Deficits in saccadic eye-movement control in Parkinson's disease

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Abstract

In contrast to their slowed limb movements, individuals with Parkinson's disease (PD) produce rapid automatic eye movements to sensory stimuli and show an impaired ability to generate voluntary eye movements in cognitive tasks. Eighteen PD patients and 18 matched control volunteers were instructed to look either toward (pro-saccade) or away from (anti-saccade) a peripheral stimulus as soon as it appeared (immediate, gap and overlap conditions) or after a variable delay; or, they made sequential saccades to remembered targets after a variable delay. We found that PD patients made more express saccades (correct saccades in the latency range of 90–140 ms) in the immediate pro-saccade task, more direction errors (automatic pro-saccades) in the immediate anti-saccade task, and were less able to inhibit saccades during the delay period in all delay tasks. PD patients also made more directional and end-point errors in the memory-guided sequential task. Their inability to plan eye movements to remembered target locations suggests that PD patients have a deficit in spatial working memory which, along with their deficit in automatic saccade suppression, is consistent with a disorder of the prefrontal-basal ganglia circuit. Impairment of this pathway may release the automatic saccade system from top-down inhibition and produce deficits in volitional saccade control. Parallel findings across various motor, cognitive and oculomotor tasks suggest a common mechanism underlying a general deficit in automatic response suppression.

Introduction

The motor impairments of Parkinson's disease (PD), including muscle rigidity and slowness of movement (Lezak, 1995), result from degeneration of dopaminergic neurons in the substantia nigra pars compacta (Bergman & Deuschl, 2002; Leenders & Oertel, 2001). In addition to their slowed movements, individuals with PD are often impaired in their ability to suppress automatic behavioral responses (Henik, Singh, Beckley, & Rafal, 1993; Hayes, Davidson, Keele, & Rafal, 1998; Owen et al., 1993).

One set of simple behavioral tasks that may provide insight into the neural control of response suppression uses saccadic eye movements to investigate and quantify motor impairments in PD (Jones & De Jong, 1971; Shibasaki, Tsuji, & Kuroiwa, 1979; White, Saint-Cyr, Tomlinson, & Sharpe, 1983). Saccades can be measured easily and precisely; and, there is considerable understanding of the neural circuitry controlling the planning and execution of saccadic eye movements (Leigh & Zee, 1999; Munoz, Dorris, Paré, & Everling, 2000; Scudder, Kaneko, & Fuchs, 2002; Wurtz & Goldberg, 1989). Two types of responses are of interest for this study: visually triggered and volitionally guided saccades. Visually triggered saccades (sometimes called reflexive or automatic saccades) are inititated by the sudden appearance of a visual stimulus and are mediated by the superior colliculus, with important inputs from the visual and posterior parietal cortices (Guitton, Buchtel, & Douglas, 1985; Hanes & Wurtz, 2001; Schiller, Sandell, & Maunsell, 1987). Volitionally guided saccades, generated by internal goals, sometimes in the absence of any overt triggering stimulus, rely upon circuitry that includes higher brain centers such as the frontal cortex and the basal ganglia (Dias & Segraves, 1999; Gaymard, Ploner, Rivaud, Vermersch, & Pierrot-Deseilligny, 1998; Hikosaka & Wurtz, 1989; Hikosaka, Takikawa, & Kawagoe, 2000). Volitionally guided saccades can be elicited by asking participants to look from a central point to the direction opposite the eccentric stimulus (the anti-saccade task; Hallett, 1978, Munoz and Everling, 2004). For success in the anti-saccade task, participants must first inhibit a visually guided saccade towards the eccentric stimulus and instead prepare a volitional saccade to an area of the visual field without visual stimuli.

The study of saccadic inhibition provides a powerful, yet simple evaluation of control over volitional and automatic-reflexive processes (Everling & Fischer, 1998; Leigh, Newman, Folstein, Lasker, & Jensen, 1983; LeVasseur, Flanagan, Riopelle, & Munoz, 2001; McDowell, Brenner, Myles-Worsley, Coon, Byerley, Clementz, 2001; Munoz & Everling, 2004; Munoz, Armstrong, Hampton, & Moore, 2003; Ross, Harris, Olincy, & Radant, 2000). The aim of this study is to use pro- and anti-saccade tasks with immediate and delayed responses to quantify the control of automatic and volitional responses in individuals with PD. In addition, our battery of oculomotor tasks included a delayed memory-guided sequential task as a test of spatial working memory. The delayed memory-guided sequential task requires participants to suppress any eye movements during the delay period while remembering the spatial location of three targets that are flashed briefly, and then to plan the direction of movement before initiating any saccades. We measured the ability of PD patients to use spatial working memory correctly to plan eye movements to the remembered locations of the sequential targets.

Section snippets

Participants

All experimental procedures were reviewed and approved by the Queen's University Human Research Ethics Board. Eighteen mild to moderate PD patients (Hoehn–Yahr stages I–III; Hoehn & Yahr, 1967) were compared with 18 age-matched normal controls. The PD participants met clinical criteria for diagnosis and were referred by a neurologist (G.P. or R.J.R.). The PD group (11 of 18 were men) had a mean age of 67 years (range: 38–81 years). All PD patients were medicated and were not asked to interrupt

Immediate pro- and anti-saccade task

Fig. 3 illustrates the distribution of reaction times for correct (values above 0 on ordinate) pro- and anti-saccades and direction errors (values below 0 on ordinate) for PD (dashed lines) and age-matched controls (solid lines) in the immediate pro- and anti-saccade tasks with gap and overlap conditions. There are several important points to make. First, in the immediate pro-saccade task, PD patients tend to elicit more short-latency responses than control subjects. Second, among PD patients,

Discussion

We have shown that specific characteristics of saccadic eye movements are impaired in PD. We stress five important observations. First, PD patients made more express saccades in the immediate pro-saccade task. Second, they generated more direction errors in the immediate anti-saccade task. Third, PD patients were less able to inhibit saccades during the delay period in all delay tasks. Fourth, PD patients had longer reaction times in the anti-saccade task. Fifth, PD patients were impaired in

Neural pathways

The mechanisms by which the voluntary system exerts inhibitory control over the reflexive or automatic system including how target locations are memorized for future actions are hallmarks of frontal lobe function. Hallet (1978) hypothesized that, in the anti-saccade task, the inhibition of reflexive saccades requires frontal processes to send a stop signal to the superior colliculus. If the stop signal is delayed beyond a critical point, a reflexive or automatic response ensues. The signals

Adaptive mechanisms?

PD patients had shorter SRT, more express saccades, more impulsive saccades toward a target; and, they did not wait for the signal to go before making a saccade to a target. Neurological deficits may elicit these behaviors directly (see above), but an alternative explanation could be that patients with PD adapt their behavior over the course of their illness to cope with disabilities. PD patients are slow to initiate voluntary, goal-directed movements. For example, correct anti-saccades have

Conclusions

We described performance of PD patients in a battery of saccadic eye-movement tasks. PD patients executed more express saccades in the pro-saccade task, had increased direction errors in the anti-saccade task, and had greater difficulty inhibiting eye movements in the delayed oculomotor tasks. Additionally, they were impaired in their ability to accurately localize remembered targets. These results are consistent with PD impairment in saccadic inhibition and working memory, thus consistent with

Acknowledgements

We gratefully acknowledge the assistance of K. Moore. A. Bell, I. Cameron, M. Dale, J. Fecteau, J. Gore, A. Lablans, R. Levy, and R. Marino who commented on an earlier version of the manuscript. This work was supported by the Canadian Institutes for Health Research and the Canada Research Chair Program.

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