Orienting of spatial attention in Huntington's Disease
Introduction
Huntington's Disease (HD) is a rare neurodegenerative genetic disease whose natural evolution is poorly understood. Its genetic basis is a pathological increase of the CAG repeats of IT 15 gene located on chromosome 4. HD entails intellectual deficits, motor disorders and psychiatric troubles. Evaluation and follow-up are difficult because of the entanglement of motor, psychiatric and cognitive disorders. The disease leads unavoidably towards dementia and death in approximately 20 years. At present, there is no validated treatment and current therapeutic trials are calling for markers of efficacy. Neural degeneration affects the striatum bilaterally before the appearance of the first symptoms (Bamford, Caine, Kido, Cox, & Shoulson, 1995). Degeneration follows two evolutional gradients: a postero-anterior gradient with a primary damage in posterior regions of the putamen, and an oblique gradient, which begins in dorsomedial regions of caudate nuclei and putamen and extents until ventrolateral regions (Vonsattel et al., 1985). With the evolution of the disease, an extra-striatal atrophy takes place in regions classically connected to the striatum like the globus pallidus, the substantia nigra ars reticulata, the thalamus, the limbic system, the cerebellum and the cortex. However, recent neuroimaging studies reported cortical impairment even in the early stages of the disease (Douaud et al., 2006; Kassubek, Bernhard, et al., 2004; Kassubek, Gaus, & Landwehrmeyer, 2004; Kassubek, Juengling, et al., 2004; Thieben et al., 2002), with an implication of insular and parietal regions. Fronto-parietal networks are important for the operations of spatial attention (Corbetta & Shulman, 2002; Fan, McCandliss, Fossella, Flombaum, & Posner, 2005; Gitelman et al., 1999, Thiebaut de Schotten et al., 2005), so it would not be surprising if HD patients displayed spatial attention disorders.
Indeed, in a longitudinal follow-up of a cohort of 22 HD patients (Bachoud-Lévi et al., 2001), several tests exploring attentional processes (both spatial and non-spatial; Stroop, digit cancellation, Trail Making Test A) resulted to be reliable markers of cognitive decline (Bachoud-Lévi et al., 2001). Using a battery tapping several aspects of non-spatial attention, Sprenglemeyer, Lange, and Hömberg (1995) found that HD patients performed poorly on tasks of vigilance, divided attention, response flexibility and response inhibition, and concluded that attentional impairments in HD could in large part account for cognitive disorders in this disease (Sprenglemeyer et al., 1995). They showed a relative preservation of the alerting system, because patients were able to decrease their response times (RTs) when an acoustic signal preceded the target. However, patients exhibited a deficit of sustained attention, expressed by a high rate of omissions on each experiment. Sprenglemeyer et al. (1995) also used a “divided attention” experiment consisting of three tasks: a speeded visual detection task, an auditory task in which participants had to respond when two sounds of the same frequency occurred one after another, and a double task requiring the performance of both tasks at the same time. Patients performed correctly each of the two component tasks, but they were slowed to detect visual targets in the double task condition, which suggested an executive deficit in switching attention between modalities.
Posner (1980) developed a response time (RT) paradigm to explore orienting of spatial attention. According to the spotlight metaphor of attention, processing of stimuli located inside the attentional focus is facilitated, thus leading to RT benefits, while processing of stimuli outside the focus is inhibited, thus determining an RT cost. According to Posner (1980), orienting of attention toward a given stimulus implies three mechanisms: (1) disengaging the attentional spotlight from the previous stimulus, (2) moving and (3) engaging to the new target. Spatial attention can either be exogenously captured by an external salient stimulus, or it can be endogenously oriented by the subject himself towards an external or internal stimulus. Refinements of the model have proposed different forms of attention for exogenous and endogenous orienting (Klein & Shore, 2000; Lupiáñez et al., 2004). The different components of such processes can be explored by using the manual RT paradigm developed by Posner (1980). Participants are presented with three boxes horizontally arranged on a screen. They fixate the central box and respond by pressing a key to a target (an asterisk) appearing in one lateral box. Before the occurrence of the target, the occurrence of a cue designates one of the lateral boxes. The cue can either be “central” (for example an arrow appearing in the central box and pointing to one of the lateral boxes) or “peripheral” (a brief brightening of one lateral box). In “valid” trials, the target can appear inside the previously cued box (valid cue); in “invalid” trials the wrong box is cued. In “neutral” trials, used to discriminate between RT costs and benefits, the central box may be cued. An advantage for cued over uncued targets, or validity effect, suggests that the cue elicits an attentional orienting toward the cued location, which speed up the processing of targets appearing inside the cued box and slows down responses to targets appearing elsewhere. Importantly, the degree of predictiveness of cues influences the attentional processes involved. When a majority of cues are valid, most cues correctly predict the site of the upcoming target and are thus spatially informative. When the cue is non-informative, the target appears with equal probability in the cued or in the uncued location. Peripheral non-informative cues attract attention automatically, or exogenously (Jonides, 1981; Müller & Rabbitt, 1989). This exogenous attentional shift (revealed by a cue validity effect) is typically observed for short stimulus-onset asynchronies (SOAs) between cue and target. For SOAs longer than about 300 ms, a cost is observed for validly cued targets (Posner & Cohen, 1984). This phenomenon is often labelled inhibition of return (IOR; Posner, Rafal, Choate, & Vaughan, 1985). IOR is traditionally interpreted as an inhibition of attention to return to a previously inspected location, but its meaning, mechanisms and interpretation are currently debated (Lupiáñez, Klein, & Bartolomeo, 2006). When most cues (e.g. 80%) are invalid, they prompt an initial exogenous orienting towards the cued box, later followed by an inhibition of this exogenous shift, to be replaced by an endogenous shift towards the uncued box (Posner, Cohen, & Rafal, 1982). Thus, for long enough SOAs this condition explores endogenous orienting in relative isolation (Bartolomeo, Decaix, & Siéroff, 2007; Bartolomeo, Siéroff, Decaix, & Chokron, 2001; Lupiáñez et al., 2004).
Using a vibrotactile choice RT task, Georgiou, Bradshaw, Phillips, and Chiu (1997) showed that HD patients were impaired in allocating their attentional resources and to shift their attentional focus from a cued location to another location. This could be related to an inability to suppress reflexive saccades to sudden visual stimuli and to a delayed initiation of voluntary saccades in HD (Lasker & Zee, 1997). Finke, Bublak, Dose, Müller, and Schneider (2006) used a visual report task in which participants had to identify target letters accompanied or not by distractors. Using a mathematical model of weighting of attention along the two hemi-fields for each stimulus, they found that HD patients showed a deficit in the allocation of attentional weights. In addition, patients demonstrated reduced perceptual processing speed and reduced capacity of visual working memory.
Fielding, Georgiou-Karistianis, Bradshaw, et al. (2006) reported an accelerated time course of IOR in a saccadic RT paradigm with peripheral non-informative cues. Saccadic IOR was present as early as 150 ms after cue onset. Saccadic trajectories were abnormally influenced by the presence of distractors (Fielding, Georgiou-Karistianis, Millist, & White, 2006), with exogenous saccades deviating leftwards irrespective of target locations, and endogenous saccades deviating towards the left if directed upward, and towards the right if directed downward.
Asymmetries of attentional processes have also been described in HD. Georgiou-Karistianis, Churchyard, Chiu, and Bradshaw (2002) showed that HD patients were slower when a pre-cue tactile stimulation appeared on the left finger relative to the right. Other asymmetries of visuo-spatial performance reported in HD patients include signs of visual neglect for the left (Ho, Manly, et al., 2003) or the right space (Ho et al., 2004). In particular, leftwards shifts on line bisection correlated with reduced density in the angular gyrus bilaterally, consistent with the implication of the inferior parietal lobule and its connections in bisection-related tasks (Fink, Marshall, Weiss, Toni, & Zilles, 2002; Thiebaut de Schotten et al., 2005).
These results suggest the interest of studying visuo-spatial performance in HD by using sensitive RT tasks, such as the Posner paradigm (Posner, 1980) which is widely used to assess lateral shifts of spatial attention in brain-damaged patients (Bartolomeo et al., 2001). In order to disentangle exogenous and endogenous contributions to patients’ performance, we used a covert attention task with peripheral visual cues and different cue–target relationships (Bartolomeo et al., 2001, Posner, 1980, Posner et al., 1982). In three different experiments, cues predicted the correct location of the target with 80%, 50% or 20% accuracy, respectively. In this way, exogenous and endogenous orienting can be studied in relative isolation from one another, by using the same visual stimuli. A neutral condition, in which the central box was cued, was used to discriminate between cue-induced benefits and costs. The use of three different time intervals between cue and target appearance (stimulus-onset asynchronies or SOA), at 100, 500 and 1000 ms, allowed us to explore the time course of these processes. For example, in the present settings IOR is expected in controls starting from 500-ms SOA. Endogenous re-orienting to uncued targets in the 20% validity experiment should also occur by 500-ms SOA, but it may be delayed in brain-damaged patients (Bartolomeo et al., 2001). Thus, comparisons were planned in controls and patients between RTs to validly and invalidly cued targets at the intermediate, 500-ms SOA. To explore the clinical implications of the observed patterns of RT performance, correlations were calculated with clinical parameters, such as scores on the Unified Huntington's Disease Rating Scale (UHDRS) (Huntington Study Group, 1996), the Mattis Dementia Rating Scale (MDRS) (Mattis, 1976), the Total Functional Capacity (TFC) (Huntington Study Group, 1996), as well as with radiological measures of caudate atrophy.
Section snippets
Participants
Fourteen patients with mild HD (6 females) and 14 age-matched controls (9 females) participated in the study. All patients had no previous neurological or psychiatric history other than HD. HD diagnosis was genetically confirmed. The control subjects had no neurological or psychiatric disorders and were matched to the patients for age (patients: mean age 48.43 years, range 36–59; controls: mean age 44.78 years, range 34–55; t = 1.34; p = 0.19) and educational level (patients: 13.29 years of
Results
Mean RTs for patients and controls in each experimental condition are reported in Table 2 and Fig. 1, Fig. 2, Fig. 3.
Discussion
We used a speeded target detection task to explore the orienting of spatial attention in HD patients. In different experiments, peripheral cues predicted the future location of the target with 80%, 50% or 20% accuracy. In this way, exogenous and endogenous orienting can be studied in relative isolation from one another, by using the same visual stimuli. For all the experiments, patients were able to decrease their RTs with increasing SOA, similar to controls. This pattern of performance
References (59)
- et al.
Motor and cognitive improvements in patients with Huntington's disease after neural transplantation
Lancet
(2000) - et al.
The phenomenology of endogenous orienting.
Consciousness and Cognition
(2007) - et al.
Neural correlates of primary and reflective consciousness of spatial orienting
Neuropsychologia
(2008) - et al.
Distribution of grey matter atrophy in Huntington's disease patients: A combined ROI-based and voxel-based morphometric study
NeuroImage
(2006) - et al.
The activation of attentional networks
NeuroImage
(2005) - et al.
Accelerated time-course of inhibition of return in Huntington's disease
Behavioural Brain Research
(2006) - et al.
Temporal variation in the control of goal-directed visuospatial attention in basal ganglia disorders
Neuroscience Research
(2006) - et al.
Task instructions influence the cognitive strategies involved in line bisection judgements: Evidence from modulated neural mechanisms revealed by fMRI
Neuropsychologia
(2002) - et al.
Ocular motor abnormalities in Huntington's disease
Vision Research
(1997) - et al.
A review of the evidence for a disengage deficit following parietal lobe damage
Neuroscience and Biobehavioral Reviews
(2001)
Visual attention in Huntington's disease: The effect of cueing on saccade latencies and manual reaction times
Neuropsychologia
Hypometric primary saccades and increased variability in visually-guided saccades in Huntington's disease
Neuropsychologia
Task-set switching deficits in early-stage Huntington's disease: Implications for basal ganglia function
Journal of Cognitive Neuroscience
Retest effects and cognitive decline in longitudinal follow-up of patients with early HD
Neurology
A prospective evaluation of cognitive decline in early Huntington's disease: Functional and radiographic correlates
Neurology
Bicaudate index in computerized tomography of Huntington disease and cerebral atrophy
Neurology
Modulating the attentional bias in unilateral neglect: The effects of the strategic set
Experimental Brain Research
Saccades in presymptomatic and early stages of Huntington disease
Neurology
Cognitive impairments in Huntington's disease: Insights into the neuropsychology of striatum
Control of goal-directed and stimulus-driven attention in the brain
Nature Reviews Neuroscience
Parameter-based assessment of spatial and non-spatial attentional deficits in Huntington's disease
Brain
Effect of directed attention in Huntington's disease
Journal of Clinical and Experimental Neuropsychology
Reorientation of attention in Huntington disease
Neuropsychiatry, Neuropsychology and Behavioral Neurology
A large-scale distributed network for covert spatial attention: Further anatomical delineation based on stringent behavioural and cognitive controls
Brain
Identification of an oculomotor biomarker of preclinical Huntington disease
Neurology
Psychlab software
A case of unilateral neglect in Huntington's disease
Neurocase
Pseudo-neglect in Huntington's disease correlates with decreased angular gyrus density
Neuroreport
Profile of cognitive progression in early Huntington's disease
Neurology
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