David E. Ross

Eye movements and psychopathology in schizophrenia and bipolar disorder.

The aim of this study was to examine multivariate patterns of relationships between oculomotor performance, psychopathology, and neuropsychology. Performance on smooth pursuit and saccadic eye movement tasks was assessed in three DSM-III-R diagnosis-based groups of subjects; normal (N = 55), schizophrenic (N = 29), and bipolar disorder (N = 26) and analyzed in relation to age, gender, scale for the Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms, and Brief Psychiatric Rating Scale scores, Shipley intelligence quotient, and Wisconsin Card Sorting Test performance. The greatest difference was a higher proportion of errors in the antisaccade task in the schizophrenic and bipolar groups, which was related to worse Wisconsin Card Sorting Test performance and was not accounted for by gender, age, education, or intelligence quotient. A significant gender and bipolar interaction showed bipolar women to have worse antisaccade performance. Abnormal smooth pursuit was more specific to schizophrenia. Antisaccade task and sine wave root-mean-square error were correlated in bipolar but not schizophrenic subjects. Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms scores had independent associations with the antisaccade task. Faster reaction times in the schizophrenic group to antisaccade errors were observed, suggesting an abnormality in visual attention processing and perhaps sensory gating functions. These results confirm abnormal smooth pursuit in schizophrenia and suggest that impairments in saccadic function are less specific to diagnostic group. Oculomotor performance and psychopathology seem related in complex ways to age, gender, intelligence quotient, and executive neuropsychological and possibly visual attention functions.

Smooth pursuit eye movements to extra-retinal motion signals: deficits in patients with schizophrenia

In order to understand mechanisms underlying the smooth pursuit abnormality(ies) in schizophrenia, new methods, which independently evaluated predictive smooth pursuit responses to extra-retinal motion signals, were developed and tested. The study compared responses to only extra-retinal motion signals in normal volunteers (n = 25), and individuals with a chronic (n = 21) and a recent onset (n = 18) schizophrenia. Subject groups with chronic schizophrenia and recent onset schizophrenia had significantly poorer predictive pursuit than normal subjects in response to only extra-retinal motion signals. The poor predictive pursuit was evident even at low target velocity when the closed-loop pursuit gain was normal in patients with schizophrenia. Ten of the 18 recent onset patients were drug-free at the time of testing and had no or minimum previous exposure to anti-psychotic medications. Re-analyses of the data showed that on most measures of predictive pursuit, drug-free patients were not significantly different from patients who received anti-psychotic drug treatment. Both patient groups had significantly poorer predictive pursuit than normal subjects. These results suggest that a deficit in processing extra-retinal motion may underlie the abnormal smooth pursuit response in schizophrenia. At low target velocities, patients with schizophrenia were able to compensate for the low extra-retinal gain by increasing the gain of response to the retinal slip velocity. This indicates that patients were able to process retinal slip velocity and generate smooth pursuit eye movements, but experienced a specific deficit in processing and/or integrating extra-retinal motion information for the smooth pursuit response.

Eye Tracking Disorder in Schizophrenia Is Characterized by Specific Ocular Motor Defects and Is Associated with the Deficit Syndrome

The objective was to determine the relationships between eye tracking disorder (ETD) in schizophrenia, specific ocular motor measures, and the deficit syndrome. Twenty-five normal comparison subjects and 53 schizophrenic patients had eye movements tested with infrared oculography using a sinusoidal target. Patients were assessed with the Schedule for the Deficit Syndrome. For the patients, the distribution of position root mean square error (a global measure of pursuit) was best fit by a mixture of two normal distributions. This information was used to divide the patients into two subgroups, those with and those without ETD. ETD was almost completely accounted for by several specific ocular motor measures and was significantly associated with the deficit syndrome. The finding that ETD was almost completely accounted for by specific measures bridges a gap of interpretation in this field. ETD and the deficit syndrome of schizophrenia may share a common pathophysiology of cerebral cortical-subcortical circuits.

Abnormal smooth pursuit eye movements in schizophrenic patients are associated with cerebral glucose metabolism in oculomotor regions

The purpose of this study was to test the hypothesis that abnormal smooth pursuit eye movements in schizophrenic patients would be related to cerebral glucose utilization in specific oculomotor regions. Eye movements were assessed with infrared oculography in 11 unmedicated schizophrenic patients and 13 normal comparison subjects. For the patients only, regional cerebral metabolic rate of glucose utilization was measured with positron emission tomography. Abnormal pursuit tracking in the patients was associated with relatively decreased metabolism in the frontal eye fields and increased metabolism in the caudate nuclei. The results are consistent with the hypothesis that these cerebral regions are involved in the pathophysiology of abnormal pursuit as related parts of a cortical-subcortical oculomotor circuit.

Does pursuit abnormality in schizophrenia represent a deficit in the predictive mechanism

Although an abnormality of smooth pursuit eye movement has been consistently noted in schizophrenia, the underlying ocular motor pathophysiology is unknown. It is unclear whether the abnormality represents deficits in processing of information provided by the moving target, generation of pursuit eye movements, or other ocular motor and related cognitive processes. To evaluate the ability to process information provided by a moving target, saccadic accuracies were studied in step-ramp and single step tasks. Schizophrenic (with and without tardive dyskinesia [TD]) and normal subjects made equally accurate initial corrective saccades to the moving target. Thus, when the target jumped and then smoothly moved (creating a position and a velocity error on the retina), the patients were able to process retinal motion information and generate a normally accurate saccadic response. After the initial corrective saccade, both groups followed the target with a combination of pursuit eye movements and occasional catch-up saccades. During this period, the retinal velocity error is minimal because the eye approximates the target motion, and the major source of target motion information both for the smooth pursuit and saccadic responses is extra-retinal (i.e., predictive mechanism). The accuracies of catch-up saccades were significantly lower in the schizophrenic patients than in the normal subjects. During this period, overall pursuit performance, measured by pursuit gain, was also significantly worse in the patients. Accuracies of subsequent catch-up saccades, but not initial corrective saccades, significantly predicted the pursuit gain. Low pursuit gain was associated with high numbers of saccades per time spent in pursuit, which were similar in both schizophrenic subgroups (i.e., with and without TD), but were only significantly higher in the patients with TD than in the normal subjects. These preliminary data suggest that schizophrenic patients are able to process retinal motion information but have difficulties in using extra-retinal motion information to generate an appropriate saccadic response.

Mixture in the distribution of haloperidol-induced oral dyskinesias in the rat supports an animal model of tardive dyskinesia.

Abstract Spontaneous adventitious oral movements which are produced in rats by very chronic (6- month) neuroleptic treatment have some phenomenologic and pharmacologic characteristics in common with tardive dyskinesia in humans. However, since not all of the features match, this putative model has been questioned and further support is warranted. Data from several laboratories support dichotomizing these neuroleptic-induced rat oral movements into “low”or “not TD-like” movements and “high”or “TD-like” movements, similar to the division of neuroleptic-induced involuntary movements in humans. Here, we have used mixture analysis to test this proposal statistically in 185 haloperidol-treated and 127 water-treated animals. Rats from several different studies were grouped together to form these two cohorts. The haloperidol dose, route of administration, rating technique, and balanced experimental groups were held constant across all experiments. Results show that two distinct groups of rat movements are induced by very chronic haloperidol treatment (1.5 mg/kg per day). The “low” vacuous chewing movement (VCM) group of rats had an average of 3.6 VCMs/5 min, and the “high” VCM group had an average of 16.1 VCMs/5 min; the conrol group, with a median VCM rate of 2.0 VCMs/5 min, demonstrated a single distribution. These data suggest that rats, like humans, dichotomize into two groups either expressing or not expressing “high” VCM dyskinesias with very chronic haloperidol treatment.

Changes in psychopathology and dyskinesia after neuroleptic withdrawal in a double-blind design

The goal of this study was to assess the time course of change in psychopathology and dyskinesia after neuroleptic withdrawal. Fifteen DSM-III schizophrenic patients were abruptly withdrawn in a double-blind fashion from stable haloperidol treatment. Weekly ratings of dyskinesia and psychopathology were performed for 4 weeks post-withdrawal. There was an overall increase in dyskinesia ratings over the 4-week period (p < 0.05) beginning in week 2, with dyskinetic movements of the fingers showing the most significant increase (p < 0.001). There were no overall changes in psychopathology, though the group appeared to be bimodal with 6 of the 15 patients showing a significant relapse in psychotic symptoms. Neither baseline TD nor psychotic relapse significantly interacted with change in TD over time. These schizophrenic patients showed an increase in global dyskinesia rating early within four weeks of neuroleptic withdrawal. This time course did not appear to be associated with reemergence of psychopathology which occurred later. A significant minority of patients relapsed within this time period. This suggests the relative safety of brief periods of neuroleptic withdrawal for carefully selected patients in a controlled setting with specific goals (e.g., for evaluation or in preparation for clozapine) and the need to further understand who is at risk for rapid relapse.

Covert visual attention in schizophrenia spectrum personality disordered subjects: Visuospatial cuing and alerting effects

A recent study observed lateralized deficit in the disengagement of covert visual attention in schizophrenic patients. Subsequent attempts to replicate this finding have had mixed results. Differences in the neuroleptic treatment or other secondary factors associated with schizophrenia are some of the possible reasons for these inconsistent findings. In this study, we examined the ability to shift covert visual attention in neuroleptic-naive, schizophrenia spectrum personality disordered (SSPD; n = 35) subjects and normal controls (n = 34) under a variety of spatial cuing and alerting conditions. We hypothesized that SSPD subjects would have difficulty with disengagement of covert visual attention from an invalidly cued left visual field when the target appeared in the right visual field in comparison to the normal subjects. As predicted, schizophrenia spectrum personality disordered subjects had significantly longer latencies for the right visual field invalid targets than normals (p = .014). Under the remaining cue conditions, spectrum subjects performed normally. Consequently, the cost of left visual field invalid cueing for the right visual field target was significantly higher in spectrum personality subjects than in normals. The cost for the invalid right visual field cue and the benefits of valid cue in both fields were very similar in the two groups. The findings of an asymmetrical deficit in the disengagement and shift of covert visual attention in schizophrenia spectrum subjects are similar to the ones observed in patients with unilateral left hemisphere lesions.

Man Versus Machine: Comparison of Radiologists’ Interpretations and NeuroQuant® Volumetric Analyses of Brain MRIs in Patients With Traumatic Brain Injury

NeuroQuant® is a recently developed, FDA-approved software program for measuring brain MRI volume in clinical settings. The purpose of this study was to compare NeuroQuant with the radiologists traditional approach, based on visual inspection, in 20 outpatients with mild or moderate traumatic brain injury (TBI). Each MRI was analyzed with NeuroQuant, and the resulting volumetric analyses were compared with the attending radiologists interpretation. The radiologists traditional approach found atrophy in 10.0% of patients; NeuroQuant found atrophy in 50.0% of patients. NeuroQuant was more sensitive for detecting brain atrophy than the traditional radiologists approach.

NeuroQuant® Revealed Hippocampal Atrophy in a Patient With Traumatic Brain Injury

Case Report At the time of the accident, he hit his occiput and suffered whiplash. He was dazed but did not lose consciousness. He had posttraumatic amnesia, headache, neck pain, and dizziness. In the emergency room, his Glasgow Coma Scale score was 15/15. Over the following days and weeks, he had multiple persistent neuropsychiatric symptoms, including distractibility, impaired short-term and long-term memory, impaired visuospatial abilities, insomnia, fatigue, and blurry vision. Neuropsychological testing confirmed impairments in memory and other cognitive abilities. Nine months after the accident, an MRI of the brain was interpreted in the traditional manner (that is, by visual inspection of the images) by the radiologist as showing two nonspecific T2 hyperintensities in the left frontal lobe. NeuroQuant volumetric analysis of the same MRI data revealed that total hippocampal volume was 4.37 cm, which was 0.29% of intracranial volume, falling below the first percentile, as compared with an age-matched normal-control group. The patient continued to work full-time at a job he had held for many years; however, his functioning was significantly impaired.