Faculty Bibliography

Abnormal smooth pursuit eye movements in patients with schizophrenia are often considered a consequence of impaired motion perception. Here we used a novel motion prediction task to assess the effects of abnormal pursuit on perception in human patients. Schizophrenia patients (n = 15) and healthy controls (n = 16) judged whether a briefly presented moving target ("ball") would hit/miss a stationary vertical line segment ("goal"). To relate prediction performance and pursuit directly, we manipulated eye movements: in half of the trials, observers smoothly tracked the ball; in the other half, they fixated on the goal. Strict quality criteria ensured that pursuit was initiated and that fixation was maintained. Controls were significantly better in trajectory prediction during pursuit than during fixation, their performance increased with presentation duration, and their pursuit gain and perceptual judgments were correlated. Such perceptual benefits during pursuit may be due to the use of extraretinal motion information estimated from an efference copy signal. With an overall lower performance in pursuit and perception, patients showed no such pursuit advantage and no correlation between pursuit gain and perception. Although patients' pursuit showed normal improvement with longer duration, their prediction performance failed to benefit from duration increases. This dissociation indicates relatively intact early visual motion processing, but a failure to use efference copy information. Impaired efference function in the sensory system may represent a general deficit in schizophrenia and thus contribute to symptoms and functional outcome impairments associated with the disorder.

Spatiotemporal discontinuity of visual input is a common occurrence in daily life. For example, when a walking person disappears temporarily behind a wall, observers have a clear sense of his physical presence despite the absence of any visual information (movement permanence). To investigate the neural substrates of biological motion permanence, we recorded scalp EEG activity of sixteen subjects while they passively observed either biological or scrambled motion disappearing behind an occluder and reappearing. The moment of the occluder's appearance was either fixed or randomized. The statistical comparison between the biological and scrambled motion ERP waveforms revealed a modulation of activity in centro-parietal and right occipito-temporal regions during the occlusion phase when the biological motion disappearance was time-locked, possibly reflecting the recall of sensorimotor representations. These representations might allow the prediction of moving organisms in occlusion conditions. When the appearance of the occluder was unpredictable there was no difference between biological and scrambled motion either before or during occlusion, indicating that temporal prediction is relevant to the processing of biological motion permanence.

Schizophrenia patients have deficits in cognitive function that are a core feature of the disorder. AX-CPT is commonly used to study cognition in schizophrenia, and patients have characteristic pattern of behavioral and ERP response. In AX-CPT subjects respond when a flashed cue "A" is followed by a target "X," ignoring other letter combinations. Patients show reduced hit rate to "go" trials, and increased false alarms to sequences that require inhibition of a prepotent response. EEG recordings show reduced sensory (P1/N1), as well as later cognitive components (N2, P3, CNV). Behavioral deficits correlate most strongly with sensory dysfunction. Oscillatory analyses provide critical information regarding sensory/cognitive processing over and above standard ERP analyses. Recent analyses of induced oscillatory activity in single trials during AX-CPT in healthy volunteers showed characteristic response patterns in theta, alpha, and beta frequencies tied to specific sensory and cognitive processes. Alpha and beta modulated during the trials and beta modulation over the frontal cortex correlated with reaction time. In this study, EEG data was obtained from 18 schizophrenia patients and 13 controls during AX-CPT performance, and single trial decomposition of the signal yielded power in the target wavelengths. Significant task-related event-related desynchronization (ERD) was observed in both alpha and beta frequency bands over parieto-occipital cortex related to sensory encoding of the cue. This modulation was reduced in patients for beta, but not for alpha. In addition, significant beta ERD was observed over motor cortex, related to motor preparation for the response, and was also reduced in patients. These findings demonstrate impaired dynamic modulation of beta frequency rhythms in schizophrenia, and suggest that failures of oscillatory activity may underlie impaired sensory information processing in schizophrenia that in turn contributes to cognitive deficits.

Perceptual organization, which refers to the ability to integrate fragments of stimuli to form a representation of a whole edge, part, or object, is impaired in schizophrenia. A contour integration paradigm, involving detection of a set of Gabor patches forming an oval contour pointing to the right or left embedded in a field of randomly oriented Gabors, has been developed for use in clinical trials of schizophrenia. The purpose of the present study was to assess contributions of early and later stages of processing to deficits in contour integration, as well as to develop an event-related potential (ERP) analog of this task. Twenty-one patients with schizophrenia and 28 controls participated. The Gabor elements forming the contours were given a low or high degree of orientational jitter, making it either easy or difficult to identify the direction in which the contour was pointing. ERP results showed greater negative peaks at ~165 (N1 component) and ~270 ms for the low-jitter versus the high-jitter contours, with a much greater difference between jitter conditions at 270 ms. This later ERP component was previously termed Ncl for closure negativity. Source localization identified the Ncl in the lateral occipital object recognition area. Patients showed a significant decrease in the Ncl, but not N1, compared to controls, and this was associated with impaired behavioral ability to identify contours. In addition, an earlier negative peak was found at ~120 ms (termed N120) that differentiated jitter conditions, had a dorsal stream source, and differed between patients and controls. Patients also showed a deficit in the dorsal stream sensory P1 component. These results are in accord with impairments in distributed circuitry contributing to perceptual organization deficits and provide an ERP analog to the behavioral contour integration task.

Schizophrenia is associated with perceptual and cognitive dysfunction including impairments in visual attention. These impairments may be related to deficits in early stages of sensory/perceptual processing, particularly within the magnocellular/dorsal visual pathway. In the present study, subjects viewed high and low spatial frequency (SF) gratings designed to test functioning of the parvocellular/magnocellular pathways, respectively. Schizophrenia patients and healthy controls attended to either the low SF (magnocellularly biased) or high SF (parvocellularly biased) gratings. Functional magnetic resonance imaging (fMRI) and recordings of event-related potentials (ERPs) were carried out during task performance. Patients were impaired at detecting low-frequency targets. ERP amplitudes to low-frequency gratings were diminished, both for the early sensory-evoked components and for the attend minus unattend difference component (the selection negativity), which is regarded as a neural index of feature-selective attention. Similarly, fMRI revealed that activity in extrastriate visual cortex was reduced in patients during attention to low, but not high, SF. In contrast, activity in frontal and parietal areas, previously implicated in the control of attention, did not differ between patients and controls. These findings suggest that impaired sensory processing of magnocellularly biased stimuli lead to impairments in the effective processing of attended stimuli, even when the attention control systems themselves are intact

BACKGROUND: Mismatch negativity (MMN) and visual P1 are established event-related potential (ERP) markers of impaired auditory and visual sensory function in schizophrenia. Differential relationships of these measures with premorbid and present function and with clinical course have been noted previously in independent cohorts, but measures have not yet been compared within the same patient group. METHODS: Twenty-six schizophrenia patients and 19 control subjects participated in a simultaneous visual and auditory ERPs experiment. Attended visual ERPs were obtained to low- and high-spatial frequency stimuli. Simultaneously, MMN was obtained to unattended pitch, duration, and intensity deviant stimuli. Premorbid function, symptom, and global outcome measures were obtained as correlational measures. RESULTS: Patients showed substantial P1 reductions to low- but not high-spatial frequency stimuli, unrelated to visual acuity. Patients also exhibited reduced MMN to all deviant types. No significant correlations were observed between visual ERPs and premorbid or global outcome measures or illness duration. In contrast, MMN amplitude correlated significantly and independently with premorbid educational achievement, cognitive symptoms, global function, and illness duration. The MMN to duration versus other deviants was differentially reduced in individuals with poor premorbid function. CONCLUSIONS: Visual and auditory ERP measures are differentially related to the pathophysiology of schizophrenia. Visual deficits correlate poorly with functional measures and illness duration and serve primarily as trait vulnerability markers. The MMN deficits are independently related to premorbid function and illness duration, suggesting independent neurodevelopmental and neurodegenerative contributions. The lack of correlation between auditory and visual ERPs in schizophrenia suggests contributions from divergent underlying neurophysiological processes

In healthy humans, passage reading depends upon a critical organizing role played by the magnocellular/dorsal visual pathway. In a recent study, we found a significant correlation between orthographic reading deficits in schizophrenia and deficits in contrast sensitivity to low spatial frequency stimuli, suggesting an underlying magnocellular processing abnormality. The interrelationship between magnocellular dysfunction and passage reading impairments in schizophrenia was investigated in 21 patients with schizophrenia and 17 healthy control volunteers using behavioral and functional MRI (fMRI) based measures. fMRI activation patterns during passage- and single-word reading were evaluated in relation to cortical areas with differential sensitivity to low versus high spatial frequency cortical regions indentified using a phase-encoded fMRI paradigm. On average, patients with schizophrenia read at the 6th grade level, despite completion of more than 12 years of education and estimated normal pre-morbid IQ. Schizophrenia patients also showed significantly impaired contrast sensitivity to low spatial frequencies and abnormal neural activity in response to stimulation with low spatial frequencies, consistent with dysfunction of magnocellular processing. Further, these magnocellular deficits were predictive of poor performance on a standardized psychoeducational test of passage reading. These findings suggest that reading is an important index of cognitive dysfunction in schizophrenia and highlight the contribution of magnocellular dysfunction to overall cognitive impairments in schizophrenia.

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