Accelerated time-course of inhibition of return in Huntington's disease

Abstract

A non-predictive peripheral cueing paradigm was used to evaluate visuospatial attentional deficits in symptomatic HD patients, employing spatially valid and invalid visual cues over a range of stimulus onset asynchronies (SOA) to elicit a saccadic response. Although both patients and controls demonstrated initial facilitation for valid versus invalid cues following the shortest SOA, and a performance decrement (inhibition of return), at the longest SOA, a clear differentiation between these groups was found for the intermediate SOAs. Unlike controls, where IOR manifested between 350 and 1000 ms, IOR was evident as early as 150 ms for HD patients. Further, the benefit of valid cueing correlated significantly with the level of impairment. Although patients exhibited poor fixation, principally attributable to saccadic intrusions, they were capable of appropriately suppressing a purely stimulus-driven response to the cue. A similar proportion of erroneous saccades to the cue were generated by both groups prior to stimulus onset, also correlating significantly with level of impairment. These results are discussed with respect to neural processes implicated in spatial cueing and within the context of reduced inhibitory activity of the BG in HD.

Introduction

Control of automatic visuospatial attention, a stimulus-driven, bottom-up process, has been extensively investigated using cue-target tasks, in which either spatially compatible, or incompatible, cue and target stimuli are presented successively [48]. In such tasks the transient presentation of a cue stimulus appears to promote independent, and conflicting, facilitatory and inhibitory processes [35], [65], representing preparation-for-action evoked by a stimulus driven shift of attention, as well as the active inhibition of this more automatic visuomotor process. These competing processes result in differential effects for short and long delays, or stimulus onset asynchronies (SOA), between cue and target presentation. Short SOAs facilitate responses to targets presented in the same location as the cue, compared to those presented in alternate locations. Longer SOAs result in a relative slowing of response to a target presented in the same location as the previous cue stimulus [49]. The latter phenomenon, known as inhibition of return (IOR), has been the subject of intensive investigation, with various theoretical and neural accounts proposed.

Attentional theories attribute the source of IOR to the orienting of attention towards a particular location, and the subsequent removal of this attention, discouraging re-inspection of an already attended-to location [27], [49], [55]. Conversely, it has also been proposed that IOR is simply a consequence of the activation of the ocular motor system. As such it may result from the inhibitory modulation of a motor program generated towards previously cued locations [61], [62]. However, these accounts are not necessarily mutually exclusive, and may simply represent different manifestations of the same underlying process [54].

Although the exact neural mechanisms underlying IOR are unclear, the involvement of the midbrain structure superior colliculus (SC) [9], [55], [64] is consistent with both sensory-attentional and ocular motor accounts, given that is implicated in both attentional [53] and ocular motor processes [58]. Further, the SC contains cells which are sensitive to a range of different sensory modalities, consistent with the presence of IOR, albeit with differing time courses, over and within a range of motor paradigms [59]. Certainly patients with progressive supranuclear palsy (PSP), a neurodegenerative disorder with predilection for the SC, fail to show inhibition at longer SOAs [51].

However, the associated reduction in facilitatory activity over the SC appears to reflect a signal reduction that has taken place cortically [10], [36], [67]. Notably, neural damage in PSP is not specific to the SC [51]. Ro et al. [54], for example, have demonstrated that the frontal eye fields (FEF), which are heavily interconnected with the SC, play a crucial role in generating IOR. Transcranial magnetic stimulation applied over the FEFs resulted in the elimination of the slowed response to cued targets [54]. This suggests that the inhibitory component of the IOR may emanate from the FEF. Further, it has been proposed that this temporary inhibitory link set up between stimuli at inhibited locations and their responses, may derive from the posterior parietal cortex [15]. Thus IOR may be characterised as the relative precedence of inhibitory activity, versus facilitatory activity, over the SC, which is determined cortically, by structures commonly involved in both eye movement and attention [6], [28].

The basal ganglia (BG) also comprise an important component of both ocular motor and attentional networks, and are primarily concerned with the focusing of neural resources via selectively facilitating or inhibiting neural activity [37]. Crucial for the efficient resolution of response conflict [70], they influence the selection and suppression of competing responses via both direct facilitatory, and indirect inhibitory pathways [56]. Significantly, the SC is normally gated by tonic inhibitory input from the BG output structure substantia nigra pars reticula (SNr) [20], [21]. Thus the BG may well influence the balance of activity over the SC under conditions which promote competing processes, including situations which generate IOR.

Given the anatomical and functional links between the BG and the SC, compromised performance may be anticipated in patients with BG dysfunction. Indeed, altered performance has been revealed in Parkinson's disease (PD), predominantly a BG disorder, although findings are varied and widely discrepant [5], [12], [26], [46], [47], [71]. These discrepancies may well be a function of methodological inconsistencies between the various studies [46], including the predictiveness of cue stimuli and the temporal properties of cue-target presentation. However, in the single study which has addressed IOR in PD within the context of eye movement, an increased magnitude in the IOR was found to correspond with disease stage [5]. These authors attributed this to over-active reflexive attentional processes in PD. As PD manifests in the overactivity of BG inhibitory output to the SC, this finding may alternatively reflect the rapid decay of facilitatory cue-related activity. Conceivably this would be reflected in the relative precedence of cortically modulated inhibitory activity over the SC regions encoding the cue-target location, over time.

Attentional control has received some attention in Huntington's disease (HD), also primarily a disorder of the BG. In the initial stages of the disease, there is preferential degeneration of indirect, inhibitory pathways, resulting in difficulty inhibiting irrelevant responses, as well as perseverative behaviour [19], [66]. Perseveration has been revealed in numerous set-shifting tasks whereby patients persist with a response set no longer appropriate to the task [16], [17], [24], [32], [60]. Whether IOR is altered in HD remains unexplored.

This study sought to determine the nature and extent of deficits in HD with respect to the allocation and control of automatic visuospatial attention over a range of SOAs, including those expected to elicit IOR. Given the intimate functional and anatomical relationship between visuospatial attention and oculomotor processes [2], we chose a saccadic paradigm similar to that of Briand et al. [5]. Cost/benefit analyses of cue presentation were ascertained by comparing latencies of valid and invalidly cued saccades with latencies of un-cued saccades. Whilst latencies following neutral cues are more conventionally used for this type of analysis, we attempted to ascertain the ‘absolute’ temporal effects of non-informative spatial cues on subsequent responses. It was considered that because response conflict is inherent in the presentation of two competing visual stimuli (i.e., discrete modulation of activity over a range of ocular motor structures) they may be inappropriate as a baseline measure of performance for patients who exhibit deficient conflict resolution. However, we do acknowledge a degree of scepticism about the appropriateness of either measure as representative of baseline performance.

Ocular motor deficits in HD parallel deficits found for other motor systems, resulting not only in difficulty initiating voluntarily saccades, but in distractibility (erroneous movement) when presented with novel stimuli [34], especially during gaze fixation tasks which require a spatially unrelated response (anti-saccade) [30], [31], [34], [66]. Thus distractibility, or poor fixation, was anticipated in HD. Accordingly, the premature release of SC activity representing the location of a cue was anticipated, resulting in a relative precedence of cortical inhibition. HD patients might therefore exhibit either increased IOR, similar to PD patients [5], or early onset of IOR. Similarly, perseverative activity, also a consequence of the reduced inhibitory output of the BG, may result in the persistence of suppressed cue-related activity, and earlier onset of IOR. Thus it was anticipated that the temporal exploration of spatial cueing in HD, might help elucidate both the impact and time-course of both facilitatory and inhibitory processes. This in turn may lead to a greater understanding of the IOR phenomenon and of the range of deficits found in HD.