Brain, Vol. 122, No. 11, 2133-2146,
November 1999
© 1999 Oxford University Press
Invited review |
Absence of a common functional denominator of visual disturbances in cerebellar disease
1 Sektion für Visuelle Sensomotorik, Neurologische Universitätsklinik Tübingen, Germany and 2 The Weizmann Institute, Rehovot, Israel
Correspondence to:
Professor Dr P. Thier, Sektion für Visuelle Sensomotorik, Neurologische Universitätsklinik, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany E-mail: thier{at}uni-tuebingen.de
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Abstract |
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Several studies have demonstrated disturbances of visual perception in patients suffering from cerebellar disease. In an attempt to determine the cause of these visual disturbances and thereby the cerebellar contribution to vision, we designed two sets of experiments in which we tested (i) the possibility of a general magnocellular deficit in cerebellar disease and (ii) the alternative possibility of impaired spatial attention underlying visual disturbances in cerebellar patients. The first set of experiments consisted of a test of position discrimination, a parvocellular function and tests tapping different aspects of motion perception including speed discrimination, direction discrimination and the ability to extract a coherent motion signal embedded in noise. The second set of experiments compared the performance on two different classes of texture discrimination. The first one required fast and precise shifts of focal spatial attention (`serial search'), the second one, testing preattentive texture discrimination (`pop-out'), did not. In the first set of experiments cerebellar patients were impaired on the position discrimination task as well as several, albeit not all, tests of motion perception. The pattern of disturbances obtained was neither compatible with the notion of a selective magnocellular deficit nor the idea, originally put forward by Ivry and Diener (J Cogn Neurosci 1991; 3: 355–66) that visual deficits are secondary to an impaired measurement of time. In the second set of experiments, cerebellar patients showed normal performance on pop-out tasks and normal performance on all variants of the serial search task except for the one requiring comparison of a single element presented with a sample of the target in short-term memory. In summary, our results support the existence of visual disturbances in cerebellar disease, but provide evidence against a common, simple denominator such as a timing deficit, deficient cerebellar modulation of magnocellular circuitry, deficits of spatial attention or visual working memory.
visual motion; memory; attention; clock; timing; cerebellum
ANOVA = analysis of variance; RDP = random dot patterns; SOA = stimulus onset asynchrony
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Introduction |
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Recent years have witnessed a dramatic change of our view of the vertebrate cerebellum. While the cerebellum has traditionally been viewed as a brain centre subserving skilled motor behaviour, recent work on the human cerebellum has suggested a much broader functional role with contributions to a wide range of cognitive functions including visual perception (Fiez, 1996
). The view that the cerebellum is involved in visual perception goes back to work undertaken on cerebellar patients by Ivry and Diener (Ivry and Diener, 1991). These authors reported that their patients, most of them suffering from degenerative cerebellar disease, were impaired on tasks requiring the discrimination of the speeds of sequentially presented patterns. The same patients were normal on a task demanding the discrimination of two simultaneously presented positions in different parts of the visual field. Recoursing to the physical definition of velocity as a position increment divided by a time increment, and having demonstrated a normal capability of sensing position increments in the face of an impaired capability to measure velocity, these authors concluded that this impairment in speed discrimination was a consequence of an impaired capability to measure time increments. This specific interpretation seemed to add support to the idea that the cerebellum is a biological clock measuring time intervals in the milliseconds range subserving motor as well as non-motor functions (Keele and Ivry, 1990). Irrespective of this very specific interpretation, the existence of a motion perception deficit received further support when Nawrot and Rizzo demonstrated that cerebellar patients were impaired on a task requiring the extraction of a coherent motion signal embedded in noise (Nawrot and Rizzo, 1995). Their experiments were designed to account for the two major objections raised against the Ivry and Diener study. The first one is that the perceptual deficits seen might have been due to an involvement of extracerebellar structures, often affected by genetically determined cerebellar disease. The second objection usually put forward is that visual disturbances might have been a consequence of subtle oculomotor disturbances such as instability of fixation during stimulus presentation. Therefore, Nawrot and Rizzo restricted stimulus presentation to 200 ms, thereby reducing the impact of possible instabilities of fixation, and they studied patients with vermal lesions of non-degenerative cause, thereby excluding the possible impact of extracerebellar pathology. While their well-controlled study has clearly strengthened the case for motion perception deficits resulting from a true cerebellar dysfunction not being secondary to oculomotor disturbances, it has not been able to unravel its cause.
A possible cause of motion deficits is suggested by previous work on the visual cortex of cats. It has been known for many years that the motion processing areas of the cat, the suprasylvian sulcus, receive a strong input from those parts of the thalamus which are under cerebellar control (Sasaki et al., 1972; Wannier et al., 1992), suggesting some kind of modulatory influence of the cerebellum on motion processing. Primate cortical areas such as MT and MST, often assumed to be homologous to the suprasylvian motion processing areas of the cat, are the major targets of an anatomically and functionally distinct pathway fed by the magnocellular part of the lateral geniculate body (Merigan et al., 1991; Maunsell, 1992). These facts in mind, we wondered if motion perception deficits in cerebellar patients might actually reflect a missing or reduced cerebellar influence on the magnocellular pathway. In this case one would expect to find impairments of all magnocellular visual functions, not only the time dependent ones such as the ability to discriminate speeds. We set out to test this idea as an alternative to the timing deficit hypothesis of Ivry and Diener by comparing cerebellar patients with healthy controls on a battery of paradigms (Study 1) tapping different aspects of motion perception including tests of speed discrimination, direction discrimination and the ability to extract a coherent motion signal embedded in noise, as well as a test of position discrimination, a function of the parvocellular pathway, the functional and anatomical complement of the magnocellular pathway. While confirming a motion perception dysfunction in cerebellar patients, the pattern of deficits obtained was neither compatible with a selective and complete magnocellular dysfunction nor with the timing deficit hypothesis of Ivry and Diener. Rather it pointed to the possibility of attentional disturbances underlying the visual disturbances observed. We therefore designed a second set of experiments (Study 2) in which we specifically compared the performance on two different classes of texture discrimination. The first one required fast and precise shifts of focal spatial attention (`serial search'), the second one, testing preattentive texture discrimination (`pop-out') did not. The results obtained are only partially compatible with the notion of an attentional dysfunction underlying visual deficits. Rather, disturbances of visual working memory have to be considered in order to account for the pattern of deficits observed in this set of experiments. Hence, the complex pattern of results from these studies is at odds with the naive view that visual disturbances in cerebellar disease could be led back to a deficient cerebellar control of a single functional element such as the measurement of time, the allocation of visual attention or a general modulation of magnocellular activity. Preliminary accounts of our findings have been given in abstract form (Thier and Treue, 1994; Thier and Haarmeier, 1998).
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Study 1
This study (see Fig. 1
, left) consisted of five tests aimed at tapping different aspects of visual motion processing and one test of position discrimination, similar to the one used by Ivry and Diener (Ivry and Diener, 1991). All visual stimuli were presented on a 20 inch computer monitor (spatial resolution 1280 x 1024; temporal resolution 72 Hz) in an otherwise dark room and viewed at a distance of 57 cm. In all experiments, subjects were asked to fixate a central white spot (diameter 0.3°). Subjects performed two alternative forced choice tasks and responded by selecting one of two response buttons on a given trial. Stimulus presentation lasted 1 s, if not specified otherwise, and a given experiment consisted of 60–80 trials. The difference between the two stimuli was varied according to the method of constant stimuli. The percentage of correct responses was plotted as a function of the size of the difference and fitted by a probit function (McKee et al., 1985). Thresholds were defined by the difference of the two manifestations for which the probit function predicted 84% correct responses. For further statistical analysis, thresholds were normalized by setting thresholds of the control group to 1. The fact that we could not test every subject on the full battery of paradigms (see Tables 1 and 2 for information on the number of subjects enrolled in a particular task) precluded a statistical analysis by two-way ANOVA (analysis of variance) with the factors group and paradigm. We therefore compared the performance of patients with controls on a given task by running Mann–Whitney U tests. Differences were considered to be significant here and later in Study 2, if P < 0.05.
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Tests used were as follows. (i) Position discrimination (Fig. 1A
): two bright dots (diameter 0.2°) were presented 6° right and left of the central fixation point. While the left one was always located on the horizontal meridian, the vertical coordinate of the right one was varied and subjects had to decide if this dot was above or below the left one. The other experiments of Study 1 were based on random dot patterns (RDPs). The diameter of the field was 11.5°, dot diameter was 0.1° and dot contrast was the maximal contrast of the monitor. Dots first appeared in randomly chosen locations, from where they moved in a direction and at a speed determined by the particular paradigm. Dots which had reached the confines of the field were erased and reborn in new, randomly chosen locations. (ii) Direction discrimination (Fig. 1B): subjects viewed a RDP consisting of 150 dots moving coherently to the right at a speed of 8°/s. A small vertical movement component was added whose size and direction was varied from trial to trial. Subjects had to indicate whether the vertical component was downward or upward. (iii) Coherent motion discrimination (Fig. 1C): subjects viewed a RDP consisting of 100 dots. While for a given movie frame one fraction, whose percentage varied from trial to trial, moved coherently at 21°/s either to the right or the left, the dots making up the other, complementary population were replotted in randomly selected locations for each frame (Newsome and Paré, 1988). Subjects had to indicate whether they saw coherent motion to the left or to the right. (iv) Sequential velocity discrimination (Fig. 1D): subjects compared the speed of dots moving coherently upward, presented in two identical RDPs consisting of 100 dots each. The fields were centred on the fixation point and were presented for 1 s each with an interval of 1 s between the two. Subjects had to determine which of the two fields contained the faster moving dots. (v) Simultaneous velocity discrimination (Fig. 1E): this experiment corresponded to the previous one except for the fact that the two RDPs were not separated in time but in space, being centred 8.5° right and left, respectively, of the fixation spot. Subjects had to discriminate which side of the fixation spot contained the faster moving dots. (vi) Velocity gradient discrimination (Fig. 1F): the RDP contained 150 dots all of which moved upward with a speed determined linearly by their horizontal position in the field. The average speed was 8°/s. The speed gradient was unpredictably oriented to the left or to the right on 50% of the trials each. Subjects had to indicate the orientation of the gradient.
Study 2
This study was designed to examine the idea that cerebellar patients might be selectively impaired on visual tasks (see Fig. 1, right) requiring the spatial allocation of attention. To this end we resorted to paradigms originally introduced by Bergen and Julész (Bergen and Julész, 1995). Subjects sat in front of a 20 inch computer monitor at a distance of 60 cm on which patterns were presented, which consisted of 36 white elements, arranged in a hexagonal array on a dark background (see Fig. 1G–I). The diameter of the array was 15° of arc and the individual elements extended for 50 min of arc. Subjects had to determine if all the elements in the array were the same or, alternatively, if one of them, the `target' element, was different. The target, the letter L, was present in half of (the usually) 60 trials and its position was varied randomly from trial to trial. The other elements, referred to as the `background' elements, were either the letter X (`pop-out' task; Fig. 1G) or the letter T (`serial' search task; Fig. 1H). Subjects were asked to fixate a small central dot which was present all the time. The patterns were presented for 40 ms only. The time available for inspection of the pattern was not limited by the presentation time but by the persistence of the afterimage induced by the high contrast images. The inspection of the afterimage was limited by the occurrence of a mask made up of elements which were composites of the target and the respective background elements (see insets in Fig. 1G and H), thereby erasing the specific retinal information needed for the discrimination. The pattern and the mask were presented for 40 ms and the stimulus onset asynchrony (SOA) between pattern and mask was varied between 50 and 500 ms (see Fig. 1I). Since pattern inspection was largely based on the retinal afterimage, which moves with the eyes, a possible impact of eye movements on the visual performance was largely excluded. Subjects signalled their decision by pressing one of two response buttons. The instruction given emphasized accuracy and the temporal response window of 4 s was generous enough to accommodate reaction time delays due to motor disabilities. In a variant of the serial search task (Fig. 1J) we kept the SOA constant at either 100 or 200 ms and varied the number of elements in the pattern (1, 2, 4 or 8). Subjects who participated in experiments 2G–J were also tested on a position discrimination task as well as a coherent motion task. Unlike the coherent motion task used in Study 1, the one used in Study 2 (Fig. 1K) required the discrimination of two regions in the visual field. Subjects were required to keep their eyes within a 2° x 2° eye position window centred on a spot with a diameter of 13.3 min of arc. If they satisfied the fixation requirements, two 12° x 12° random dot fields were presented simultaneously on the horizontal axis with their inner borders at 2° left and right of the fixation spot. Each random dot field contained 400 dots (diameter 7 min of arc, local contrast 0.1) moving at a specified velocity for a lifetime of 100 ms. For each trial a common direction of movement was chosen randomly between 0° and 360° for the coherently moving dots. The field containing coherent motion was chosen at random and the percentage of coherently moving dots was varied based on a PEST-staircase procedure (Taylor and Creelman, 1967). Subjects had to indicate the field containing coherent motion by pressing the appropriate response button. A coherence threshold was determined at which subjects responded correctly 75% of the time (where 50% correct is the performance expected by chance). Presentation time and dot velocity were varied systematically, as described in the Results section. The position discrimination task (Fig. 1L ) corresponded to the one comprising experiment 1A with the qualification that the vertical position offsets of both spots were varied by the same amount but opposite sign, that stimulus duration was only 200 ms and that the position differences were based on a PEST-staircase procedure. The position discrimination threshold was defined as the difference which gave 75% correct responses.
In those tasks requiring subjects to stay within an eye position window, eye position was monitored using a CCD-infrared reflection system (AmTech®, Weinheim, Germany) at 72 or 200 Hz. Head movements were minimized by means of a bite bar.
Subjects
Study 1 and Study 2 tested different cerebellar patients. Most of the patients suffered from either genetically determined or sporadic degeneration of the cerebellum. All patients diagnosed with multiple system atrophy had predominantly cerebellar symptoms. No patient suffering from a variant of multiple system atrophy involving the basal ganglia contributed to the studies. Tables 1 and 2 summarize the relevant information (age, gender, diagnosis) on the patients and, moreover, clarify which patient participated in which task. Subjects' consent was obtained according to the declaration of Helsinki (BMJ 1991; 302: 1194) and the study had been approved by the ethics committee of the University of Tübingen. The majority of control subjects participating in both studies were drawn from the hospital staff; a minority were in-patients suffering from diseases of the peripheral nerves or the spinal cord without any affection of supraspinal structures and without medication affecting the CNS.
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Results |
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Study 1
Figure 2A
shows the means and standard errors of the normalized thresholds of the whole group of cerebellar patients tested in this study (`all patients') and of controls (mean threshold = 1). Since not every patient participated in all tests (see Tables 1 and 2), we show in addition the means and standard errors of the subgroup of patients (`complete' patients) tested on all tasks. As can be seen, the performance of the cerebellar patients was impaired relative to healthy controls in five out of the six tasks used in this study. Patients exhibited normal thresholds on the sequential speed discrimination task, but significantly elevated thresholds (Mann–Whitney U test, P < 0.05) on the position discrimination task, the direction discrimination task, the coherent motion task, simultaneous speed discrimination task and the gradient discrimination task. Note that the subgroup of `complete' patients shows the same pattern of performance as the whole group. Five out of the 20 patients suffered from circumscribed lesions of the cerebellum due to stroke or tumours. The normalized thresholds of this subgroup of patients, compared with the complementary subgroup in Fig. 2B, did not differ in any obvious way. However, the small number of patients suffering from non-degenerative cerebellar disorders precluded a statistical comparison of the two subgroups.
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Discussion of study 1
The results of Study 1 suggested several conclusions, which led to the design of the experiments of Study 2. (i) The specific pattern of visual disturbances with normal performance on at least one out of the six tasks is inconsistent with the view that disturbed vision in cerebellar patients is simply an unspecific reflection of a general cognitive impairment. (ii) Elevated thresholds in the position discrimination task contradict the report of normal position discrimination thresholds by Ivry and Diener (Ivry and Diener, 1991
). Our finding of impaired position discrimination is at odds with the notion of a selective timing deficit underlying impaired visual perception in cerebellar patients. Another example of a non-time dependent visual function impaired by cerebellar disease is direction discrimination. This task taps magnocellular circuitry. (iii) A look at the performance on the other tasks, however, shows that patients do not exhibit a general and selective magnocellular deficit. Patients were impaired on position discrimination, a task not dependent on magnocellular circuitry. On the other hand, the same patients showed normal performance on the sequential velocity task, a test dependent on magnocellular circuitry. (iv) Visual deficits in cerebellar patients do not reflect pathology outside the cerebellum. This very tentative conclusion is based on the fact that the performance of the two subgroups of patients, the smaller one comprising patients with lesions confined to the cerebellum, the larger one comprising patients with genetically determined or sporadic forms of cerebellar degeneration, was very similar. This conclusion is in accordance with the work of Nawrot and Rizzo (Nawrot and Rizzo, 1995). (v) Oculomotor disturbances such as an instability of fixation are not likely to account for the specific pattern of visual disturbances observed. The reason for this tentative conclusion is that patients were normal on a visual task (sequential velocity) whose demands on fixation were similar to those of the other tasks. These considerations of course do not rule out the possibility that oculomotor disturbances might have contributed to some of the visual deficits observed. The first aim of Study 2 was to exclude the confounding effects of altered oculomotor behaviour of cerebellar patients on vision more convincingly. The second aim was to test the idea, prompted by the results of Study 1 that at least some of the visual disturbances observed might actually be secondary to disturbances of the precise allocation of spatial attention. This idea was suggested by the observation that patients in Study 1 were impaired on the simultaneous speed discrimination task, requiring the comparison of information derived from two spatial locations, but normal on the sequential speed discrimination task, in which there was no need to divide spatial attention between two regions or, alternatively, to redirect a `spotlight' of attention between these two regions. Impaired spatial attention would also account for the deficit on the position discrimination task and the gradient task, likewise requiring comparison of two (position discrimination task) or many (gradient task) spatial locations. We add, however, that the idea of an impairment of spatial attention would not account for the deficits observed on the discrimination task.
Study 2
In the `pop-out' task (Fig. 1G and I) subjects had to detect the target element (L) in the presence of 35 background elements corresponding to the letter X. Figure 3A compares the probability of correct detections of the target element as a function of the SOA in healthy controls with groups 1 and 2 of cerebellar patients. As can be seen, performance increased monotonically with SOA in all groups and reached detection rates >80% in all three groups (two-way ANOVA with the factors SOA and group; significant main effect of SOA, P < 0.001). There was no significant difference between the three groups tested (non-significant main effect of group, P = 0.89; non-significant two-way interaction, P = 0.893). In the `serial search' task (Fig. 1H and I), subjects had to detect the same target element (L) in the presence of 35 background elements, corresponding to the letter T. As shown in Fig. 3B, the probability of correct detection did not show the fast increase with SOA found for the previous task. Even at the longest SOA used, performance barely exceeded chance level (i.e. 50% correct) with no significant difference between patients and controls (two-way ANOVA; non-significant main effect of group, P = 0.82; non-significant two-way interaction, P = 0.22). The slow, albeit significant, increase in performance with SOA (significant main effect of SOA, P < 0.003) reflects the serial character of target search on this task. Given the large number of elements in the array and the finite time required to shift the `inner eye' from one element to the next, the likelihood of spotting the target becomes too low to yield high detection rates, even for the longest SOAs available (cf. Bergen and Julész, 1995).
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If subjects indeed used a serial mode of processing in order to detect the target letter L amidst the Ts, detection rates should benefit from a reduction of the size of the number of elements in the set. We therefore varied the number of elements (1, 2, 4 or 8) in a modification of the `serial search' task while keeping the SOA constant at either 100 or 200 ms (Fig. 1J
). Figure 4, which shows plots of detection rates as a function of the number of elements in the set, shows that both patients (group 1) and controls demonstrated the expected increase with decreasing numbers of elements in the set (three-way ANOVA with the factors group, SOA and set size; significant main effect of set size, P < 0.001). However, this benefit was significantly less for cerebellar patients compared with controls (significant two-way interaction of set size and group, P < 0.004) and not dependent on the SOA (non-significant three-way interaction of set size, group and SOA, P = 0.946). Further analysis of the significant two-way interaction by post hoc Scheffé tests demonstrated that patients had significantly lower detection rates for the set size of one only (P < 0.014). For this configuration, detection rates of patients were ~15% smaller than those of controls.
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All the patients of group 1 and all controls who had participated in the experiments on preattentive vision and serial search were also tested on the extraction of coherent motion in a random dot field (Fig. 1K
). Figure 5 shows plots of detection rates for patients and controls for the coherent motion test. Panel A shows the detection rates for different stimulus durations from 200 to 1000 ms and a fixed dot velocity of 6°/s. Panel B is a plot of detection rates as a function of dot velocity, ranging from 4 to 20°/s for a fixed duration of 200 ms. As can be seen, patients exhibited higher thresholds, independent of the duration (Fig. 5A; two-way ANOVA with the factors duration and group: significant effect of group, P < 0.015; significant effect of duration, P < 0.0002; non-significant interaction, P < 0.069) or the velocity of the stimulus (Fig. 5B; two-way ANOVA with the factors velocity and group: significant effect of group, P < 0.0068; significant effect of velocity, P < 0.001; non-significant interaction, P < 0.86).
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Figure 6
is a comparison of the distributions of the position discrimination thresholds of patients and controls. Thirteen out of 14 patients from group 1 plus two from group 2 participated in this task. As can be seen, the distribution for the patients is wider and, moreover, shifted to thresholds which, on average, are twice as large as those of controls (13.9 versus 27.0 min of arc). This difference in thresholds was significant as shown by a non-parametric comparison (Mann–Whitney U test, P < 0.05).
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In Study 2, patients were impaired on the one-element version of the serial search task as well as on the position and the coherent motion discrimination tasks. In case of a common pathophysiological denominator underlying these deficits, we might expect to find correlations between the performances of individuals on these three tasks. Figure 7
shows plots of the performance of controls (left column) and patients (right column) on one task as a function of the performance on another task. The pairwise regressions for controls were without exception non-significant (P > 0.5) and for patients only the one for coherent motion discrimination as a function of position discrimination turned out to be significant at the P < 0.01 level. The tentative conclusion suggested by this analysis is that position and coherent motion discrimination might be affected by the same pathophysiological process, unrelated to the one responsible for the specific serial search deficit.
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Discussion |
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We conducted two studies which were designed to compare the performance of patients suffering from cerebellar disease with that of controls on a number of visual tasks, in an attempt to pinpoint a specific visual mechanism dependent on the cerebellum. The starting point of our interest had been reports of visual motion perception deficits by Ivry and Diener (Ivry and Diener, 1991
) and Nawrot and Rizzo (Nawrot and Rizzo, 1995). The former study had been especially intriguing since it had tried to offer an explanation of the motion perception deficit, making use of the fact that the same patients presenting with impaired motion perception had shown normal thresholds on a position discrimination task. Reasoning that the measurement of visual motion requires the comparison of a spatial increment and, moreover, a temporal increment, the authors concluded that the motion perception deficit might result from a cerebellar deficit in measuring time increments, adding further support to the idea that the cerebellum is a clock working in the milliseconds range (Keele and Ivry, 1990). While seemingly offering a formally correct interpretation of their findings, the idea that the measurement of visual motion might involve a dedicated clock is obviously at odds with prevailing models (Hassenstein and Reichardt, 1956; Reichardt, 1957, 1961; Barlow and Lewick, 1965; Torre and Poggio, 1978; Adelson and Bergen, 1985) of visual motion analysis, getting by without a dedicated clock. The temporal aspect in these models is usually incorporated in an implicit way by having linear filters with time constants and/or delays. The biological underpinnings of these computational elements are thought to be synapses and membrane properties (Torre and Poggio, 1978). In view of these conceptual discrepancies we designed experiments allowing us to test alternative interpretations of the motion perception deficit seen by Ivry and Diener and later corroborated by Nawrot and Rizzo. The objective of Study 1 was to test the assumption of a general magnocellular dysfunction resulting from cerebellar disease (see Introduction). As already discussed earlier, our findings allowed us to discard this hypothesis as well as the hypothesis of Ivry and Diener of a timing deficit as the functional denominator of visual disturbances in cerebellar disease. One reason to reject the latter interpretation was the fact that our patients were clearly impaired on the position discrimination task, a finding which we could replicate in Study 2. The discrepancy between our findings on position discrimination and those of Ivry and Diener is lessened by the fact that even their patients had exhibited a clear, albeit non-significant, tendency towards higher position discrimination thresholds.
Studies based on patients suffering from hereditary or non-hereditary degenerative cerebellar disease face the criticism that the deficits observed might reflect more or less prominent non-cerebellar pathology accompanying the cerebellar disease. This concern is clearly warranted also with respect to our patients. Although in all our patients cerebellar symptoms were to the fore as revealed by standard clinical assessment, our sample included two patients suffering from Friedreich's ataxia, a degenerative disease in which non-cerebellar pathology is actually dominating (Oppenheimer, 1979; Lamarche et al., 1984; Junck et al., 1994) and several cases of other types of spinocerebellar ataxia known to involve extracerebellar structures (e.g. Wenning and Quinn, 1992; Klockgether et al., 1996, 1998; Abele et al., 1997; Geschwind et al., 1997; Gomez et al., 1997; Schöls et al., 1997). However, we are confident that the putative extracerebellar manifestations of disease on the visual tasks in Study 1 did not determine the visual deficits found. The reason is that the pattern of deficits in the five patients who contributed to Study 1 with localized lesions of the cerebellum due to ischaemia or tumour did not segregate them from the others suffering from degenerative disease. Moreover, we did not find any obvious differences between the various groups of degenerative cerebellar disease. However, given the small number of patients in the various subgroups of degenerative cerebellar disease, clearly more cases will have to be studied before definite conclusions as to different patterns of visual deficits in the different types of degenerative cerebellar disease are justified.
Depending on the site of the cerebellar pathology, different types of oculomotor disturbances including unstable fixation or nystagmus may be expected in cerebellar patients (for review, see Leigh and Zee, 1991). This raises the concern that the visual deficits observed in the patients of Study 1 might actually have resulted from impaired image stability due to insufficient fixation of the central spot, especially in view of the long duration of stimulus presentation. This, however, does not seem to be very likely since patients in Study 1 showed normal performance on one task, whose demands on fixation were similar to those of the five tasks on which they were impaired. Nevertheless, a possibly confounding effect of oculomotor disturbances cannot be dismissed with any degree of certainty because eye movement measurements were not carried out. Furthermore, the comparatively long stimulus presentation duration (1 s) in Study 1 might give possible oculomotor deficits sufficient time to interfere with the scrutiny of the visual material. One of the aims of Study 2 was to dispel the concerns that visual deficits in patients might actually be artefacts of oculomotor deficits. We decided not to resort to high-resolution eye movement recordings, since they, at best, might have allowed us to document oculomotor differences between patients and controls without necessarily revealing their impact. Rather we decided to shape the visual paradigms such as to reduce the impact of altered oculomotor behaviour. In the experiments testing texture discrimination, which stood at the centre of Study 2, this was achieved by basing visual scrutiny on retinal afterimages. These afterimages, moving with the eyes and thereby being insensitive to impaired fixation, were induced by flashing a high-contrast stimulus and erased by an appropriate mask. The clear-cut deficit of patients on one of the texture discrimination tasks, discussed in detail below, proves that specific visual deficits persist in cerebellar patients even under conditions which preclude any contribution of disturbed eye movements. There are two further observations from Study 2 which are evidence against a significant role of unnoticed oculomotor disturbances. (i) The deficit of patients on the test of coherent motion discrimination was independent of stimulus duration. (ii) The deficit on the position discrimination task, also part of Study 2, replicated the deficit observed on the same task in Study 1, although stimulus duration in Study 2 was only 200 ms compared with 1000 ms in Study 1. Since the detrimental effect of most oculomotor disturbances resulting from cerebellar disease should be larger the longer the need to maintain fixation, the absence of a duration effect indicates lack of a significant role of oculomotor disturbances.
The major aim of Study 2 was to test the idea, prompted by the results of Study 1, that at least some of the visual disturbances might actually be secondary to disturbances of the precise allocation of spatial attention. To this end, we applied tests of texture discrimination, differing with respect to the amount of focal spatial attention involved. One of the tasks required serial shifts of focal attention in the visual field (`serial seach task'), while the other one was solvable in a purely pre-attentive, parallel mode of visual processing (`pop-out task'). In accordance with the speculation that visual disturbances in cerebellar patients might reflect disturbances of spatial attention, we indeed found a normal performance of patients on the pop-out task and selective impairments on the serial search task. However, on closer examination of the deficits on the serial search task, it becomes clear that they can hardly be attributed to deficits of spatial attention. The reason is that the deficit was confined to arrays containing one item only, which on 50% of the trials was the target item and on the other trials the irrelevant distractor. The only way to decide if the item presented is the target or the distractor in this one-item configuration is to compare the stimulus with a memory trace of the target and/or the distractor, based on earlier presentations. A poorer performance of patients therefore reflects a disturbance of this memory based comparison, rather than a less rapid and/or less precise covert shift of attention to the item presented in non-predictable locations in the visual field. Unlike the one-item configuration, those containing two or more elements can be analysed without reference to this memory trace based on earlier presentations of stimuli, while still requiring serial shifts of attention from one item to the next. If the elements within the array are the same, all have to be distractors. However, if one is different from the others, it has to be the target. The `pop-out' task is not only characterized by the lack of a need to allocate attention; rather, it also lacks the need to resort to a memory based feature comparison in order to detect the target. Hence, the most parsimonious explanation of the performance of our patients on both types of texture discrimination tasks would be to assume disturbances of operations involving visual object working memory. Whether it is the storage of visual information which is disturbed, its retrieval or its usage for the comparison with new visual material has to be left open. The conclusion that disturbances of memory-related functions may be the basis of specific visual deficits in cerebellar disease may, at first glance, be surprising. However, the cerebellum has traditionally been implicated in the learning and memory of motor behaviour including the conditioning of discrete behavioural responses (Marr, 1969; Thompson, 1986; Bloedel, 1987) and recent work has substantially extended this view of memory-related functions of the cerebellum. For instance, functional activation studies have provided evidence that specific parts of the cerebellum are involved in different aspects of working memory (Courtney et al., 1996; Fiez et al., 1996; Desmond et al., 1997; Jonides et al., 1998) and episodic memory (Nyberg et al., 1996). Of particular interest with respect to our own finding of a memory based deficit on a feature detection task is the PET study by Courtney and colleagues (Courtney et al., 1996), which showed a significantly stronger activation of the midline cerebellum by visual object working memory relative to spatial working memory.
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An anatomical denominator of visual disturbances? |
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Could an impairment of visual memory-related operations subserve as a common pathophysiogical principle underlying visual disturbances in cerebellar disease in general? The answer is `no'. None of the other tasks on which patients were shown to be impaired by us and by others require the storage of visual information for later comparison. For instance, the position discrimination task (Ivry and Diener, 1991
; this study, Studies 1 and 2), the simultaneous variant of the speed discrimination task (Study 1) or the variants of the coherent motion task used by Nawrot and Rizzo (Nawrot and Rizzo, 1995) and by us (this study, Studies 1 and 2) offered all the visual material required for discrimination simultaneously without need for temporal buffering of information. On the other hand, the only task on which patients were normal in our Study 1, the sequential speed discrimination task, clearly required the storage of the first pattern for comparison with the later pattern.
We set out to find a common denominator of visual disturbances in cerebellar patients, possibly based on a hypothetical functional principle involved in vision housed by the cerebellum. However, our results clearly suggest that the idea of a common functional denominator must be rejected. None of the functional principles considered such as timing, a general magnocellular modulation, spatial attention or visual memory turned out to be able to account for all the visual deficits observed. Is there an alternative to the idea of a common functional denominator? A speculative answer might be that we should consider a common anatomical denominator rather than a common functional denominator. The cerebral projections of the cerebellum have long been thought to be restricted to motor cortex, one of the reasons that the cerebellum has long been regarded as being confined to the control of movement. However, based on the transneuronal transport of virus tracers, it has become clear that multiple cerebrocortical areas, including premotor, prefrontal and parieto-occipital cortex receive cerebellar input via the thalamus (Middleton and Strick, 1997). While significant parts of parieto-occipital cortex and cerebral cortex at large seem to receive cerebellar inputs, distinct areas or even parts of cerebral cortex seem to be spared. Visual functions based on these spared regions would not be affected by cerebellar dysfunction, whereas, conversely, those based on regions receiving cerebellar input would be expected to be impaired. Obviously, we have to learn more about the details of the pattern of cerebellocerebral projections in order to decide if this idea is useful.
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We wish to thank Marc Repnow for skilful computer programming and many helpful suggestions. This work was supported by grants from the Deutsche Forschungsgemeinschaft (KFG Neuroophthalmologie, Zr 1/9–2), the German Israeli Foundation (GIF I-234–040.01/92) and the IZKF Tübingen (BMBF Fó. OIKS9602).
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Received April 12, 1999. Accepted April 17, 1999.
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