Visuospatial activities have been classified according to different criteria. O'Keefe and Nadel (1) divided them on the basis of the sensorimotor responses of persons moving in their own environment, classifying them as "position (or egocentric) responses" when subjects use their body as a reference, as "cued responses" when movements are guided by external cues, and as "place responses" when movements are guided by relationships between external references. Grusser (2) classified the space around the subject as consisting of three functionally different "subspaces": the body surface, the grasping space, and the distal space. It seems that different brain regions are responsible for directing attention to different regions of space. For example, experimental studies on monkeys have local-
From: Current Clinical Neurology: Atypical Parkinsonian Disorders Edited by: I. Litvan © Humana Press Inc., Totowa, NJ
ized the representation of personal space to parietal area 7a and postarcuate frontal area 6. Peripersonal space seems to be encoded by parietal areas 7a and 7b and frontal areas 6 and 8. Extrapersonal space is represented in frontal area 8, parietal area 7a, and the superior colliculus (3).
For the purpose of this review we present a classification of visuospatial abilities that divides them into spatial perception, visuomotor coordination, visuospatial attention, perception of size, spatial memory, and visuospatial imagery. Although any classification of this sort is somewhat arbitrary, we believe it is useful to list the different domains to be examined during neuropsychological testing. Furthermore, the various parkinsonian disorders can affect some of these skills while leaving others intact.
Spatial perception is the ability to analyze the spatial relationships both between the stimulus and the observer and between different stimuli. Visual, tactile, and auditory information can contribute to spatial perception. However, visual-perceptual skills predominate disproportionately over the other perceptual skills. According to current theories (4,5) visual information is processed by two distinct pathways: the occipitotemporal (ventral) pathway, which conveys information about shape and patterns, and the occipito-parietal (dorsal) pathway, which is involved in spatial analysis. Three fundamental aspects of spatial perception are stimulus localization, perception of line orientation, and depth perception. All can be impaired after brain damage.
Different methods have been proposed to examine stimulus localization. Warrington and Rabin (6) presented two cards, either simultaneously or in succession, and asked subjects to evaluate whether the position of a point was the same or different on the two cards. Hannay et al. (7) projected onto a screen one or two dots for 300 ms, then, after a 2-s delay, they presented a display showing 25 numbers in different positions: the subject's task was to read aloud the numbers corresponding to the correct dot positions. The performances of right-posterior brain-damaged patients are typically impaired.
The most widely used instrument in the assessment of this component of visuospatial perception is the Benton's Judgement of Line Orientation Test (8). This test requires subjects to identify the orientation of a pair of lines on an 11-line multiple-choice display. A number of studies have used this test to assess visuospatial abilities in PD patients, and given varying results. Boller et al. (9) demonstrated that PD patients with a normal IQ are impaired in line orientation judgement. Similar results were obtained by Goldenberg et al. (10). However, Richards, Cote, and Stern (11) did not find differences between 14 patients with idiopathic PD and 12 normal controls matched for age and education. Similarly Levin and colleagues (12,13) did not identify line orientation abnormalities in their mildly and moderately affected PD patients. In a large sample (76 patients and an equal number of matched normal controls), Montse et al. (14) demonstrated that, in line orientation judgment, PD patients make proportionally more complex intraquadrant and horizontal line errors, but fewer simple intraquadrant errors than controls. Girotti et al. (15) reported that when PD patients were divided into those with and those without dementia, the line orientation test was one of the few tasks that distinguished the nondemented PD patients from controls, whereas many tasks differentiated the demented PD patients from controls. In conclusion, the line orientation test is often abnormal in PD patients but may be normal in patients in whom the disease is less advanced.
The perception of depth is based on both monocular and binocular sources (16,17). Monocular cues include apparent size of familiar objects, texture and brightness gradient, linear perspective, occluding contours, shading, and monocular parallax (i.e., the ability to analyze disparate retinal images successively produced by the same object on the retina). Stereopsis is the ability to discriminate depth on the basis of binocular information. Stereoacuity is commonly tested using the quantitative Titmus stereotest, which requires the subject, who is wearing appropriately polarized lenses, to detect circles that appear on a closer plane with respect to the background. Global stereopsis is tested using Julez's random dot stereograms, geometric forms that can—if viewed stereoscopically—be seen from below or above the background plane.
Both the striate and the peristriate and parietal visual areas play a pivotal role in depth perception based on binocular cues (18-20). To the best of our knowledge, no systematic study of depth perception in patients with parkinsonian disorders has to date been conducted.
The impaired ability to reach for visually presented stimuli, not related to motor, somatosensory, visual-acuity, or visual-field deficits, is named optic (visuomotor) ataxia. To detect subtle visuomotor ataxia, the subject is asked to reach for an object that requires a precision grip (i.e., true opposition of thumb and index finger). In a clinical setting, the examiner will hold the object (a coin or a paper clip) by its edge while the patient attempts to grasp it between the index finger and thumb. In the most severe cases, the disorder is apparent even when the patient is fixating when reaching for the object. More frequently, the impairment is only apparent when the target is located at the periphery of the visual field, or when the patient is not allowed to look at his reaching arm (21).
Reaching for an object is a movement that can be divided into two components: the proximal component (the reaching or transportation phase) and the distal component (the grasping or manipulation phase). This dichotomy has received particular attention because it reveals the difference between two pathways of visuospatial perception respectively devoted to determining the target coordinates in a body-centered space (the occipito-parietal pathway) and to computing shape, size, and weight of the target object (the occipitotemporal pathway) (4).
Examining in detail the different components of reaching for an object requires frame-by-frame analysis of a video recording of the movement. Studies of visuomotor coordination in PD patients show no deficit in the "transportation" and in the "manipulation" components of the reaching-to-grasp movement (22). On the contrary, PD patients demonstrate some dysfunction when they are required to respond appropriately to modification of object size and location (23,24). Rearick et al. (25) demonstrated that global features observed in five-digit grasping are preserved in PD patients. However, more subtle aspects of the coordination between digits, as revealed by frequency domain analysis, are not preserved, possibly owing to action tremor.
When we move in the environment, we are confronted with a vast array of sensory information that the nervous system cannot deal with on an equal basis. Thus, the brain must select which information to process. Visuospatial attention refers to the processes engaged by the nervous system in the selection of relevant information from the mass of information presented by the visual environment.
The neglect syndrome has been characterized as a failure to report, respond to, or orient attention to novel or meaningful stimuli presented to the side opposite to a brain lesion, when this failure cannot be attributed to either sensory or motor defects (26). In severe neglect, patients may behave as though one-half of the world had suddenly ceased to exist. They may fail to eat the food on the left side of their plate, or omit to shave, groom, and dress the left side of the body. In other patients, the symptoms are much subtler and might not be detected by observation of their spontaneous behavior. In the latter cases, special maneuvers may be needed in order to disclose the presence of neglect.
Cancellation tasks are often used for diagnosis of the syndrome. Albert (27) developed the simplest form of these tasks, a test in which subjects are required to cancel each item in an array of 40
scattered lines. In the Bells Test (28), rather than scattered lines, 315 small, silhouetted objects are distributed in a pseudorandom manner on the page, with 35 bells scattered among them. Despite their apparently random positions, the bells are actually arranged in seven columns with five bells to a column. The subjects' task is to circle the bells as quickly as possible. Similarly, Mesulam (29), with the purpose of enhancing the method's sensitivity to inattention to the right as well as to the left side, devised verbal and nonverbal cancellation tasks consisting of four sheets, two (nonverbal) with various shapes, and two (verbal) with randomized letters.
A different technique for investigating unilateral inattention is to ask the patient to bisect a line. In the traditional version, patients are asked to mark the midpoint of a horizontal line drawn on a sheet of paper. Normal subjects tend to bisect the line 1-2 mm left of its true center (30,31). Patients with left hemineglect tend to place their mark rightward of the center. To interpret this finding, both space representation and premotor impairment have been invoked. Assuming perceptual factors are responsible, bisection toward the right would be a result of underestimation of the length of the left part of the line, whereas the influence of premotor factors would result in reduced action toward the left (directional hypokinesia) or in reduced amplitude movement toward the left (directional hypometria). Different modifications of the line bisection paradigm have been devised to disentangle the representational and premotor component of bisecting a line. In the landmark test (32), the subject's task is to point to the shorter side of a correctly prebisected line: when patients choose the left side as the shorter their neglect can be attributed to a representational deficit. In the line extension test (33), patients are requested to extend a horizontal line leftward to double its original length. If premotor factors dominate, they should cause a relative left underextension (compared to the right) because of left hypokinesia-hypometria.
Animal studies have shown a central role of the dopaminergic system in the regulation of directional attention. Some authors believe that these circuits are purely premotor (34), whereas others maintain that dopaminergic circuits also mediate perceptual aspects (35,36). In humans, some case reports have shown significant improvement of patients with chronic neglect syndrome after therapy with dopaminergic drugs (37,38). Asymmetric degeneration of the dopaminergic nigrostriatal pathways is the major mechanism underlying the motor symptoms of PD.
A number of early studies have found that patients with left hemi-PD tend to neglect the left side of space (13,39-41). However, the rightward bias of left hemi-PD is at most mild and some authors (42,44) were not able to demonstrate visual neglect in their patients. In a more recent study Lee et al. (43) examined PD patients with two line bisection tasks. One was a conventional paper- and pencil-test. In the other, subjects were required to bisect a line presented on a computer screen by adjusting the position of a cursor operated by two pushbuttons, one in each hand. No significant differences were found on the paper-and-pencil test. On the contrary, predominantly left-sided PD patients showed significant rightward bias in their setting of the cursor. The same bias was found when subjects repeated the task with the pushbuttons switched between the hands, so that the cursor was moved to the left by the right hand and vice versa, thus suggesting a perceptual rather than a premotor bias.
Adopting a different approach, Ebersbach et al. (44) demonstrated that patients with predominantly right-sided PD, as well as normal controls, were more likely to start visual exploration on the left side of texture arrays requiring attentive oculomotor scanning. On the contrary, PD patients with predominantly left-sided disease showed a rightward directional bias for initial exploration, a behavior similar to that demonstrated by patients affected by visuospatial neglect following cortical lesions of the right parietal lobe.
Work by Posner and colleagues (45) has provided a theoretical framework within which the different processes involved in orienting attention might be interpreted. They distinguish between two distinct modes of spatial orienting. "Overt" orienting involves turning the eyes toward a particular location of interest, whereas "covert" orienting requires attention to be shifted to this location while the eyes remain fixated elsewhere. Several studies have examined overt orienting in PD patients, and there is a general consensus that internal control of eye movements through voluntary saccades
(remembered, delayed, and predictive saccades and antisaccades) is deficient in PD patients (4649). At the same time there appears to be no deficit in PD patients for purely reflexive (or visually guided) saccades (46,47,50,51). Thus, studies in PD patients suggest deficits in voluntary (internal) control, but no deficit in reflexive (external) control of overt orienting of attention. To evaluate covert orienting, subjects, all the time maintaining central fixation, are asked to press a key as soon as a peripheral stimulus appears. At the beginning of each trial subjects are given a visual cue, meant to draw their attention to the side where the stimulus is to appear. In most trials the target is presented where it was cued to appear (valid trials), but in some it appears on the opposite side (invalid trials). As it might be expected, normal subjects are significantly faster on valid than invalid trials. Patients with parietal lesions, even if nearly as good as normal controls on valid trials, are severely impaired on invalid trials, which require them to respond to a stimulus contralateral to the lesion. This impairment indicates defective attentional disengagement from a cued location. A number of researchers have reported conflicting results regarding the performance of PD patients in covert orienting tasks, with some studies reporting small covert orienting effects in PD patients (52,53), and others finding no difference (54-56). It turns out that, as for overt attention, it is important to distinguish between voluntary and reflexive control of spatial attention. Voluntary covert attention is assessed by using symbolic cues (e.g., arrows) presented at a central location. The purpose of these cues is to make the subject shift his or her attention to the intended location. Reflexive covert attention is evaluated by presenting a brief cue stimulus in the visual periphery that automatically draws attention to the location of the cue. A couple of studies (57,58) compared voluntary and reflexive covert control of spatial attention in PD patients. Both reported relatively normal cuing effects with voluntary (i.e., internally controlled) cues at short (250 ms) and intermediate (500 ms) intervals between cue and target. However, in PD patients facilitatory effects were eliminated with longer (800-1000 ms) intervals, thus demonstrating defective voluntary control of covert attention. On the contrary, PD patients appear to be significantly faster than control subjects on covert reflexive orienting (59). Progressive supra-nuclear palsy (PSP) and corticobasal degeneration patients (CBD) can show specific impairments in visual-orienting tasks that will be discussed later in this chapter.
In human perception theories, it is commonly assumed that size is processed independently of shape. Experimental animal studies in monkeys (60,61) have confirmed that object size is processed in the brain independently of other stimulus characteristics. An important consequence of this distinction between form and size concerns our general ability to identify objects of different size as identically shaped. The disorder of size perception of which patients are aware is termed dysmetropsia (also called dysmegalopsia or metamorphopsia). Objects can appear either shrunk (micropsia) or enlarged (macropsia), compared to their actual size (62). Size perception can be also distorted in visuospatial neglect (63), but in this case patients are unaware of the symptom.
It has recently been demonstrated (64) that predominantly left PD patients, probably because of right-hemisphere impairment, perceive a rectangle presented in the left and upper visual space as smaller compared to rectangles presented in different regions of space. The same authors (65) have raised the possibility that perceptual errors might have a causal role in determining PD patients' difficulties in negotiating doorways, narrow corridors, and other confined spaces. They asked PD patients to judge whether or not they would fit through a life-size schematic doorway shown on a large screen. Predominantly left PD patients obtained an increased ratio between the door width for which 50% of the judgments were positive and the width of the participant's body at the shoulders. This finding was interpreted as suggesting that the visual representation of the doorway (or of its relationship to perceived body size) is compressed in left PD. However, the clinical implications of this finding are not yet clear, since the authors could not demonstrate a causal role of these perceptual distortions in freezing episodes experienced by PD patients.
Within spatial memory it is possible to identify short- and long-term components. Short-Term Spatial Memory
According to a widely accepted theoretical model (66) short-term memory is viewed as a "working memory," where information can be temporarily stored and accessed for use in a wide range of cognitive tasks. Working memory, on the other hand, is made up of an attentional system of limited capacity (the so-called "central executive") and of at least two "slave" subsystems: the "articulatory loop" and the "visuospatial sketchpad," respectively dealing with phonological and visuospatial items. In this scheme, the visuospatial sketchpad would appear to keep visuospatial information "on line" for subsequent processing by the "central executive." This hierarchical organization could allow the concurrent performance of phonological and visual tasks as long as they remain within the capacity limits of the two "slave" systems, whereas the "central executive" would be called upon should the information to be processed exceed these limits. A series of neuroimaging studies (67) has determined that spatial working memory is mediated by a network of predominantly right-hemisphere regions that include posterior parietal (BA 40 and BA 7), anterior occipital (BA 19), and inferior prefrontal (BA 47) sites. It has been hypothesized that the premotor area and the superior parietal area might mediate spatial rehearsal, whereas the inferior posterior parietal area and the anterior occipital area might mediate storage of spatial information (67,68).
A simple way to test the visuospatial short-term memory is to measure its span with the Corsi Block Tapping Test (69). The test consists of nine blocks arranged on a board. The examiner taps the blocks in sequences of increasing length, and after each one the subject is requested to copy the sequence just tapped out. The longest sequence correctly tapped out by the subject constitutes his or her visuospatial memory span. An important limitation regarding use of this task in a clinical setting with parkinsonian patients is the fact that it requires a motor response: the spatial span might be underestimated owing to the presence of bradykinesia. Nonetheless, studies that have used Corsi's test (70) failed to find any difference between PD patients and normal controls. On the contrary, Bradley, Welch, and Dick (71) found that PD patients are slower that normal controls when performing complex visuospatial memory, but not verbal memory, tasks. Postle et al. (72) also found a selective impairment of spatial (but not object) delayed response in PD, indicating a selective disruption of spatial working memory. A selective impairment of spatial working memory was also demonstrated in PD patients by Owen et al. (73) using a computerized battery of tests designed to assess spatial, verbal, and visual working memory. In the spatial working memory task, subjects were required to search systematically through a number of boxes to find "tokens" while avoiding those boxes in which tokens had previously been found. In the visual and verbal conditions, the subjects were required to search in exactly the same manner, but through a number of abstract designs or surnames, respectively, avoiding designs or names in which a token had previously been found. Medicated PD patients with severe clinical symptoms were impaired on all three tests of working memory. In contrast, medicated patients with mild clinical symptoms were impaired on the test of spatial working memory, but not on the verbal or visual working memory tasks. Nonmedicated patients with mild clinical symptoms were unimpaired on all three tasks. Further investigations by the same group (73-76) focused on the cognitive heterogeneity in PD. Taken together, the results demonstrate that impairment of spatial working memory can occur in the early stages of the disease in a subgroup of PD patients with frontostriatal circuitry involvement.
Using the dual-task paradigm to measure the ability to cope with concurrent task demands, a number of investigators (77-80) have hypothesized that the "central executive" is impaired in PD patients. Le Bras et al. (81), using a specifically designed testing procedure, concluded that PD patients are impaired in all steps of executive information processing involved in spatial working memory (stimulus encoding, storage, and response programming). More recently, Lewis et al. (76) have found that PD patients performing badly on the Tower of London Test (a standard visuospatial task of executive functioning) were specifically impaired in manipulating information within verbal working memory.
Recent functional magnetic resonance imaging studies (82) have implicated the rostral caudate nucleus in the transformation of spatial information in memory to guide the action. Dorsal premotor cortex (82) and premotor cortex (Brodmann's areas 46 and 9) are also involved (83-85) in performing spatial memory tasks. PD patients are known to suffer loss of dopaminergic input to the rostral caudate. Extensive two-way connections link the striatum, the premotor, and the dorsolateral prefrontal cortices. It is therefore conceivable that the functional impairment of these brain regions is the basis of spatial working memory impairment in PD patients.
Memory for location is commonly tested by presenting a sheet showing a number of figures, representing objects, and then asking patients, after various time intervals, to relocate them on another sheet in exactly the same position (86). Using a similar procedure Pillon et al. (87) demonstrated that, compared to controls, PD patients show significantly impaired spatial location of pictures, a result that contrasts with their relatively preserved verbal memory and only mildly impaired perceptual visuospatial and executive functions. Subsequently, the same group (88,89) carried out a number of experiments specifically aimed at determining the nature of the deficit and its relationship with the dopaminergic depletion that characterizes the disease. Results suggested that the memory deficit for spatial location observed in PD patients is a consequence of a disturbance of strategic processing and of decreased attentional resources, which may be a result of dopaminergic depletion and related striatofrontal dysfunction.
Postle et al. (72) examined the performances of PD patients and normal controls on a visual delayed-response test with a spatial condition and a (nonspatial) object condition, equating the perceptual difficulty of the tests for each participant. The stimuli were irregular polygons presented at different locations on a computer screen. Results revealed a disruption of spatial memory unconfounded by sensory processing difficulties. The authors hypothesized that the selectivity of this deficit might reflect the circumscribed nature of pathophysiological change affecting the caudate nucleus in early PD.
Maze learning can also be used to evaluate long-term spatial learning. Wallesch et al. (90), to analyze spatial learning and cognitive processes described as impaired in PD, used a computerized maze task that allowed only partial vision of the maze. Results demonstrated that PD patients require more trials than controls to solve the maze problems. Differences between the performances of patients and controls were interpreted as owing to a response bias in the PD patients that resulted in a tendency to repeat the previous action and in impaired multistep plan generation.
The ability to create and manipulate images plays a central role in many daily activities: from navigation to memory and to creative problem solving. According to Kosslyn (91) imagery abilities fall into at least four categories: image generation, image inspection, image maintenance, and image transformation. Several neuroimaging studies (92-94) have provided strong evidence that visuospatial imagery activates the same brain areas that are involved in visuospatial processing. In line with this finding Levin et al., on the basis of the double dissociating performance of two patients, demonstrated that the distinction between the "what" and "where" cortical visual systems extends to mental imagery tasks. An open question is whether or not image generation, besides being associated with activation of the same representations that are involved in visuospatial processing, also involves the activation of circuits specifically devoted to mental image generating per se. In investigating visuospatial impairments of patients with movement disorders, imagery tasks have the advantage that they do not involve overt motor components liable to interfere with the recording of subjects' responses.
Image generation was investigated by Jacobs et al. (95). These authors demonstrated that PD patients are impaired on a task of emotional facial imagery but not on an object imagery control task. They are also impaired on tasks of perceiving and making emotional faces. Performance on both the perceptual and motor tasks of facial expression correlated significantly with performance on the emotional facial imagery task.
Image transformation was investigated in Brown and Marsden's study (96). They employed a mental rotation task that required subjects to align mentally an arrow with one arm of a Maltese cross and to decide whether a dot was on the left or the right of the arrow. PD patients, although slower than controls, did not perform differentially worse in the conditions that required a greater amount of reorientation (e.g., when the arrow was pointing down), thus demonstrating lack of a generalized visuospatial deficit in PD. However, in a subsequent study, Lee et al. (97), using both two- and three-dimensional visual rotation tasks, demonstrated that PD patients make more errors on mental rotations involving larger rotations in depth (or three-dimensional rotations). Furthermore, when three-dimensional rotation is involved, they showed a pattern of reaction time suggesting a specific impairment with larger rotations, thus indicating that PD patients may indeed have some problems in extrapersonal space image transformation.
An individual's successful navigation of the environment depends on his or her ability to establish an integrated viewpoint from which objects are represented spatially in relation to her or himself and to each other. To achieve this, visual inputs have to be processed and the results of visuospatial processing associated with information already stored in long-term memory (2). Disorders at any of these levels may affect route finding. Bowen et al. (98) demonstrated that a standardized "route walking test" yields deficiencies in PD patients, especially those with left-sided or bilateral symptoms. However, natural environments usually provide a subject with a much richer supply of external cues, which have been shown to facilitate performance (99). Indeed, there is one report in the literature that may account for the thesis that mild-to-moderate PD patients' object-in-location memory does not show spatial deficits when tested in a natural setting (100). Yet, Montgomery et al. (101) compared the ability of mild and moderate PD patients and controls to remain oriented to the starting position after being transported passively in a wheelchair. They examined subjects under the condition of either visual or vestibular processing. The moderate PD group demonstrated the poorest performance in both sensory conditions. The visual condition discriminated between the mild PD group and the controls, but both groups gave similar performances in the vestibular condition. Poor performance in the visual condition correlated significantly with poor performance on judgment of line orientation in the mild PD group. The authors concluded that spatial updating, or maintaining a sense of orientation while being moved in the environment, is impaired in PD. More recently, Leplow et al. (102) corroborated the view that PD patients show spatial memory deficits also in real-life settings. They devised a "search through" locomotor task incorporating the basic features of two paradigms (the radial maze and the water maze) widely used to assess spatial behavior in animal research (103,104). The participants had to find and remember 5 out of 20 hidden locations within a completely controlled environment. The performances of PD patients were found to worsen if the starting position was moved by 90° and the proximal cues were deleted simultaneously. The results were interpreted as indicating patients' inability to generate rules that can be used flexibly in changing environments.
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