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Disrupted smooth pursuit eye tracking characterizes a greater proportion of individuals with schizophrenia than in the normal population. The finding of a similar increased incidence of eye tracking abnormality in first degree relatives of schizophrenics implicates this disorder as a potential biological marker for schizophrenia. To test the assumption that the eye tracking dysfunction of schizophrenics is genetically related, left and right smooth pursuit gain and phase shift were compared between 20 schizophrenics with a family history of schizophrenia or schizophrenia-related disorders, 18 schizophrenics without a family history, as well as for 18 normal controls. Subjects tracked pendular targets on an LED light bar moving at frequencies of 0.2 and 0.7 Hz. Horizontal eye movements were recorded using DC-electro-oculography. Results indicate that schizophrenics with a positive family history had significantly reduced right pursuit gain compared with controls, while right gain for negative family history schizophrenics did not differ from either group. Schizophrenic subjects also were administered neuropsychological tests. Linear regression by groups analyses reveal that neuropsychological measures significantly predicted right gain to slower targets (0.2 Hz) for the positive family history schizophrenics, but not for negative family history schizophrenics.

Increasing evidence suggests that smooth pursuit eye movement (SPEM) dysfunction may serve as an endophenotype or genetic marker of schizophrenia. The authors tested SPEM and visual fixation (VF) in 31 patients with schizophrenia, 33 of their first-degree relatives, and 24 patients with major depressive disorder. A high rate of abnormal VF was found in schizophrenic patients and their first-degree relatives, but not in affective disorder patients with or without psychotic features. Rate of VF abnormality distinguished schizophrenic patients from acutely depressed mood disorder patients; SPEM did not. VF and SPEM performance correlated only moderately, suggesting that the pathophysiologies of these two eye movement abnormalities may be partially independent. Implications for identifying a schizophrenia endophenotype are discussed.

Schizophrenia patients have a deficiency of smooth pursuit eye movement initiation. We addressed whether this deficit is specifically related to a predisposition for schizophrenia. Thirty-two relatives of schizophrenia patients, eight schizotypals, 13 psychiatric comparison, and 33 nonpsychiatric subjects were assessed on smooth pursuit initiation. The nonpsychiatric subjects had significantly higher eye accelerations than did subjects in the other three groups, who did not significantly differ. The relatives were subdivided into three groups: (a) those with a schizophrenia spectrum disorder (n = 4) performed similarly to the schizotypals; (b) those with a major depression history (n = 7) were similar to the psychiatric comparison subjects; and (c) those with no psychiatric history differed from the nonpsychiatric subjects only on 30 degrees/s targets. There was also a significant relationship between offspring and parent eye accelerations to 30 degrees/s targets (r = .476). These results suggest that pursuit initiation deficits may be associated with a nonspecific, genetically transmitted neurological abnormality among schizophrenia spectrum disorder subjects.

Although the range of normal ocular motor performance is broad, little is known about the sources of variability. Genetic transmission of eye movement deficits has been described but such possible control of normal function has been little investigated. Characteristics of smooth pursuit and saccades can be examined for the degree of concordance in related individuals. In this pilot study, we studied saccades and pursuit in eight monozygotic (MZ) twin pairs. The statistical analysis of the data used the intraclass correlation of MZ twins (rMZ) to estimate what fraction the covariance of the twin pairs was of the population variance. All saccadic measures showed significant MZ correlations (p < 0.05). Smooth pursuit gains were even more highly correlated (p < 0.001). These results indicate considerable similarity within pairs of twins, particularly for horizontal smooth pursuit, and suggest that larger studies on monozygotic and dizygotic twins would be desirable, to help separate out the relative contributions of environmental and genetic factors.

Both animal and human studies suggest that the GABA-benzodiazepine receptor complex may be involved in the acute effects of ethanol, as well as the development of tolerance and dependence with chronic ethanol use. The current study was performed to assess sensitivity to benzodiazepines, and thus the functional sensitivity of the GABA-benzodiazepine receptor system, in subjects at high risk for alcoholism. Sons of alcoholic fathers (SOAs; n = 27) were compared with male controls without a family history of alcoholism (n = 23) in response to diazepam versus placebo. SOAs and controls received four logarithmically increasing doses of intravenous diazepam or placebo in randomized order on 2 days at least 1 week apart. Effects of diazepam were assessed using two eye movement tasks, peak saccadic eye movement velocity, and average smooth pursuit eye movement gain, which provide reliable, quantitative measures of benzodiazepine effects. In addition, memory, self-rated sedation, and pleasurable drug effects were measured. In comparison with control subjects, SOAs displayed significantly less diazepam effects on peak saccade velocity, average smooth pursuit gain, memory, and self-rated sedation, but significantly greater pleasurable drug effects. Differences in response to diazepam between SOAs and male controls may reflect altered functional sensitivity of the central GABA-benzodiazepine receptor system or a more general difference between groups in the effects of CNS active or sedating drugs.

We agree with Levy et al.'s conclusion (Schizophrenia Bulletin, Vol. 19, No. 3, 1993) that global quantitative measures of eye tracking dysfunction (ETD) have an important role in studies of ETD in schizophrenia. We clarify some misunderstandings of our own work contained in their review. In particular, an explanation is presented of how we computed a fit of our data to their Mendelian latent structure model, when testing for a fit to their hypothesis of essential genetic homogeneity. We also point out that our mixture analyses, as with our reported abnormality rates obtained by using cutting scores, are not in agreement with their reported rates of ETD in schizophrenia.

Smooth-pursuit eye-tracking performance was examined in 100 schizophrenic patients and various control groups under both attention-enhancing and attention-distracting conditions. The level of attentional demand was varied by introducing a secondary reaction time task that directed attention either toward or away from the visual-tracking target. Distraction from the target led to a significant deterioration of tracking performance in all subjects, which was most pronounced in the group of schizophrenic patients. Attention-enhancement, on the other hand, did not normalize performance in this group. In schizophrenic patients, mainly in the distraction condition, there was a moderate association between performance in tracking and tests presumably measuring prefrontal functions. Tracking accuracy from both conditions was related to general motor performance as measured by the Neurological Evaluation Scale. It was concluded that in schizophrenic patients attentional factors (distraction) may contribute to eye-tracking impairment, and that the impairment may be viewed as an aspect of general motor dysfunctions.

The replications of the finding of eye tracking dysfunction (ETD) in schizophrenia patients and their first-degree relatives suggest that ETD may be informative in studies of a schizophrenia genotype having broadly defined phenotypes. We review and critically assess the literature on ETD with respect to syndrome and familial specificity and discuss the quantitative assessment of eye tracking.

Peripheral and central aspects of motor dysfunction were assessed in 12 schizophrenic and 12 normal subjects, using a test of control of finger movement based on the widely used smooth pursuit eye movement task. This was performed in order to investigate the basis of neuromotor dysfunction in schizophrenia. In this task, subjects used finger movement to track a visual target. Simultaneously, an electromyogram of the extensor digitorum communis, the primary muscle utilized in the task, was recorded. Smooth pursuit eye movements were also assessed. Accuracy of finger-based and smooth-pursuit eye movement tracking was analyzed by fast Fourier transform and expressed as a log signal-to-noise ratio. The electromyograms were analyzed by motor unit potential discrimination and by interspike interval histography. Schizophrenics demonstrated significantly poorer finger tracking than did controls, with a mean score of 2.01 +/- 0.63 (SD) versus 2.81 +/- 0.42 (t = 3.52, d.f. = 21, p < 0.005). However, there was no evidence for motor-unit dysfunction. Schizophrenics also performed more poorly on smooth-pursuit eye movement, with a mean score of 2.06 +/- 0.62 versus 3.33 +/- 1.21 (t = 3.21, d.f. = 22, p < 0.005). Severity of extrapyramidal symptoms was correlated with poorer performance on the finger tracking task, but not smooth-pursuit eye movement. These findings support the hypothesis that schizophrenics' tracking abnormalities are due to central nervous system deficits rather than peripheral pathology.

Eye tracking dysfunction (ETD) has been found in large numbers of schizophrenia patients and their first-degree relatives. Because of the many replications of the central findings, ETD has been proposed as a useful way of expanding the schizophrenia phenotype in genetic studies. We critically review the literature on ETD with respect to issues of measurement and the search for quantitative indices of ETD; syndrome and familial specificity of ETD for schizophrenia; statistical, interpretive, and methodological considerations in the use of mixture analysis; the association of ETD with clinically and psychometrically defined schizotypy; and the questions of trait stability and medication effects.

Smooth-pursuit eye movements (SPEM) were assessed in healthy subjects and in drug-naive, chronic, and residual schizophrenic patients. SPEM gain was found to be decreased in all the schizophrenic patients who also exhibited a significant increase in the rate of saccades. The frequency of square-wave jerks was the same in schizophrenic patients and normal controls, suggesting that the primary abnormality in schizophrenic patients was a low gain rather than a defect of the saccadic system. Patients were retested 1 month later, and stability of gain was high even in formerly drug-naive subjects who had been treated for 1 month with neuroleptic drugs. Altogether these results confirm the conclusions of most previous studies, extend them to drug-naive schizophrenic patients, and favor the hypothesis that SPEM impairment is a trait marker in schizophrenia.

The advent of powerful molecular biological techniques have already led to the discovery of chromosomal loci linked to some genetically transmitted diseases. These techniques, however, lose their power if applied to a disease trait that is not Mendelian in its transmission. The low familial prevalence of psychiatric diseases such as schizophrenia make these techniques unsuitable for linkage studies of these conditions, if identification of schizophrenia relies solely on the clinical manifestation of the schizophrenic psychosis. Broadening the disease phenotype in diseases such as schizophrenia, with low recurrence risk, and narrowing it in diseases such as major affective disorder, with very high recurrence risk, may be an effective strategy for linkage studies of these diseases. Several alternative phenotypes are discussed, including smooth pursuit eye movement abnormalities, event related potentials, and deficient attentional deployment as measured by the continuous performance test. The strategy assumes that schizophrenia is a pleiotropic disorder, and that the psychosis is the rare form of the condition. The paper focuses principally on smooth pursuit eye movement abnormalities, and claims a plausible place for them as an independent expression of schizophrenia. With this strategy, the possibility for successful linkage studies increases, since familial distributions of schizophrenia and pursuit abnormalities, considered together, appear to fit an autosomal dominant pattern.

Objective: Evidence suggests that poor eye tracking relates to genetically transmitted vulnerability for schizophrenia. The authors tested competing models for the genetic transmission of poor eye tracking in a search for major gene effects., Method: Samples from three studies (conducted in Minneapolis, New York, and Vancouver, B.C.) were pooled. Probands (N = 92) were diagnosed as schizophrenic by DSM-III criteria. Of the comparison subjects (N = 171), Vancouver patients were an epidemiologic first-episode group; at other sites unselected admitted patients were studied. First-degree relatives (N = 146) of 65 probands were also studied. Eye tracking was measured while subjects followed a horizontally moving, sinusoidally driven (0.4 Hz) spot of light on a screen. Performance was quantified by root mean square error. Data analysis was by complex segregation analysis (Bonney's class D regressive models)., Results: A single major gene is needed to account for poor eye tracking in schizophrenic patients and their relatives. This gene alone can explain about two-thirds of the variance in eye tracking performance. A single gene alone (regardless of dominance) will, however, not account for the data; polygenic factors are also required., Conclusions: Results support postulation of a single gene for ocular motor dysfunction, which may be a risk factor for schizophrenia. Eye tracking may be useful as a gene carrier test in genetic studies of schizophrenia.

We wished to determine the specificity of smooth-pursuit eye tracking dysfunction to schizophrenia and the prevalences of dysfunction among functionally psychotic and normal individuals. Therefore, we investigated pursuit tracking in a large sample of psychotic patients, normal subjects, and first-degree relatives (N = 482). Patients were recruited as part of an epidemiological study of first-episode psychosis that used a broadly based referral network to identify all cases in a major metropolitan area over a 2 1/2-year period. Patients received diagnoses of schizophrenia, schizophreniform disorder, psychotic mood disorder, and paranoid or other psychotic disorder based on the third edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1980). The distribution of tracking performance was bimodal for the schizophrenic patients and their relatives, perhaps reflecting major gene action. Moreover, poor tracking ran in families. Pursuit tracking dysfunction was relatively specific to schizophrenic patients and their relatives and occurred infrequently in other psychotic patients and normal subjects.

Forty-one nonpsychiatric subjects, 38 probands with schizophrenia, and 99 of their relatives were studied. Oculomotor functioning was bimodally distributed for probands and relatives. Oculomotor dysfunction was not present in all families with a schizophrenic proband. In those families in which it was present, there were significant phenotypic correlations between oculomotor functioning and schizophrenia-related characteristics. The patterns of familial resemblance in the families in whom oculomotor dysfunction was present were consistent with nonadditive genetic variance contributing both to oculomotor dysfunction and to the relationship between oculomotor dysfunction and clinical symptoms. These results suggest that schizophrenia may be etiologically heterogeneous and that oculomotor dysfunction may help to identify nonadditive genetic variance for this disorder.

Twenty-five DSM-III-diagnosed schizophrenics and 37 normal and age-matched controls were examined using an oddball paradigm for the generation of P300 and smooth eye-pursuit tasks. Results were compared between groups and related to clinical characteristics, including a family history of psychiatric illness. Group differences were found for P300 amplitudes, latencies and eye-tracking. A family history of psychiatric illness was associated with normal eye-tracking in patients. Small P300 amplitudes alone and in combination with long P300 latencies were associated with a family history in controls.