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Abstract

Objective: Our aim was to review smooth pursuit eye movement (SPEM) studies in schizophrenia and groups at high risk for schizophrenia, with a view to evaluating the utility of SPEM dysfunction as a biological marker of risk for schizophrenia.

Method: Smooth pursuit eye movement studies, related saccade function and the unresolved issues in this area of schizophrenia research were addressed. The different perspectives on the trait marker status of SPEM dysfunction, provided by both high-risk studies and related developmental research were considered. Attention was also given to the relationship between eye movement dysfunction and symptom profiles.

Results: Converging evidence points to the robust and specific nature of SPEM dysfunction in schizophrenia, and highlights the role of frontal lobe and a related network dysfunction. The vast majority of ‘high risk’ studies support the view that SPEM dysfunction is also genetically specific to schizophrenia, and is not simply due to the overt expression of this illness. Studies assessing SPEM in relation to symptomatology show an association with the Disorganisation syndrome in particular.

Conclusions: Evidence for the specificity of SPEM dysfunction to diagnosed schizophrenia, as well as to healthy individuals with a genetic vulnerability to schizo-phrenia, suggests that the SPEM task has efficacy as a test of gene carrier status in schizophrenia, and therefore as a trait marker of risk for schizophrenia. Future studies should seek to explore the relationships between SPEM and other eye movement dysfunctions (antisaccades, express saccades), in view of evidence that some of these dysfunctions also show specificity for schizophrenia.

Keywords

genetics high risk saccade schizophrenia smooth pursuit eye movement (SPEM)

Smooth pursuit eye movements (SPEM) occur when subjects track a smoothly moving target that typically oscillates in the horizontal plane. From the large literature on SPEM dysfunction in schizophrenia, there is consensus that it may be a trait marker of risk for schizophrenia. The disturbances consist mainly of saccadic intrusions and compensatory saccades (catch-up saccades) when the eyes lag behind the target. However, the question of whether the fundamental causal deficit in SPEM dysfunction is one of reduced inhibition of the saccade/fixation system (producing saccadic intrusions) or one of diminished eye compared to target velocity (producing frequent catch-up saccades) remains unclear.

In this review, we first summarise SPEM studies into schizophrenia, unresolved issues in this area, and related saccade function research. In subsequent sections, we discuss family and high-risk studies of SPEM, followed by related developmental studies, in which each provides a different perspective on the trait marker status of SPEM dysfunction. The final section considers the heterogeneity of eye movement dysfunction in schizophrenia in relation to symptom profiles, and our conclusion focuses on the convergence of SPEM evidence.

Smooth pursuit eye movement dysfunction in schizophrenia

Initial studies by Holzman and colleagues reported that over half of their schizophrenia patient sample (52–86%%) exhibited SPEM dysfunction, whereas only a relatively small proportion of patients with nonschizophrenic psychotic conditions (22%%), patients with nonpsychotic disorders (21%%) and normal control groups (8%%) showed the dysfunction [1],[2]. A large number of subsequent studies have confirmed the specificity of SPEM dysfunction to schizophrenia [3]. Reports of SPEM dysfunction in patients with bipolar disorder have been accounted for by the influence of lithium carbonate medication [4],[5]. Previous studies have shown that typical neuroleptics neither cause nor improve SPEM dysfunction in schizophrenia [3],[6],[7]. Findings of SPEM dysfunction in high-risk groups have been limited to schizophrenia spectrum disorders, including patients with schizotypal personality disorder and questionnaire-identified normal individuals with high levels of schizophrenia-like traits [8],[9]. Illness chronicity has also not been associated with SPEM dysfunction; both acute and chronic patients with schizophrenia exhibit these disturbances [10–12].

There has been some controversy over the fundamental nature of SPEM dysfunction in schizophrenia, and the associated debate over the most effective way to measure SPEM dysfunction remains a similarly unresolved issue. The vast majority of SPEM studies reporting a dysfunction in schizophrenia have used global measures of SPEM, including qualitative ratings, a root mean square error (RMSE) measure of the cumulative differences between the position target and position of the eye, and the signal to noise ratio (see Clementz and Sweeney for further detail [13]). Some researchers have suggested that qualitative ratings or the global quantitative RMSE may be more sensitive to SPEM dysfunction than precise quantitative parameters, such as pursuit gain and frequency of different saccade types [14]. Such global and specific measures may in fact be complementary [15].

The most commonly used specific parameters have been measures of saccade frequency and pursuit gain to observe whether disturbances during SPEM reflect saccadic intrusions or reduced speed of pursuit. Schizophrenia studies using the specific measures have produced controversial results, leading to a lack of certainty about the underlying ocular motor pathophysiology. Several studies indicate that the underlying mechanism in SPEM dysfunction is low gain (the ratio of eye velocity to target velocity), requiring frequent catch-up saccades as compensatory strategy [16–18]. Others argue that the incidence of intrusive anticipatory saccades is a more fundamental indicator of SPEM dysfunction in schizophrenia, reflecting a lack of inhibition in the system controlling saccades and eye fixations [19–21]. While these two view-points have been the major competing theories of SPEM dysfunction in schizophrenia, Flechtner et al. recently raised doubts about these specific quantitative SPEM measures in general [22]. It was suggested that small saccades occurring near the target could be falsely defined as either catch-up or anticipatory saccades, as the currently used eye movement recording systems do not provide an absolute index of eye position. The significance of specific disturbances to SPEM dysfunction, relative to global measures, remains to be determined.

Given the controversies in research into SPEM dysfunction in schizophrenia, neuroimaging studies might provide complementary information about these disturbances. Healthy SPEM performance depends upon multiple sites of activation in the frontal cortex (frontal eye field (FEF), supplementary eye field (SEP)); the intraparietal cortex (parietal eye field (PEP)); the junction of occipital and temporal cortex (MT/MST or V5) cortex; and the precuneus (the dorso-medial parietal visual area), as well as in subcortical areas, such as the superior colliculus, pontine nucleus or cerebellar structures [23–25]. Attempts to characterise the basis of SPEM dysfunction in schizophrenia have emphasised the role of the frontal lobe in SPEM performance [26]. Neuropsychological frontal lobe tasks, such as working memory or the Winsconsin Card Sorting Task (WCST), were reported to be associated with SPEM dysfunction [27],[28]. Neuroimaging studies have confirmed that SPEM dysfunction is subserved by schizophrenic abnormalities in the frontal lobe [29],[30]. Nevertheless, parietal lobe lesions involving the MT/MST areas have been found to produce SPEM impairments [31],[32]. As the smooth pursuit of a moving target is dependent upon visual motion information that is processed in the MT/MST areas, these lesion data may have been of recent interest to schizophrenia SPEM researchers, but the evidence as to whether the MT/MST functions are intact or dysfunctional in schizophrenia is contro-versial [33],[34]. In this regard, it might be important to note Holzman's suggestion that the MT/MST regions involve projections to the frontal cortex, as a network [35].

In view of the converging evidence for the role of the frontal lobe in SPEM impairment, one might consider the implications for specific aspects of this impairment. The suggestion that low pursuit gain may be the core feature of SPEM dysfunction in schizophrenia is consistent with the notion of frontal lobe damage, and FEF in particular [36]. However, SPEM dysfunction in schizophrenia includes not only low gain, but also saccade intrusions that are more difficult to explain directly in terms of frontal lobe damage. An alternative possibility might be that different brain structures that should participate together to produce normal SPEM may fail to interact with each other as a whole system in schizophrenia. Given that the SPEM task taps complex and multiple dimensions of information processing, including self-generated mental activity [37], it is unlikely that a single brain region is responsible for SPEM performance. From this viewpoint, however, the frontal cortex would have a central role in the coordination and synchronisation of effective SPEM performance, and the failure of integration resulting from frontal abnormalities could produce the group of observed SPEM aberrations. Recent studies on saccade function might also provide additional insights into SPEM dysfunction in schizophrenia.

Saccade dysfunctions in schizophrenia

Antisaccades

The antisaccade task has frequently been used in conjunction with the SPEM task, as a complementary index of voluntary eye movement control. Antisaccades occur when subjects are instructed to move their eyes in the direction opposite to a visual target, whereas prosaccades (or visually guided saccades) refer to eye movements directed towards a target. The main performance indices in the antisaccade task are direction error and saccade latency. Fukushima et al. were the first to demonstrate that patients with schizophrenia have difficulties in controlling their eye movements during the antisaccade task [38], and their results have since been consistently replicated [39–41]. Antisaccade errors have also been found to be positively correlated with perseveration errors on the WCST [42–45], and with poor working memory on neuropsychological tests [41] in schizophrenia subjects.

The frontal cortex is even more strongly implicated in antisaccade performance than it is in SPEM. Impaired performance occurs in patients with frontal lobe lesions (particularly in the dorsolateral prefrontal cortex (DLPFC) and FEF), but not those with temporal lobe damage [46],[47]. Brain imaging studies have also implicated frontal areas (e.g. DLPFC, FEF and SEP) in impaired antisaccade performance [48], as well as in healthy antisaccade, compared to prosaccade performance [49]. In schizophrenia patients, antisaccade deficits have been associated with both frontal lobe and reduced activation of the DLPFC [29].

Despite the strong evidence for antisaccade dysfunction in schizophrenia, similar dysfunctions have also been observed in other psychiatric disorders, such as obsessive compulsive disorder and bipolar disorder (see Everling and Fischer for a review [50]). Antisaccade dysfunctions in schizophrenia might also be partly accounted for by medication effects [51]. Therefore, similarly to the WCST, the antisaccade task may be highly sensitive, but not necessarily specific, to schizophrenia.

Express saccades

The onset latency for the generation of a typical saccade is greater than 200 ms. However, neurophysiological studies have clearly established that brief ‘express saccades’ can occur within 90–130 ms in humans and 65–100 ms in monkeys when there is no initial fixation stimulus [52]. Express saccades can be tested within a prosaccade task, where the temporal gap between fixation stimulus and target is typically 200 ms. Lesion evidence indicates that the FEF may play a role in the generation of express saccades [53]. However, the superior colliculus, which receives direct input from the retina, is thought to be primarily involved in the production of express saccades [54]. The functional significance of express saccades has been demonstrated in primates during visual scanning; express saccades are more likely to occur just before starting saccade than just after [55],[56]. As express saccades could be more frequently generated during the period of saccade preparation, high frequency of express saccades in patients with schizophrenia points to an unstable fixation system, possibly associated with distractibility in this disorder.

Only a few studies have examined express saccades in schizophrenia [57–59]. In these studies, patients with schizophrenia produce a greater number of express saccades than normal controls, even when a fixation point is present as a means of directing attention. (For examples see Clementz [57] and Matsue et al. [58]). The high frequency of express saccades associated with schizophrenia reflects their often-reported distractibility in the face of irrelevant information, and may indicate a weakened inhibitory mechanism in the fixation system [60],[61]. The evidence as to whether express saccade dysfunction is specific to schizophrenia is more compelling than that for antisaccades. Sereno and Holzman found that schizophrenia patients are discriminated from bipolar subjects on express saccade performance [59]. Dyslexic individuals have shown similar express saccade impairments to schizophrenia patients, but only in conditions where there is no fixation point; they show fewer express saccades in the presence of a fixation stimuli [52],[62]. Patients with frontal lesions show a similar pattern of express saccade dysfunction to dyslexic subjects [63], indicating that express saccade disturbances in schizophrenia are generally more severe than in other disorders, and may not be entirely explained by frontal lobe abnormalities.

The relationship between smooth pursuit eye movement and saccade dysfunctions in schizophrenia

A number of studies have addressed the links between SPEM and antisaccade dysfunctions in schizophrenia. Schizophrenia patients who exhibit SPEM dysfunction have also been found to show a greater number of errors and longer latencies on the antisaccade task than schizophrenia patients who do not have a SPEM dysfunction [64],[65]. Interestingly, Clementz et al. noted that the antisaccade task is in fact superior to SPEM in discriminating patients with schizophrenia from normal controls [40]. Concerning SPEM and express saccades, schizophrenia patients with SPEM dysfunction also show significantly more frequent express saccades than patients without SPEM dysfunction [58],[59].

In summary, therefore, both antisaccade and express saccade dysfunctions are positively correlated with SPEM abnormalities in schizophrenia. Nevertheless, the evidence suggests that these eye movement abnormalities may differ with regard to their specificity to schizophrenia and their neural basis. While global SPEM and severe express saccade dysfunctions may be specific markers of schizophrenia, antisaccade impairments have been found in other psychotic disorders. Frontal lobe abnormalities might underlie antisaccade dysfunctions, as well as less-specific SPEM, but cannot fully account for express saccade impairments.

Family and high risk studies of smooth pursuit eye movement

In view of the robust and specific nature of SPEM dysfunction in schizophrenia, it has long been proposed as one of the most promising trait markers for genetic liability to schizophrenia. Studies of first-degree relatives of schizophrenia sufferers, as well as other ‘high risk’ groups, have directly addressed this issue.

First-degree relative studies provide compelling evidence that SPEM dysfunction is a specific genetic marker of risk for schizophrenia. An initial study by Holzman et al. reported that almost a half (45%%) of the unaffected first-degree relatives of schizophrenia sufferers exhibited SPEM dysfunction, whereas only 10%% of control group relatives showed this dysfunction [2]. The genetic specificity of SPEM dysfunction to schizophrenia is supported by evidence that neither relatives of bipolar sufferers, nor relatives of major depressive patients show SPEM dysfunction [66–68].

Another line of research pointing to the genetic specificity of SPEM dysfunction has sought to consider this dysfunction in relation to additional risk factors for schizophrenia. Other risk factors implicated in the aetiology of schizophrenia include obstetrical complications and extreme weather at time of birth [69]. Kinney et al. reported that patients with schizophrenia, but without SPEM dysfunction, were significantly more likely to be born in months with intemperate weather (both hot and cold) than either patients with SPEM dysfunction or people in the general population [70], suggesting that the ‘weather’ risk factor does not compound vulnerability in terms of SPEM dysfunction. Moreover, Kinney and coworkers reported that the combination of SPEM dysfunction and obstetrical complication could discriminate patients with schizophrenia from both nonschizophrenic siblings of schizophrenia and normal controls [71]. This evidence was interpreted as indicating that both environmental (i.e. birth-month weather and obstetrical complications) and genetic components play a role in aetiology of schizophrenia, and SPEM dysfunction is associated with the genetic component.

Studies addressing direct family histories show that schizophrenia patients with SPEM dysfunction tend to have at least one parent who also exhibits SPEM dysfunction [72]. Patients with schizophrenia who come from families where there is a history of schizophrenia also show greater SPEM dysfunction, together with poorer performance on neuropsycho-logical tests, than patients without such a family history [73]. Several researchers have also considered the incidence of schizophrenia spectrum personality disorders (SSPD) with regard to SPEM dysfunctions in relatives of schizophrenia sufferers. Schizophrenia relatives with SSPD tend to show poorer SPEM quality (including anticipatory saccade and pursuit gain measures) compared to relatives without SSPD and compared to control SSPD subjects who have no family history of schizophrenia [74],[75]. Family members of schizophrenia patients also show associations between global SPEM dysfunction (RMSE) and reduced pursuit gain, and schizophrenia-like features of psychoticism and social–interpersonal dysfunctions [76]. The differentiation between SSPD subjects with and without a family history of schizophrenia indicates that SPEM dysfunction in family members with SSPD is not simply due to their psychotic-like SSPD symptoms, but is instead due to the incidence of schizophrenia in their family.

Genetic analysis of SPEM dysfunction in schizophrenia patients and their relatives indicates that either a single dominant gene [77] or a poly genic mechanism (a major gene together with other gene effects) [78] explains SPEM dysfunction in schizophrenia. While researchers disagree over how best to measure SPEM dysfunction in schizophrenia [3],[79], they agree on the strong genetic basis of SPEM dysfunction, and the utility of SPEM as a gene carrier test.

The issue of exactly which components of SPEM dysfunction might be genetically transmitted remains a contentious issue. For instance, Grove et al. found that global SPEM dysfunction (indexed by RMSE) has a familial basis but did not distinguish relatives of patients with schizophrenia from control subjects, whereas gain did not appear to be familiarly transmitted but did differentiate relatives from controls [80]. Clearer results have been obtained for anticipatory saccades [81]. Both schizophrenia patients and obligate carrier parents show similarly increase anticipatory saccade during SPEM compared to controls, while noncarrier parents had even fewer anticipatory saccades than age matched normal controls. Rosen-berg and colleagues also reported that anticipatory saccades are more specific to offspring of schizophrenia sufferers than a global SPEM measure [82].

There is also some evidence that antisaccade impairments have a familial basis. McDowell et al. found increased antisaccade error rates in large samples of patients with schizophrenia as well as in their first-degree relatives [83]. Ross and coworkers also found more error rates in patients with schizophrenia and their parents when there was a family history of schizophrenia, than in parents with no family history or normal controls [81]. However, Crawford et al. found no evidence that first-degree relatives have a similarly high antisaccade error rate to patients with schizophrenia [84]. Thaker and colleagues reported delayed antisaccade latency (but not error rate) in relatives of schizophrenia [74]. Together, these studies suggest that, while there is strong support for the genetic basis of SPEM dys-function, antisaccade impairment may not represent a similarly specific marker for risk of schizophrenia [85]. Instead, the fact that antisaccade performance relies more heavily on an intact DLPFC than SPEM, suggests that it may be a more sensitive, global index of psychopathological conditions.

Another less common strategy for examining high risk for schizophrenia is to look at healthy nonrelatives scoring highly on scales of schizophrenia-like traits. College students with high levels of schizotypal personality traits have been found to show poor SPEM quality, whereas nonschizophrenia-related personality traits are independent of SPEM dysfunction [8],[86]. Similarly, Siever and coworkers reported that college students exhibiting SPEM dysfunction were more likely to experience schizotypal symptoms and to have several cognitive and attentional deficits [87], but not affective symptoms [88]. Smooth pursuit eye movement dysfunction has also been associated with high scores on both positive (perceptual aberration) and negative (physical anhedonia) aspects of schizotypy [89],[90].

As in both schizophrenia and relative samples, O'Driscoll and colleagues found that both SPEM and antisaccade impairments were greater in high ‘schizotype’ subjects compared to control subjects, and that SPEM and antisaccade measures were correlated [91]. High ‘schizotypes’ also displayed impairments in a delayed oculomotor working memory and an antisaccade task, which were both linked to signs of thought disorder, as assessed by the Rorschach test [85]. Nevertheless, some researchers question the trait marker status of SPEM dysfunction in this population, suggesting that it may instead reflect general cognitive abnormalities [92].

The vast majority of SPEM studies support the genetic basis of SPEM dysfunctions in schizophrenia. However, there are also at least two negative findings. In contrast to other studies of family history, Malaspina and coworkers found that SPEM performance was poorer in schizophrenia patients without a family history than in those with a family history [93]. In a sample of 12 monozygotic twins (one twin with schizophrenia and one unaffected), Litman and colleagues found that SPEM performance in the unaffected cotwins was within normal range, and suggested therefore that SPEM dysfunction is linked to the expression, rather than the genetic vulnerability, of the illness [94].

Development of smooth pursuit eye movement and saccade functions

While eye movements may provide a useful tool for examining neuropathology and genetic factors in schizophrenia, basic research on the developmental course of SPEM and saccade performance is still lacking. Studies addressing the development of SPEM performance indicate that there are two separate components in SPEM; one (low gain and catch-up saccade) is age-dependent, the other (saccade intrusion) is relatively age-independent (Ross et al. [95],[96] and Spooner et al. [97] provide examples).

Children with schizophrenia show SPEM dysfunctions akin to their adult counterparts. Jocobsen and colleagues revealed SPEM dysfunction (increased RMSE and anticipatory saccades frequency) in 17 children patients with schizophrenia (range: 10–18 years) compared with patients with attention deficit hyperactivity disorder and normal controls [98]. Similarly, Ross and coworkers found that anticipatory saccades are more frequent in the normally developing children (range: 6–15 years) of schizophrenic parents [99].

The voluntary and involuntary components of eye movement control may be dissociated by age [100]. Children below age 11 are almost unable to perform the antisaccade task and the error rate decreases until age 20. On the other hand, the number of express saccades does not change with age. The improvement in antisaccade performance with age seems to reflect the major developmental changes in the DLPFC that continue into the mid-twenties [101], whereas the relative independence of age and express saccades suggests that a separate oculomotor fixation system develops much earlier [102].

Smooth pursuit eye movement dysfunction and symptomatology

Longitudinal studies of SPEM in schizophrenia have suggested that SPEM dysfunction is stable over time, regardless of fluctuations in the illness state [11],[12],[103]. However, some cross-sectional studies report that SPEM dysfunction differs among specific symptom subtypes. Of studies examining the relationship with the broad positive/negative symptom distinction, some studies found an association between SPEM dysfunction and negative symptoms while other studies failed to find such an association [104],[105]. Gaebel and Ulrich also found an association between negative symptoms and SPEM, but this relationship was no longer present when duration of illness was controlled for [106]. An initial study by Holzman found that the individual positive symptom of thought disorder is associated with SPEM dysfunction [107],[2].

Our recent study, using a large, representative schizophrenia sample, suggests that more specific SPEM-symptom relationships might be revealed by consideration of Liddle's [108] three schizophrenia syndromes of Disorganisation, Reality Distortion and Psychomotor Poverty [109]. Like SPEM, these three syndromes have been found to be stable over time, and remain relatively independent [41],[110]. Of the three syndromes, only the Disorganisation dimension showed a significant association with increased global SPEM dysfunction. Nieman and colleagues found that the Disorganisation syndrome is associated with poor performance on the antisaccade task as well [41]. Given that Disorganisation has also been associated with specific genetic and familial factors [111],[112],[113], it is possible that this syndrome represents a fundamental schizophrenia pathology, and that SPEM dysfunction provides a trait marker for this core pathology. However, further studies of symptom profile in additional schizophrenia samples are required to substantiate this proposal.

Conclusion

Longitudinal studies of SPEM in schizophrenia have established that SPEM dysfunction is stable over years of evaluation despite fluctuations in medical state [11],[12],[103]. Smooth pursuit eye movement dysfunction consistently discriminates schizophrenia from other psychiatric disorders and controls. The stability, sensitivity, and specificity of SPEM dysfunction to schizophrenia has prompted research into the genetic marker status of SPEM. Family and twin studies provide strong evidence that SPEM is a specific marker of genetic vulnerability for schizophrenia. Evidence that SPEM dysfunction is not influenced by environmental factors relevant to the expression of schizophrenia also supports the utility of SPEM dysfunction as a genetic marker for schizophrenia. As such, SPEM dysfunction may be useful for segregating environmental and genetic components involved in the aetiology of this complex disorder.

The frontal lobe is likely to play a central role in producing eye movement dysfunction, particularly for antisaccade performance and pursuit gain in schizophrenia. However, involvement of multiple brain regions in SPEM performance indicates that a lesion model of SPEM dysfunction would be insufficient in explaining its occurrence in schizophrenia. Instead, the dysfunction may represent an abnormal interaction between frontal lobe and its functionally connected cortical and subcortical areas. Developmental studies also suggest that the age-related variation of frontal lobe function should be taken into account.

The fundamental nature of SPEM dysfunction remains an unresolved issue. While there is little doubt that SPEM dysfunction is a specific trait marker of schizophrenia, there is a consensus that SPEM dysfunctions reflect central nervous system neuropathology in schizophrenia. The relative lack of research into eye movement indices other than SPEM deserves attention as a means of providing comple-mentary information. In this regard, express saccades and their proposed link to fixation system, are a viable area of future research. As several studies have also found free viewing eye movement abnormalities in schizophrenia [114],[115],[116], the relationship between pursuit and free visual scanning would also be of interest. Simultaneous assessment of express saccade during scanning eye movement (for an example see Sommer [56]) may be particularly useful for evaluating the relationship between these measures in patients with schizophrenia.

Our review of SPEM evidence in schizophrenia shows that there is little dispute about previous claims that SPEM dysfunction is a feasible trait marker of schizophrenia. However, future studies might seek to clarify the basic biological basis of SPEM dysfunction and its relationship with other eye movement aberrations.

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