Don’t look now or look away: Two sources of saccadic disinhibition in Parkinson's disease?
Introduction
Parkinson's disease (PD) is associated with nigrostriatal and mesocorticolimbic dopamine depletion, which produces not only characteristic motor symptoms but also cognitive and oculomotor impairments. Investigations of oculomotor function often use the recording of saccades (fast eye movements), and make a distinction between reflexive (exogenous) saccades and voluntary (endogenous) saccades. The generation of reflexive saccades is usually found to be normal or faster than normal in PD (Armstrong, Chan, Riopelle, & Munoz, 2002; Briand, Strallow, Hening, Poizner, & Sereno, 1999; Chan, Armstrong, Pari, Riopelle, & Munoz, 2005; Ventre, Zee, Papageorgiou, & Reich, 1992). In contrast, studies using voluntary saccadic tasks (e.g. delayed response, memory guided or antisaccade tasks) have found evidence of prolonged latencies, hypometria and impaired voluntary suppression of unwanted saccades in PD (Amador, Hood, Schiess, Izor, & Sereno, 2006; Armstrong et al., 2002; Briand et al., 1999; Crawford, Henderson, & Kennard, 1989; Crevits, Versijpt, Hanse, & De Ridder, 2000; Chan et al., 2005; Grande et al., 2006; Hood et al., 2006; Le Heron, MacAskill, & Anderson, 2005; Lueck, Tanyeri, Crawford, Henderson, & Kennard, 1990; O'Sullivan et al., 1997; Shaunak et al., 1999; Ventre et al., 1992). This pattern of results is consistent with the tonic inhibition model of eye movement control, in which dysfunction of the voluntary eye movement system results in impaired execution of voluntary saccades as well as saccadic disinhibition (Amador et al., 2006; Chan et al., 2005; Hood et al., 2006; Sereno and Holzman, 1995, Sereno and Holzman, 1996). The inhibitory function of the voluntary saccadic system involves prefrontal processing and saccadic disinhibition in PD is thought to be associated with disruption of fronto-striatal circuitry (Amador et al., 2006, Briand et al., 1999, Chan et al., 2005). This argument is strengthened by studies of eye movement control in clinical populations with known prefrontal dysfunction, where deficits of response inhibition are found also (Munoz, Armstrong, Hampton, & Moore, 2003; Nieman et al., 2000; Reuter & Kathmann, 2004). Furthermore, it has been suggested that oculomotor deficits in PD reflect a general deficit of automatic response suppression, extending to non-motor domains including cognitive function (Amador et al., 2006, Chan et al., 2005).
The tonic inhibition model of eye movement control predicts that people with PD who are impaired at generating voluntary saccades also have a decreased ability to suppress unwanted saccades (Amador et al., 2006). However, in their investigation of these issues, Amador et al. (2006) reported a negative correlation between latencies and error rates in antisaccade tasks. Also, if saccadic disinhibition in PD is evidence of fronto-striatal dysfunction, saccadic disinhibition would be expected to be associated with impaired cognitive function. So far, however, eye movement studies in PD have not included a detailed assessment of cognitive abilities of the subjects. The aim of the present study was to investigate the source of saccadic disinhibition in PD by exploring correlations between different measures of oculomotor function and correlations between measures of oculomotor function and measures of cognitive ability.
To investigate the source of saccadic disinhibition it is necessary to assess both reflexive and voluntary saccades (Kingstone et al., 2002). The neural systems responsible for reflexive and voluntary saccades are thought to operate at least partly in parallel (Massen, 2004) before converging in the superior colliculus, where saccades are triggered (Hikosaka, Takikawa, & Kawagoe, 2000). The reflexive saccadic system is investigated with prosaccade tasks in which the subject is instructed to look, as quickly and accurately as possible, at an unpredictable peripheral target onset. The voluntary saccadic system can be investigated with antisaccade or delayed response tasks. In the antisaccade task, the subject is instructed to suppress a reflexive saccade towards an unpredictable peripheral stimulus onset and to make a saccade in the opposite direction (‘look away’) as quickly as possible after stimulus onset. In delayed response tasks, the subject is instructed to suppress a reflexive saccade towards an unpredictable peripheral target onset and delay a saccade (‘don’t look now’) until a further cue occurs. Eye movements towards the stimulus in the antisaccade task and eye movements initiated prematurely in the delayed response task are categorised as direction and timing errors respectively.
Response latencies and error rates are important indicators of the integrity of the saccadic system. Response latencies are modulated by temporal characteristics of the stimulus presentation and by task requirements. Saccadic latencies are shortest when a temporal gap of 200 ms is inserted between fixation point offset and target onset. This ‘gap effect’ is a combination of exogenous and endogenous effects. Fixation point offset automatically disinhibits saccade related neurons in the superior colliculus and it warns the subject of the upcoming target appearance (Kingstone & Klein, 1993; Spantekow, Krappmann, Everling, & Flohr, 1999). In reflexive saccadic tasks the gap effect promotes the generation of express saccades, which are very fast reflexive responses with latencies in the range 90–140 ms (Chan et al., 2005; Fischer, Gezeck, & Hartnegg, 2000; Munoz & Fecteau, 2002). Response latencies in the antisaccade task are, on average, longer than response latencies in reflexive saccade tasks. This ‘anti-effect’ represents the time needed to attend covertly to the peripheral stimulus (without making a reflexive saccade), and select the spatial parameters for the correct antisaccade (Everling & Fischer, 1998; Munoz & Fecteau, 2002). Proportions of directional errors (incorrect reflexive saccades) in antisaccade tasks and timing errors (premature responses in the correct direction) in delayed response tasks provide measures of saccadic disinhibition. In addition, abnormally high proportions of express saccades also can be considered a result of saccadic disinhibition (Matsue et al., 1994).
The present study used prosaccade, delayed response and antisaccade tasks to assess the integrity of the reflexive and voluntary saccade systems and to obtain different measures of saccadic disinhibition in people with PD and a control group. A range of standard neuropsychological tests was used to obtain measures of memory and attentional functions for each participant.
Section snippets
Subjects
Approval for this study was obtained from the Upper South A Regional Ethics Committee of the New Zealand Ministry of Health. Participants gave informed consent. Eye movement and neuropsychological data were obtained from 18 mild to moderate (Hoehn and Yahr stages 1–3), non-demented (Mini Mental State Exam score ≥ 27) and non-depressed (Beck's Depression Inventory score < 14) PD patients and 18 control subjects. The diagnosis of subjects in the PD group was confirmed by a movement disorder
Latencies
Mean latencies for each group in the prosaccade and antisaccade tasks, with and without a gap, are shown as a function of fixation condition in Table 2. Latencies of correct responses were analysed with ANOVA for repeated measures with group (PD or Control) as between subjects factor, and task (prosaccade or antisaccade) and fixation condition (with or without gap) as within subject factors. As expected, a significant main effect of task was found, with mean latencies of prosaccades shorter (182
Discussion
Oculomotor deficits associated with PD include impaired initiation of voluntary saccades and saccadic disinhibition. In the search for a unitary model of impaired eye movement control in PD, researchers have attributed these deficits to a single source: impairment of the voluntary saccadic system. The tonic inhibition model (Amador et al., 2006) suggests that dysfunction of the voluntary saccadic system results in impaired performance of voluntary saccades as well as disinhibition of reflexive
Conclusion
This study compared measures of oculomotor control and cognitive abilities of a group of people with PD and a control group. Increased production of express saccades, and higher error rates in antisaccade and delayed response tasks confirmed reports of saccadic disinhibition in the PD group. On average, the PD group scored lower in the neuropsychological tests than the control group. The pattern of associations between oculomotor measures and between oculomotor measures and neuropsychological
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