Introduction
Healthy elderly adults and patients with Parkinson's disease (PD) are generally less proficient in the cognitive control of goal-directed actions than healthy young adults. Proficiency in cognitive control involves a wide range of processes that are relevant for personal independence in everyday task performance. A key characteristic is the cognitive anticipation of actions that need to be executed. This capacity is affected by aging (Falkenstein et al., 2006; Roggeveen et al., 2007; Sterr and Dean, 2008) and in Parkinson patients. Impaired cognitive anticipation has been observed in several cognitive control tasks such as the antisaccade task and in task switching tasks. In the Stroop task, as well as in oculomotor switch tasks, switch costs increase with PD, specifically when patients switch from a more automatic to a more voluntary response (Woodward et al., 2002).
Some generic factors have been found to alleviate these problems in the elderly. Performance improves, for instance, if specific information on the upcoming response is available in advance (Sterr and Dean, 2008). Likewise, older adults may benefit from prolonged preparation time (Loveless and Sanford, 1974; Bonin-Guillaume et al., 2000).
In the current study, we are interested in whether action preparation can be optimized using motivational factors. One powerful motivator of goal-directed behavior is the prospect of obtaining a reward. Rewards come in many shapes and forms: apples, juices, money, and even symbolic tokens (e.g., game points) are considered powerful rewards. The weighting of the potential rewards and punishments associated with behavioral options is instrumental to efficient behavior (Opris and Bruce, 2005; Schultz, 2006). Expectations of upcoming rewards influence systems concerned with action preparation and motor control. Indeed, for primates (Lauwereyns et al., 2002; Kawagoe et al., 2004) as well as humans (Ramnani and Miall, 2003), it is shown that actions are executed with greater efficiency when their goals are rewarded. Reward thus seems to play an important role in shaping behavior, but it is unclear as to whether it can also exert remedial effects on behaviors that show signs of decline, such as those associated with aging. Given that the neural substrates of reward processing are deemed to be vulnerable to the effects of advancing age (Marschner et al., 2005; Mell et al., 2005, 2009; Schott et al., 2007; Weiler et al., 2008), remedial effects may in fact be unobservable.
To investigate the remedial potential of reward expectations on declining action preparation, we focus on antisaccade performance. Antisaccades are particularly demanding in terms of action preparation (Reuter et al., 2006), and the efficiency of this type of process declines with age and in PD. For the generation of antisaccades, subjects are to inhibit an eye movement toward a peripheral stimulus and instead generate an eye movement in the opposite direction (Hallett, 1978; Munoz and Everling, 2004). This requires deliberate control over automatic reflexes. The onset latency of the antisaccade indexes the level of preparation; the shorter the latency, the better one is prepared (Milstein and Dorris, 2007). Latency may be more informative as to the level of preparation than accuracy; elderly tend to display low error rates as they prefer accuracy over speed, even when forced to react fast (Smith and Brewer, 1995). PD patients show increased onset latencies compared to healthy elderly, and elderly in turn display increased antisaccade onset latencies when compared to young adults, reflecting progressive decline in preparation processes. PD patients also display difficulty suppressing reflexive prosaccades and premature responses, reflecting patients’ greater difficulty with self-initiation of movement than with performing externally guided movement (Butler et al., 1999; Klein et al., 2000; Nieuwenhuis et al., 2000; Chan et al., 2005; Amador et al., 2006). Antisaccades engage multiple cognitive processes including working memory, response inhibition, incompatible stimulus-response mapping and action preparation. Many studies have discussed age-related decrements in this task with regard to the involvement of inhibitory control (Butler et al., 1999; Nieuwenhuis et al., 2000; Sweeney et al., 2001; Butler and Zacks, 2006), working memory (Eenshuistra et al., 2004), and goal neglect (Nieuwenhuis et al., 2004).
The conditions under which age-related and PD-related antisaccadic decline can be improved, a topic of particular relevance for the current study, have been addressed less extensively. Little is known about the influence of reward expectation on age-related and pathology-related decline of oculomotor behavior. Oculomotor tasks have been shown to be sensitive to reward manipulations in non-human primates (Lauwereyns et al., 2002; Hikosaka et al., 2006), in healthy young adults (Milstein and Dorris, 2007), and in depressed and anxious individuals (Jazbec et al., 2005). The interface between motivation and declining action is central to the current behavioral study. In this study our focus will be on the influence of reward anticipation on declining oculomotor preparation.
To examine effects of reward anticipation on oculomotor preparation in elderly and PD patients we used the antisaccade paradigm. We adopted a variation of Rosenbaum's (1980) precuing technique where different amounts and types of advance information were provided to the participants. Motivational instruction cues informed the participant in advance that a reward is at stake when the antisaccade action is performed well. Preparatory instruction provided specific spatial information on the upcoming response, e.g., the side of the screen where the peripheral cue, that indexes the direction of the antisaccade response, will appear. This paradigm builds on existing frameworks of oculomotor control non-human primates linking similar corticostriatal mechanisms of reward anticipation with those of action preparation (Sato and Hikosaka, 2002; Hikosaka et al., 2006; Nakamura and Hikosaka, 2006) and explores their potential for remediating declining cognitive control in aging and PD.
While healthy aging involves a certain degree of dopaminergic cell loss in the basal ganglia, specifically in the substantia nigra pars compacta (SNc) (Hubble, 1998; Marschner et al., 2005) and bilateral shrinkage of caudate and putamen (Gunning-Dixon et al., 1998), PD is commonly associated with a more profound degeneration (e.g., more than 70% of dopaminergic cells in the SNc). The age-related loss of SNc cells doesn't seem to constitute an important factor in the pathogenesis of PD, as other parts of the SNc degenerate in aging than in PD. PD dominantly affects the lateral and medial ventral tier of the SNc (average loss 91%), a part that is relatively spared in aging (2.1% loss per decade) (Fearnley and Lees, 1991). Direct correlations have been reported between measures of PD related dopaminergic denervation in the caudate and cognitive dysfunction (Cropley et al., 2006) such as impaired verbal episodic memory (Holthoff-Detto et al., 1997), attention and response inhibition (Rinne et al., 2000; Bruck et al., 2005). These findings are consistent with reports that executive dysfunction in PD is accompanied by reduced activity within the caudate nucleus (Marklund et al., 2009) and prefrontal regions (Lewis et al., 2003). Marklund et al. (2009) observed a decrease in caudate activation that was transient rather than sustained in nature, which may suggest that the differential caudate activation stemmed from PD-related deficiencies in phasic dopamine release.
These neural changes in caudate nucleus also affect the neural underpinnings of antisaccades because antisaccade action requires cortico-subcortical integration. The widespread oculomotor network encompasses, besides the eye fields in all the major cortices and portions of the visual cortex, several structures within the basal ganglia (Raemaekers et al., 2006). The basal ganglia component of the oculomotor network originates in the caudate and then converges on the substantia nigra reticulata (SNr), which in turn projects to the oculomotor-executor in the brainstem, the superior colliculus, to modulate saccadic eye-movement. Direct projections between caudate and superior colliculus have also been observed. The superior colliculus receives excitatory inputs from many cortical brain areas, when stimuli attract attention and gaze. These inputs are, however, often incapable of activating superior colliculus neurons, because the SNr (with the help of the caudate) acts as a gate for saccade generation by inducing GABAergic inhibition on the superior colliculus. Only when the caudate/SNr reduce inhibition, do the superior colliculus neurons spike leading to action execution (Hikosaka et al., 2000). Altered patterns of SNr firing such as single-spike or burst firing are found in Parkinson's disease (Tseng et al., 2000). The underlying decrements of these altered patterns in the SNr are not clear. They presumably stem from decrements in the dopamine release of the ventral projecting dendrites from the SNc to the SNr (Prescott et al., 2009).
Taken together, the progressive decline in antisaccade performance in aging and PD may be associated with progressive dopaminergic cell loss in the SNc to the caudate/SNr inflicting a reduction of the caudate/SNr inhibition on the superior colliculus. Antisaccadic deficits are also observed in other basal ganglia disorders, including Huntington's disease. The similarity between Parkinson's and Huntington's diseases is noteworthy because they are caused by different mechanisms, the former by a loss of neurons mainly in the SNc and the latter by a loss of neurons mainly in the caudate. This suggests that also in humans, the SN and the caudate work together for the control of saccadic eye movements (Hikosaka et al., 2006). Accordingly, the antisaccade task has been found to be sensitive to dopamine changes; in PD patients the number of errors on the antisaccade task decreases with levodopa medication (Hood et al., 2007).
Importantly, the caudate is not only involved in anticipatory antisaccade programming, but also in anticipatory motivational processes within the mesolimbic dopamine system (Hikosaka et al., 2006). Many caudate neurons fire not only before the onset of an expected saccadic target but also in preparatory responding to signals that predict reward. Reward-related processes are prevalent in the entire striatum (caudate, putamen, nucleus accumbens), which receives massive input from the limbic system (e.g., amygdala, orbitofrontal cortex Selemon and Goldman-Rakic, 1985; Fudge et al., 2002). Functionally, the caudate specifically is thought to reinforce plans for complex behavior (Kawagoe et al., 1998; Cromwell and Schultz, 2003; O'Doherty et al., 2004) based on an evaluation of action-outcomes provided by the nucleus accumbens, who is less selective for sensorimotor events (Schultz et al., 1992). The caudate thus plays a key role in sensorimotor/cognitive action preparation on the basis of motivation.
Consistently, a number of primate studies have underlined the crucial role of the caudate nucleus in transforming motivational information into eye movement signals. In an oculomotor task, neurons of the primate caudate nucleus were found to respond in anticipation of reward-predicting stimuli, which in turn modulated neural oculomotor signals (Kawagoe et al., 1998, 2004) and corresponded to the saccade onset latency (Takikawa et al., 2002). This mechanism of motivational control of saccadic eye movement in caudate nucleus is supported by initial human findings, where participants received monetary rewards, following an anticipatory cue or following a button press response (Tricomi et al., 2004). Results showed only differential activation in the caudate nucleus if a perception of contingency existed between a button press response and a reward outcome.
Such a nexus between the oculomotor- and reward systems may be instrumental for the optimization of antisaccade performance in seniors and PD patients. In PD, the most rostro-dorsal part of the caudate is subjected to greater disruption than the relatively spared ventral region of the caudate (Grahn et al., 2008). This may leave the ventral connections of the caudate relatively intact and receptive for input from the ventral striatum and the limbic nodes of the reward circuit.
Thus oculomotor preparation may be facilitated by a transient increase of caudate activation as induced by the prospect of reward (Lauwereyns et al., 2002; Watanabe and Hikosaka, 2005), and this facilitation might alleviate the deficits associated with aging and PD. However, reward processing in itself is also affected by age and PD. Older adults have shown greater difficulty in learning reward associations, needing more trials before reaching the learning criterion, compared to young adults (Mell et al., 2005). Similar behavioral decrements have been found in non-medicated PD patients (Bodi et al., 2009). PD patients show poorer performance on reward-motivated probabilistic classification learning. These decrements have been related to changes in anticipatory reward cue processes. Neural evidence on age- and PD-related changes in the reward system is not unequivocal. While Samanez-Larkin et al. (2007) observed intact ventral striatal activation (and activation of the medial caudate and anterior insula) during gain anticipation in both younger and older adults, Schott et al. (2007) observed ventral striatal activation during reward anticipation only in the young. Healthy elderly and PD patients did not activate the ventral striatum during reward anticipation, only during reward feedback. As compared to healthy elderly, PD patients showed additional functional alterations in reward cue processing and reduced functional connectivity between the nucleus accumbens and the ventral tegmental area. Neural decrements in reward cue processing presumably reflect pre-synaptic degeneration of dopamine neurotransmission in PD and (milder) changes during aging in both the pre-and postsynaptic dopamine system throughout the human brain (Kaasinen et al., 2000; Bäckmann and Farde, 2001; Backman et al., 2006). This age-related vulnerability of the reward system has been further taken to explain loss of cognitive flexibility in older ages, by leading to impairments in reward processing, stimulus-response association learning and adaptation of existing associations to new situations (Marschner et al., 2005; Mell et al., 2005, 2009; Weiler et al., 2008). On the other hand, PD patients demonstrate increased search efficiency with increasing reward (Goerendt et al., 2004). Also, when required to adapt their manual force to an increasing reward, patients were able to exhibit greater force on trials in which larger rewards can be won, showing the same proportional increase as in controls (Schmidt et al., 2008).
Reward processing thus appears to be affected by age and PD in some studies but not in others. In this state of affairs the question whether deficient oculomotor preparation among seniors and PD patients can be facilitated by the prospect of reward remains unanswered. The presumably more intact ventral and limbic reward structures might trigger a transient increase of caudate activation, thereby enhancing inhibitory forces on the superior colliculus to improve goal-directed oculomotor function. The mesolimbic dopamine system may thus play a compensatory role in “boosting” the efficiency of interactions between motivational and impaired cognitive control processes in healthy aging and PD.
To address this question, we administered an antisaccade task to healthy young and older adults and PD patients, providing them pseudorandomly with the prospect of reward on some trials but not on others. This pseudorandom reward cuing is based on the principle that DA neurons in the reward system respond to the cue positively (with a phasic increase in firing) if the cue indicates an upcoming reward and they respond to the cue negatively (with a phasic decrease in firing) if the cue indicates no reward (Schultz et al., 1992; Kawagoe et al., 2004).
We expected older (compared to young) adults to display deficient oculomotor preparation (as indexed by increased antisaccade latencies), whilst PD patients were expected to perform worse than healthy elderly. We hypothesized further that oculomotor preparation would benefit from the prospect of reward. Most importantly, we examined whether such reward benefits can be observed in healthy elderly and in PD patients. In addition we manipulated spatial preparation and the duration of the interval between the instruction cue and the target, both to replicate typical findings and to ensure that our approach has the potential for oculomotor preparation benefits to become manifest even in older adults and PD patients. Thus we expected antisaccade latencies to be shorter and accuracy to be higher after specific preparation cues providing spatial information on the upcoming response, than after neutral preparation cues that give no spatial information. Likewise, we expected faster and more accurate antisaccades after long compared to shorter cue-target intervals.