This review illustrates the growing number of investigations of saccadic eye movements in adult psychiatric patients. A variety of oculomotor tasks designed to assess reflexive and volitional saccades have been administered in the hopes of discerning more about the processes that are impacted by the mental disorders and the pathophysiological mechanisms by which these processes are disrupted. In this section, we attempt to summarize findings across the disorders, and highlight the similarities and differences that have emerged from the literature. In the final section of our discussion, we consider the ways in which saccadic research can further the field of psychiatric and neurological research, and the potential that this work has in terms of clinical practice, genetics, and pharmacology.
Among schizophrenia patients, it appears that performance on simple visually guided saccadic tasks is normal, and patients display the gap effect. Their performance on predictive saccade tasks is also indistinguishable from healthy controls. In contrast, on complex prosaccade tasks, schizophrenia patients show marked deficits. They show elevated error rates on antisaccade tasks and memory-guided (oculomotor delayed response) tasks. Furthermore, schizophrenia patients make fewer exploratory eye movements on visual search tasks than either nonschizophrenic psychiatric comparison groups or healthy controls. It is noteworthy that individuals with schizotypal traits and/or schizophrenia spectrum disorders display a similar pattern of normal saccadic and aberrant antisaccade performance.
Despite the relative sparseness of data in nonschizophrenia patient populations, tentative conclusions can be drawn regarding distinct patterns of impairment. Overall, mood disordered patients display antisaccade task impairments, though these deficits may be state-related. The patients with more severe forms of illness, such as bipolar disordered disorder with psychotic features, or major depressive disorder of the melancholic subtype, are more likely to display elevated antisaccade task errors. Although bipolar patients show difficulties with antisaccade tasks, they display normal performance on ODR tasks. Melancholic depressive patients display problems with reprogramming saccadic tasks, and decreased exploratory search behavior as well as antisaccade task deficits. Among another group of patients with affective instability, namely, individuals with borderline personality disorder, patients with psychotic symptoms performed significantly worse on the antisaccade task than healthy controls.
Adults with ADHD display aberrant performance on fixation tasks, as well as antisaccade tasks and memory guided saccade tasks. Despite a few early reports to the contrary, it appears that patients with OCD perform within normal limits on antisaccade tasks. Some individuals with Tourette Syndrome produce excessive errors on delayed antisaccade tasks, and some have difficulty delaying saccades in memory-guided sequential saccade tasks. The data suggest that in the TS population, saccadic suppression varies according to the patients’ level of motoric control.
Most of these saccadic tasks are complex behavioral assays, involving multiple components, rendering it difficult to pinpoint exactly what process underlies the performance difference between the patients and controls. A technique of behavioral parsing (c.f. Levy et al., 1998
) can allow one to infer likely sources of patients’ abnormal performance on the more complex saccadic tasks. For example, schizophrenic and ADHD patients show impaired performance on both antisaccade and oculomotor delayed response tasks, while bipolar patients show impairments only on the former task. In , we have parsed the different component processes involved in each of these saccadic tasks. As one can see, the two tasks share some molar processes in common, though some of the subprocesses differ. The ODR task requires sustained attention, so that the subject encodes the location of the target to be held on line over the delay. In contrast, the antisaccade task requires a covert shift of exogenous attention from the central fixation to the peripheral cue. Furthermore, the antisaccade task requires a spatial transformation from the position of the cue to the position of the saccade goal –-two positions which are usually in the mirror opposite locations. Both tasks, however, require inhibition. The finding that bipolar patients are able to perform ODR tasks as well as healthy control subjects suggests that their antisaccade task impairments may not be due to an inability to inhibit responses, but rather to a difficulty inhibiting responses when it is appropriate to do so, i.e., difficulty implementing inhibition. This interpretation of bipolar patients’ antisaccade task deficits is consistent with their antisaccade task deficits being state-dependent as well. This could also account for other individuals with mood disorders and/or affective lability; perhaps due to their mood disturbances, they are more susceptible to and/or more easily distracted by environmental stimuli such as the peripheral cue and thus are unable to implement inhibition in a context in which another response is more potent.
Component Processes Implicated in Saccadic Task Paradigms
One can also look at the patients’ performance across various saccadic tasks in order to discern more about the brain circuitry that is likely to be implicated in their underlying pathophysiology. Overall, all patient groups are likely to have normal saccadic eye movement brainstem circuits. Patients with Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), affective disorder, and schizophrenia have no obvious abnormalities of saccadic eye movement characteristics, provided the tasks are simple and the target of the saccade remains illuminated. Some reports indicate that these patient groups show altered latencies of visually-guided saccades. However, changes in latency of saccades are not generally considered a sign of brainstem alterations. Rather changes in latency are likely to reflect alterations in the descending drive to brainstem circuits (reviewed in Munoz and Everling, 2004
Schizophrenia, ADHD, and TS patient groups show deficits that are consistent with the overarching hypothesis that they are unable to make eye movements to goals that are represented internally. Striking saccade abnormalities appear in these adult psychiatric patients in tasks that rely on memory, prediction or other higher-order cognitive processing. For example, one common theme that appears in this complex and at times contradictory literature is that during performance of the antisaccade task, patients with schizophrenia, ADHD and TS all have increased error rates. Most of the studies agree that each of these patient groups has an inability to inhibit the reflexive prosaccade to the cue. Thus, one general conclusion is in all three patient groups, there is disruption in the circuitry underlying suppression of unwanted responses, i.e., the frontostriatal circuitry. Indeed, these patients’ inhibitory deficits in the antisaccade task suggest a dysfunction in the top-down inhibition of saccade brainstem circuits, largely consistent with a deficit in the DLPFC (see glossary).
Patients with DLPFC lesions show increased prosaccade errors in the antisaccade task (Fukushima, Fukushima, Miyasaka, & Yamashita, 1994
; Guitton, Buchtel, & Douglas, 1985
; Gooding et al., 1997
; Pierrot-Deseilligny et al., 1991
; Machado & Rafal, 2004
). In the Fukushima et al. (1994)
investigation, the frontal lesion patients displayed higher error rates as well as longer latencies in the antisaccade task compared to the control subjects. Pierrot-Deseilligny et al. (1991)
conducted a comparative study of a group of patients with neurological lesions located in various frontal (FEF, supplementary motor area, DLPFC) regions with subjects with posterior parietal lesions and normal controls. They observed that only those patients with dorsolateral prefrontal lesions had a significantly higher error rate than the controls on the antisaccade task.
In patients with schizophrenia, ADHD and TS there are variable reports of increases in saccade latency. Thus, those patients with latency changes in addition to changes in error rate on the antisaccade task may point toward involvement of multiple cortical areas in their psychiatric illness. The differences in the magnitude and number of additional saccadic eye movement abnormalities relative to healthy controls may suggest the relative extent of dysfunction in the corticostriatal circuitry. For example, the psychiatric patient groups also differ in terms of their ability to perform tasks requiring sequencing of saccadic eye movements. Schizophrenia patients make fewer exploratory eye movements on visual search tasks than depressive patients and healthy controls. This finding supports the assertion that schizophrenia patients’ frontal dysfunction is more extensive than that found in the other psychiatric groups compared here, with additional disruption in the SEF, which are involved in cortical control of internally guided decision-making and sequencing of saccades (Tehovnik, Sommer, Chou, Slocum, & Schiller, 2000
; Gold & Shadlen, 2007
). We also noted that depressive patients with the melancholic subtype of the disorder experience significant difficulty on a task requiring reprogramming of saccadic eye movements. This finding suggests that the melancholic subtype of major depressive disorder may be more associated with corticostriatal dysfunction than other forms of depression (Rogers et al., 2000
). Comparing patients with basal ganglia disease such as Parkinson’s Disease to those with psychiatric disease may shed further light on the neural substrates of deficits. In contrast to what one might predict, patients with Parkinson’s Disease often have reduced saccade latencies for prosaccades and often make more express saccades in the gap task than healthy, age-matched controls (Chan et al 2005
). Interestingly although variably reported, Parkinson’s patients often make more prosaccade errors on the antisaccade task than healthy controls (Briand et al 1999
; Fukushima et al., 1994
; Vidailhet et al., 1994
; Chan et al., 2005
). Thus Parkinson’s Disease patients display an inability to suppress reflexive saccades as well as alterations in saccade latency. Deficits in the generation of both prosaccades and antisaccades suggests that these impairments may result from a similar underlying process that is altered in Parkinson’s Disease, whereas in schizophrenia, ADHD, TS and OCD, where prosaccades are largely intact and antisaccades are impaired, only part of the saccadic system is compromised.
Two recent investigations in nonhuman primates by Basso and Liu (Basso & Liu, 2007
; Liu & Basso, 2008
) demonstrate the effects of altering basal ganglia input on saccades. Electrical stimulation of an output nucleus of the basal ganglia resulted in a reduced latency and decreased variability in the latency of visually- guided saccades (Liu & Basso, 2008
). The stimulation also resulted in an increased latency of memory guided saccades (Basso and Liu, 2007
). Furthermore, the investigators observed that directional errors occurred only for memory saccades, whereas the direction of visually guided saccades was largely unaffected. It is noteworthy that basal ganglia dysfunction is implicated in both Parkinson’s Disease and schizophrenia. These phenomena are similar to the pattern of deficits generally observed in patients with Parkinson’s Disease (Briand, Strallow, Hening, Poizner, & Sereno, 1999
; Brown et al., 1993
; Corin, Elizan, & Bender, 1972
; DeJong & Melvill Jones, 1971
; Fukushima, Fukushima, Miyasaka & Yamashita, 1994
) and schizophrenia. Through basal ganglia inputs to the superior colliculus (see glossary) (Liu and Basso, 2008
) the resulting effects on saccades may appear very similar in spite of very different neuropathological processes. One hypothesis is that the alterations in dopaminergic tone that occur in either Parkinson’s Disease or schizophrenia may alter the signaling within the basal ganglia. Therefore, one interesting future direction would be to compare the variability in saccade reaction times across psychiatric patient populations. When prosaccades and antisaccades occur in rapid alternation, Tourette Syndrome patients are better than healthy controls subjects at suppressing the occurrence of reflexive saccades in the antisaccade task. This result argues strongly that TS patients are able to suppress movements even better than control subjects. Given that many TS patients practice suppressing their tics, this finding may be unique to this patient population. Nevertheless, the result may have occurred because of a compensatory mechanism in which subjects exert extra effort to suppress movements. Indeed, it is important to consider the possibility that compensatory strategies may influence saccade behavior whenever interpreting the results of oculomotor assays.
As this review illustrates, the study of saccadic eye movements holds great potential for the fields of psychiatry and neurology. Our survey of the extant literature also indicates considerable variability in saccadic performance both within and across patient populations. It may instructive to administer multiple permutations of the same task in the same study. This strategy can be used in order to create a more specific profile of the patient group’s behavioral performance across tasks, potentially providing more insight into the nature of the underlying dysfunction (Levy et al., 1998
; Nieuwenhuis et al., 2004
). Just as some investigators (Winograd-Gurvich et al., 2006a
) observed performance differences between depressive patients with versus without melancholia, it would be useful in future studies to parametrically alter saccadic tasks specifically to tease apart the mechanisms underlying the melancholic patients’ saccadic deficits. Furthermore, it is possible that in some patient groups, such as schizophrenia patients, different subtypes may have different mechanisms underlying their antisaccade deficits. Indeed, this area of inquiry would be advanced by including tasks in which the ability to inhibit reflexes in other modalities or across different contexts is assessed.
The variability in saccadic performance across patient populations could be used to clinical advantage. A potential clinical application of saccadic research would be the development of typical performance profiles across a battery of saccadic tasks for different psychiatric patient groups. In order to achieve this goal, researchers in this area would need to include multiple saccadic tasks in each battery on a regular basis. Once a sufficient database is developed, individuals’ performance on the saccadic battery could be compared against the prototypical profiles for each patient group. Sufficiently large samples would be needed to develop reliable profiles and to insure adequate statistical power. Research based on extremely large samples such as the COGS study (Radant et al., 2007
) looks promising, though the researchers will be limited in the number of antisaccade task conditions they can include in their battery. This strategy namely, developing prototypical performance profiles based upon a combination of saccadic tasks and the use of several saccadic parameters, could be used to aid in the differential diagnosis of commonly misdiagnosed disorders, such as schizophrenia versus bipolar disorder, or progressive supranuclear palsy versus Parkinson’s Disease (see, for example, Antoniades, Bak, Carpenter, Hodges, & Barker, 2007
Saccadic research also holds great promise for informing current efforts in the field of genetics. Genetic heterogeneity undoubtedly stymies progress in the effort to uncover the etiology of complex genetic disorders. Observations of performance differences between subgroups within a given diagnostic group can be used to help establish more homogeneous subtypes, perhaps improving the efficiency of gene detection. One example of a disorder in which this strategy would be helpful is Tourette’s Syndrome, which is sometimes accompanied by obsessive compulsive behavior and/or symptoms (Robertson, 2000
). It would be interesting and informative to determine whether there are performance differences between Tourette’s patients with and without OCD. If there are reliable performance differences, these findings may help to assist subtyping before the genetic studies commence.
Another application for saccadic research lies in the area of pharmacology. With the exception of schizophrenia, in which antisaccade task performance appears to be a trait-related characteristic, saccadic task performance may be used to test the effects of pharmacological interventions. Test-retest designs investigating aspects of saccadic performance can be used to determine the efficacy of pharmacological agents purported to improve attentional functioning and/or motor control. Alternatively, clinicians could refer patients to investigators for oculomotor assays in order to test for adverse effects of medications on cognitive functions such as attention, memory, and reaction time. In summary, combining batteries of saccade tasks with state of the art genetic, pharmacological and clinical tools/procedures holds much promise for unlocking the mysteries of heterogeneous and varied psychiatric illness.