity assessment. Poor performance was modestly related to the extent of symptoms but robustly related to cognitive impairments. Following the educational intervention, the performance of subjects with schizophrenia was equal to that of the nonill comparison group. CONCLUSIONS: Many persons with schizophrenia may be challenged by the cognitive demands of an informed consent process for research participation. In many cases, their reduced capacity can be compensated by a more intensive educational intervention as part of the informed consent process.

Neuropsychological assessment of monozygotic twins discordant for schizophrenia.

A comparison of monozygotic twins discordant for schizophrenia controls for genetic variance and reduces variance due to environmental circumstances, thus serving to highlight differences due to phenotypic-related variables. In this study, we assessed 16 such twin pairs on a wide range of neuropsychological tests. The affected twins tended to perform worse than their unaffected counterparts on most of the tests. Deficits were especially severe on tests of vigilance, memory, and concept formation, suggesting that dysfunction is greatest in the frontotemporal cortex. While manifest symptoms were not highly associated with neuropsychological scores, global level of functioning was. To address the issue of genetic liability, we also compared the sample of discordant unaffected twins with a sample of seven pairs of normal monozygotic twins. No significant differences between the groups were found for any neuropsychological test. In fact, the results suggest that neuropsychological dysfunction is a consistent feature of schizophrenia and that it is related primarily to the clinical disease process and not to genetic or nonspecific environmental factors.

Visuospatial working memory in patients with schizophrenia.

Recent investigations have documented abnormalities in working memory related processes in schizophrenics on tasks assessing the central executive component of this cognitive model. This preliminary study investigated the function of another component of the working memory system, the visuospatial scratch pad in schizophrenia. The "scratch pad's" passive visual store--responsible for the temporary retention of visual material--was assessed via a computerized spatial delayed response task, whereas its active spatial rehearsal subsystem--specialized for retaining the temporal properties--was explored through visual block span. To assess elemental visual spatial abilities we used the Judgment of Line Orientation test. Thirty-two schizophrenics and 27 controls were tested. Although we discovered the basic perceptual abilities of patients to be intact, we determined that whenever memory was necessitated on spatial tasks, patients demonstrated marked deficits. This pattern of cognitive dysfunction is consistent with impairments in a neural network involving prefrontal and/or posterior brain regions in schizophrenia.

Effects of contextual processing on visual conditional associative learning in schizophrenia.

BACKGROUND: We adapted visual conditional associative learning paradigms to assess the contextual processing deficit model of schizophrenic cognitive impairment proposed by J.D. Cohen and D. Servan-Schreiber in 1992. In this task subjects learn the associations between four sets of stimuli through the use of feedback. We administered two experimental conditional associative learning conditions: in one, the eight stimuli used to make four pairs were all different; in the other, the pairs were made from different combinations of four identical stimuli, requiring the use of contextual information to mediate correct performance. Two additional associative learning tasks were administered where subjects generated the stimulus pairings or observed the experimenter form the pairs, eliminating the need to learn from feedback. METHODS: We tested 37 patients with schizophrenia and 20 healthy control subjects in each conditional associative learning task condition. RESULTS: Patients demonstrated significant impairments on all four conditional associative learning tasks. The demand to process contextual information did not differentially impact patient performance. Patients were better able to learn associations if they generated or observed the pairings rather than utilized feedback to guide learning. CONCLUSIONS: Patients with schizophrenia demonstrate pronounced deficits in the ability to utilize feedback to guide learning. We found no evidence of an additional deficit in processing of contextual information.

Tardive dyskinesia: neuropsychological, computerized tomographic, and psychiatric symptom findings.

Prior studies have suggested that schizophrenic patients with tardive dyskinesia (TD) have an unusual incidence of cognitive impairment, structural brain abnormalities, and negative symptoms. Twenty-seven schizophrenic patients with TD and an equal number of age-, gender-, and education-matched schizophrenic controls were studied. Each patient received neuropsychological testing, psychiatric symptom ratings, and most had cerebral computed tomography (CT) scans. Patients with TD significantly differed from controls on only 1 of 23, cognitive measures, and the overall group performance profiles were highly similar. No differences were observed on symptom ratings. Patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls. These data fail to support an association of TD with global measures of "organicity." Abnormal movements may result from specific dysfunction within the more purely motor circuits of the basal ganglia without compromising other neural systems involved in cognitive processing.

Neuropsychological performance of monozygotic twins discordant for bipolar disorder.

BACKGROUND: A paradigm that involves cognitive assessment of monozygotic (MZ) twins discordant for a neuropsychiatric disorder (here bipolar illness) allows for the examination of both disease-specific impairments (in the comparison of affected to unaffected twins) and risk factors (in the comparison of unaffected twins to normal twins). METHODS: Neuropsychological functions were evaluated in seven MZ twin pairs discordant for bipolar illness and seven pairs of normal MZ twins in an attempt to highlight cognitive abilities associated with manifestations of disease and genetic risk factors. At the time of testing, 3 of the affected twins were euthymic, 2 had depressive symptoms, and 2 had manic symptoms; all were receiving medication. All twins receive neuropsychological tests to evaluate intelligence, attention, visuospatial skills, language, learning and memory, and problem solving. RESULTS: Statistical analyses revealed that the affected twins were significantly impaired as compared to the unaffected (and normal) twins on some measures of visuospatial functioning and some verbal memory measures. In contrast to a sample of MZ twins discordant for schizophrenia studied previously, the cognitive impairments we observed in bipolar twins were mild in nature and fairly circumscribed. The unaffected twins performed significantly worse than normal controls on a Brown-Petersen memory task, verbal list learning, and overall Wechsler Memory Quotient. CONCLUSIONS: These data suggest that while some visuospatial deficits and verbal memory deficits may be features of bipolar disorder related to disease parameters, mild attenuations in overall memory or retrieval function may be related to genetic factors associated with the illness.

Unnatural practices, unspeakable actions: a study of delayed auditory feedback in schizophrenia.

OBJECTIVE: It has been suggested that auditory hallucinations and delusions of control in persons with schizophrenia could involve a disconnection between an "intention center" and a "monitoring center." METHOD: To test this model directly, the authors used a delayed auditory feedback paradigm in which the subject hears his or her own speech delayed electronically by a fraction of a second. In normal, subjects this produces dysfluency, which is thought to occur because an expectancy about the perceptual arrival of speech, formed in a monitoring center on the basis of corollary discharge from an intention center, is violated. If, however, a disconnection were present in schizophrenia, such an expectancy would not be formed; hence, less dysfluency should occur. Fifteen patients with chronic schizophrenia (10 of whom experienced auditory hallucinations and/or delusions of control) and 19 normal subjects were studied. RESULTS: Rather than exhibiting less dysfluency than the normal subjects, patients with delusions and/or hallucinations exhibited significantly more dysfluency. CONCLUSIONS: These results do not support a cognitive model of disconnection.

Prediction of neuropsychological performance by neurological signs in schizophrenia.

OBJECTIVE: The major purposes of this study were 1) to examine whether neurological signs predict cognitive performance in both schizophrenic patients and healthy subjects and 2) to determine the ability of neurological signs and neuropsychological tests to discriminate schizophrenic patients from healthy subjects. METHOD: Eighty-five patients with a DSM-III-R diagnosis of schizophrenia and 36 normal comparison subjects were included in the study. All subjects were administered a comprehensive neuropsychological test battery, and neurological signs were assessed with the Neurological Evaluation Scale. Stepwise regression analyses were used to predict neuropsychological test performance from the subscale scores on the Neurological Evaluation Scale. Forward stepwise linear discriminant function analyses were used to examine the discriminative ability of neurological subscale scores, neuropsychological test scores, and the two combined. RESULTS: Scores on the Neurological Evaluation Scale predicted the neuropsychological test performance of both patients and comparison subjects. The sensory integration subscale score was the most frequent predictor of neuropsychological test performance. In contrast, the "others" subscale, which includes frontal release signs, abnormalities in eye movements, and short-term memory, was the most highly discriminating subscale, correctly classifying 78.5% of the total study group. The best predictors from the neuropsychological battery (category fluency and Trail Making Test, part A, time test) correctly classified 81.8%. When both sets of variables were used, the Neurological Evaluation Scale "others" subscale entered the discriminant function first. CONCLUSIONS: Neurological signs are reliably related to measures of neuropsychological performance and also reliably discriminate between patients and healthy subjects. However, some neurological signs may be more sensitive to the presence of schizophrenia, while others may be more predictive of neuropsychological performance.