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Muscimol-induced inactivation of the monkey frontal eye field: effects on visually and memory-guided saccades. Although neurophysiological, anatomic, and imaging evidence suggest that the frontal eye field (FEF) participates in the generation of eye movements, chronic lesions of the FEF in both humans and monkeys appear to cause only minor deficits in visually guided saccade generation. Stronger effects are observed when subjects are tested in tasks with more cognitive requirements. We tested oculomotor function after acutely inactivating regions of the FEF to minimize the effects of plasticity and reallocation of function after the loss of the FEF and gain more insight into the FEF contribution to the guidance of eye movements in the intact brain. Inactivation was induced by microinjecting muscimol directly into physiologically defined sites in the FEF of three monkeys. FEF inactivation severely impaired the monkeys' performance of both visually guided and memory-guided saccades. The monkeys initiated fewer saccades to the retinotopic representation of the inactivated FEF site than to any other location in the visual field. The saccades that were initiated had longer latencies, slower velocities, and larger targeting errors than controls. These effects were present both for visually guided and for memory-guided saccades, although the memory-guided saccades were more disrupted. Initially, the effects were restricted spatially, concentrating around the retinotopic representation at the center of the inactivated site, but, during the course of several hours, these effects spread to flanking representations. Predictability of target location and motivation of the monkey also affected saccadic performance. For memory-guided saccades, increases in the time during which the monkey had to remember the spatial location of a target resulted in further decreases in the accuracy of the saccades and in smaller peak velocities, suggesting a progressive loss of the capacity to maintain a representation of target location in relation to the fovea after FEF inactivation. In addition, the monkeys frequently made premature saccades to targets in the hemifield ipsilateral to the injection site when performing the memory task, indicating a deficit in the control of fixation that could be a consequence of an imbalance between ipsilateral and contralateral FEF activity after the injection. There was also a progressive loss of fixation accuracy, and the monkeys tended to restrict spontaneous visual scanning to the ipsilateral hemifield. These results emphasize the strong role of the FEF in the intact monkey in the generation of all voluntary saccadic eye movements, as well as in the control of fixation.

Background Perceptual closure refers to the ability to identify objects with partial information. Deficits in schizophrenia are indexed by impaired generation of the closure-related negativity (NCL) from ventral stream visual cortex (lateral occipital complex, LOC), as part of a network of brain regions that also includes dorsal stream visual regions, prefrontal cortex (PFC) and hippocampus. This study evaluates network-level interactions during perceptual closure in schizophrenia using parallel ERP, fMRI and neuropsychological assessment. Methods ERP were obtained from 24 patients and 20 healthy volunteers in response to fragmented (closeable) and control scrambled (noncloseable) line drawings. fMRI were obtained from 11 patients and 12 controls. Patterns of between group differences for predefined ERP components and fMRI regions of interest were determined using both analysis of variance and structural equation modeling. Global neuropsychological performance was assessed using elements of the WAIS-III, WMS-III and MATRICS batteries. Results Patients showed impaired visual P1 generation, reflecting dorsal stream dysfunction, along with impaired generation of NCL components over PFC and LOC. In fMRI, patients showed impaired activation of dorsal and ventral visual regions, PFC and hippocampus. Impaired activation of dorsal stream visual regions contributed significantly to impaired PFC activation. Impaired PFC activation contributed significantly to impaired activation of hippocampus and LOC. Impaired LOC and hippocampal activation contributed significantly to deficits on WAIS-III Perceptual Organization Index (POI) and other tests of impaired perceptual processing in schizophrenia. Conclusion Schizophrenia is associated with severe activation deficits across a distributed network of sensory and higher order cognitive regions. Deficit in early visual processing within the dorsal visual stream contributes significantly to impaired frontal activation which, in turn, leads to dysregulation of hippocampus and ventral visual stream. Dysfunction within this network underlies impairment in more traditional measures of neurocognitive dysfunction such as POI, supporting distributed models of brain dysfunction in schizophrenia.

1. 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. 2. Objective To assess mechanisms underlying visual working memory dysfunction in schizophrenia relative to impairment of early visual processing. 3. Design, Setting and Participants Between-group design in a chronic treatment setting, with 30 individuals with schizophrenia and 17 healthy comparison subjects. Three versions of AX-CPT, with parametric variations of the proportions of trial types, were used to test performance and underlying neural activity under differential challenge situations. Contrast sensitivity measures were obtained from the majority of subjects. 7. 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, 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. 8. 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) components 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. 9. Conclusions Working memory deficits in schizophrenia have increasingly been attributed to impairments in stimulus encoding, rather than to failures in memory retention. The present 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.

Objective The ability to read passages of information fluently and with comprehension is a basic component of socioeconomic success. Reading ability depends upon the integrity of underlying visual and auditory (phonological) systems. This study investigates the integrity of reading ability in schizophrenia relative to the integrity of underlying visual and auditory function. Methods Participants were 45 schizophrenia patients, 19 clinical high risk patients, and 65 controls. Reading was assessed using tests sensitive to visual vs. phonological reading dysfunction. Sensory, neuropsychological and functional outcome measures were also obtained. Results Schizophrenia patients showed reading deficits that were far more severe (effect size>2.0) than would be predicted based upon general neurocognitive impairments (effect size 1.0–1.4). The deficits correlated highly with both visual and auditory sensory measures, including impaired mismatch negativity (MMN) generation (r=.62, n=51, p=.0002). Patients with established schizophrenia showed both visual and phonological impairments, whereas high-risk patients showed isolated visual impairments. >70% of schizophrenia patients met criteria for acquired dyslexia, with 50% reading below 8th grade level despite intact premorbid reading ability. Reading deficits also correlated significantly (rp=.4, n=30, p=.03) with failure to match parental socioeconomic achievement, over and above contributions of more general cognitive impairment. Conclusions Patients with schizophrenia show severe deficits in reading ability that represent a potentially remediable cause of impaired socioeconomic function. Such deficits are not presently captured during routine clinical assessment. Deficits most likely develop during the years immediately surrounding illness onset and may contribute to the reduced educational and occupational achievement associated with schizophrenia.