Impaired implicit learning in schizophrenia

Schizophrenia patients consistently show deficits on tasks of explicit learning and memory. In contrast, their performance on implicit processing tasks often appears to be relatively intact, although most studies have focused on implicit learning of motor skills. This study evaluated implicit learning in 59 medicated schizophrenia outpatients and 43 controls using 2 different cognitive skill tasks. Participants completed a probabilistic classification task to assess procedural habit learning and an artificial grammar task to assess incidental learning of complex rule-based knowledge, as well as an explicit verbal learning and memory task. In addition to performing worse than controls on the explicit learning task, patients showed worse overall performance on the probabilistic classification task, which involves gradual learning through trial-by-trial performance feedback. However, patients and controls showed similar levels of learning on the artificial grammar task, suggesting a preserved ability to acquire complex rule-based knowledge in the absence of performance feedback. Discussion focuses on possible explanations for schizophrenia patients' poor probabilistic classification task performance.     

Probing attentional dysfunctions in schizophrenia: Startle modification during a continuous performance test

Startle eyeblink modification was measured in 20 relatively asymptomatic medicated schizophrenia outpatients and 18 matched controls in order to test for deficits in early and later stages of attentional processing during a memory-load version of the Continuous Performance Test. Participants viewed a series of digits and pressed a button after the digit 7 of each 3–7 sequence. On some trials, a startling noise burst was presented either 120 or 1200 ms following cues that a response might be needed soon (the digit 3) and also following noncues. Controls showed greater startle inhibition at 120 ms following cue than noncue prepulses, whereas patients showed equal inhibition to both, suggesting a deficiency in allocation of controlled attentional resources in early stages of processing. The patients, however, did show large startle inhibition at 120 ms when a distracting stimulus accompanied the task-relevant cue, unlike the controls, who ignored the distracting stimulus. In contrast, both groups showed equal startle inhibition 1200 ms following cue and noncue prepulses, indicating that later modality-specific attention processes are not impaired in patients during this paradigm. Both groups also showed equal inhibition at 120 ms during passively attended prepulses, suggesting that automatic attentional processes were not impaired in these patients.     

Visual masking as a probe for abnormal gamma range activity in schizophrenia.

BACKGROUND: Visual masking procedures assess very early stages of visual perception. Patients with schizophrenia consistently show deficits on visual masking tasks, and these deficits likely reflect vulnerability to schizophrenia. We conducted two experiments to determine whether visual masking procedures can reveal underlying abnormalities in gamma range oscillations in schizophrenia. METHODS: In the first experiment, we conducted nonlinear modeling of visual masking performance data from 89 male schizophrenic patients and 20 male comparison subjects. In the second experiment, electrophysiological recordings of event-related gamma activity were taken during a visual masking task in a subset of eight patients and seven control subjects. RESULTS: In the first experiment, nonlinear modeling of the performance data revealed evidence of oscillations in the gamma range (30 and 35 Hz) for the comparison group but not patients. In the second experiment, the comparison group, but not the patients, showed a burst of gamma range activity 200-400 msec following target presentation. The difference between patients and comparison subjects in this time period was significant (p <.05). CONCLUSIONS: Visual masking procedures can serve as a probe for underlying gamma range activity, which appears to be aberrant in schizophrenia. Perceptual problems in schizophrenia may, at least in part, be due to a failure to establish and/or maintain gamma range oscillations.     

Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics.

We scanned 18 patients with schizophrenia who had never received neuroleptic medication and 20 age- and sex-matched controls by positron emission tomography with 18-F-fluorodeoxyglucose (fludeoxyglucose F 18) as a tracer of glucose metabolism. Subjects performed the Continuous Performance Test during 18-F-fluorodeoxyglucose uptake. Scan results were converted to metabolic rates, and computer algorithms were used to identify cortical regions. Previous reports of relative hypofrontality in schizophrenia were confirmed, indicating that this finding is not an artifact of previous treatment. Significantly reduced ratios of inferior and medial frontal regions to occipital cortex were found, together with diminished metabolism in the basal ganglia. This suggests the presence of a combined frontostriatal dysfunction in schizophrenia.     

Effect of attention on frontal distribution of delta activity and cerebral metabolic rate in schizophrenia

15 patients with schizophrenia and nine normal volunteers had 32 channel topographic EEG recorded for spectral analysis during the uptake of 18-F-deoxyglucose (FDG) for positron emission tomography (PET). Both patients and controls performed the Continuous Performance Test, a visual vigilance task, during FDG uptake. EEG was also obtained during an initial pre-FDG resting period. Each EEG epoch was individually inspected for eye movement artifacts. Analysis confirmed increased delta activity in the frontal region of patients with schizophrenia in comparison to normal controls, and a significant correlation between increased frontal delta and relative reduction in frontal lobe metabolism among patients with schizophrenia. This finding of increased delta is consistent with PET, blood flow and topographic EEG studies of schizophrenia, suggesting reduced frontal activity.     

A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia

OBJECTIVE: On April 23, 2004, a joint meeting of the FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop guidelines for the design of clinical trials of cognitive-enhancing drugs for neurocognitive impairments in patients with schizophrenia. METHOD: Experts were asked to address specific questions relating to clinical trial design of adjunctive/co-treatment and broad spectrum agents. At the workshop, experts reviewed relevant evidence before offering the discussion panel proposed guidelines for a given subset of questions. The discussion panel, which consisted of presenters and representatives from FDA, NIMH, academia, and industry, deliberated to reach consensus on suggested guidelines. When evidence was insufficient, suggested guidelines represent the opinion of a cross-section of the presenters and discussion panel. RESULTS: Guidelines were developed for inclusion criteria, the use of co-primary outcome measures, and statistical approaches for study design. Consensus was achieved regarding diagnostic and concomitant medication inclusion criteria and on the use of cognitive screening measures. A key guideline was to limit the trial to patients in the residual phase of their illness, who have a predefined level of positive, negative, and affective symptoms. The most difficult issues were the feasibility of including a co-primary measure of functional improvement and the choice of comparator agent for a trial of a broad spectrum agent (with antipsychotic and cognitive-enhancing effects). CONCLUSIONS: The suggested guidelines represent reasonable starting points for trial design of cognitive-enhancing drugs, with the understanding that new data, subsequent findings, or other methodological considerations may lead to future modifications.     

Visual processing in schizophrenia: Structural equation modeling of visual masking performance

Schizophrenic patients consistently demonstrate performance deficits on visual masking procedures. In visual masking, the subject's ability to process a target stimulus is reduced by another stimulus (mask) presented either before (forward masking) or after (backward masking) the target. Masking procedures employed in schizophrenia research have used several experimental paradigms. Most early studies have used high-energy masks (i.e., the mask is stronger than the target) and spatially overlapping target and mask. More recently, studies have begun to employ relatively weak (i.e., low-energy) masks, as well as masks that surround, but do not spatially overlap, the target. Data for forward and backward masking components of four masking conditions (target location and identification with a high-energy mask, target identification with a low-energy mask, and target identification with equal energy paracontrast/metacontrast) were collected from 75 patients with schizophrenia. Based on theoretical distinctions among masking procedures, we compared four models of visual masking using structural equation modeling. Although high zero-order correlations were found among the masking parameters, a four-factor model, in which factors were separated on the type of response (target location and identification), the shape of the function (monotonic and non-monotonic), and the overlap of the stimuli (overlapping and non-overlapping), provided the best fit for the data. These findings suggest that the four masking procedures used in this study may tap unique aspects of visual processing and are not redundant. The results also support theories of the different mechanisms underlying performance on these measures.     

The temporal stability of electrodermal variables over a one-year period in patients with recent-onset schizophrenia and in normal subjects

Test-retest stability of electrodermal (EDA) variables indexing both general autonomic arousal (e.g., skin conductance level, number of nonspecific skin conductance responses) and attention to external stimuli (e.g., number of skin conductance orienting responses, electrodermal responder/nonresponder status) was assessed in 71 young, recent-onset schizophrenia patients and 36 demographically matched normal subjects. Significant stability over a 1-year period was found for both patients and normal subjects for most EDA variables and for responder/nonresponder status, with test-retest correlations generally being higher for normal subjects. The lower reliability for patients was not attributable to symptomatic fluctuations during the follow-up period and may reflect poorer arousal regulation among the patients. Among measures of responding to nontask stimuli, a simple count of the number of orienting responses occurring was more stable than was a traditional trials-to-habituation measure.     

Forward and backward visual masking in schizophrenia: influence of age

BACKGROUND: Visual masking tasks assess the earliest stages of visual processing. This study was conducted to address: (1) whether schizophrenia patients show masking deficits after controlling for sensory input factors; (2) whether patients have relatively intact forward masking (when the mask precedes the target) compared with backward masking (when the mask follows the target); and (3) whether the masking deficits in schizophrenia reflect an accelerated age-related decline in performance. METHOD: A staircase method was used to ensure that the unmasked target identification was equivalent across subjects to eliminate any confounding due to differences in discrimination of simple perceptual inputs. Three computerized visual masking tasks were administered to 120 schizophrenia patients (ages 18-56) and 55 normal comparison subjects (ages 19-54) under both forward and backward masking conditions. The tasks included: (1) locating a target; (2) identifying a target with a high-energy mask; and (3) identifying a target with a low-energy mask. RESULTS: Patients showed deficits across all three masking tasks. Interactions of group by forward versus backward masking were not significant, suggesting that deficits in forward and backward masking were comparable. All three conditions showed an age-related decline in performance and rates of decline were comparable between patients and controls. Two of the masking conditions showed increased rates of decline in backward, compared to forward, masking. CONCLUSIONS: We found age-related decline in performance that was comparable for the two groups. In addition, we failed to find evidence of a relative sparing of forward masking in schizophrenia. These results suggest that: (1) early visual processing deficits in schizophrenia are not due to a simple perceptual input problem; (2) sustained channels are involved in the masking deficit (in addition to transient channels); and (3) for the age range in this study, these deficits in schizophrenia are not age-related.     

The factor structure of schizophrenia spectrum personality disorders: signs and symptoms in relatives of psychotic patients from the UCLA family members study

The dimensions and limits of the concept of schizotypy are examined using an exploratory factor analysis of the 36 signs and symptoms in the Cluster A DSM-III-R personality disorders as well as those in Borderline Personality Disorder and Avoidant Personality Disorder in the 307 first-degree relatives and half-siblings of 123 probands with schizophrenia/schizoaffective disorder. The personality disorders examined were assessed using sections of the Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and hospital and clinic records. Interviewers were blind to the proband diagnosis. The resulting six-factor solution accounted for 40% of the variance. The results of the six-factor solution accounted for the greatest variance and gave the most easily interpretable simple structure of all the solutions examined. The six factors are labeled as (1) Borderline Symptoms, (2) Schizoid Symptoms, (3) Paranoid Symptoms, (4) Avoidant Symptoms, (5) Positive Schizotypy Symptoms, and (6) Disorganized Symptoms. The Schizotypal Personality items are spread across all but the 'Borderline Symptoms' factor. We conclude schizotypy is a multidimensional construct that is not adequately characterized by any one DSM-III-R personality disorder. It appears to consist of six distinct dimensions, which, interestingly, parallel current thinking on dimensions in schizophrenia.