Dissociated long lasting improvements of straight-ahead pointing and line bisection tasks in two hemineglect patients

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1 Neuropsychologia 40 (2002) Dissociated long lasting improvements of straight-ahead pointing and line bisection tasks in two hemineglect patients Laure Pisella a, *, Gilles Rode a,b, Alessandro Farnè c, Dominique Boisson a,b, Yves Rossetti a,b a Institut National de la Santé et de la Recherche Médicale, Unité 534: Espace et Action, 16 a enue Lépine, Case 13, Bron, France b Hôpital Henry Gabrielle-B.P. 57-F Saint Genis La al Cedex, France c Dipartimento di Psicologia, Uni ersità di Bologna, Bologna, Italy Received 12 May 2000; received in revised form 31 January 2001; accepted 3 May 2001 Abstract In this experiment, we evaluated over a longer time period the previously demonstrated effects of a short prism adaptation on hemispatial neglect. We followed two patients (PE and SA), during a period of 5 days (1 day before and 4 days after the prism adaptation procedure), repeatedly measuring their performances on a straight-ahead pointing task and a line bisection task. We also assessed the comparative temporal evolution of the rightward biased egocentric reference frame (as measured by the straight-ahead demonstration) and a classical neuropsychological symptom of neglect, namely the rightward bias observed on line bisection. Firstly, the results showed that prismatic effect could be maintained for 4 days, on the two tasks (separately straight-ahead for PE, line bisection for SA). This long-term effect implies a very profound action of prism adaptation based on active processes and opens large possibilities for clinical applications. Secondly, no correlation was found between the evolution of the performances on the two tasks, neither for patient PE, nor for patient SA (within-subject double-dissociation). Moreover, a double-dissociation between subjects was demonstrated on long-term effects. A new conception has thus to be found to explain the various symptoms manifested in neglect and more investigations have to be performed in order to establish to what extent they can be considered independent. It can be concluded that elucidating the mechanism through which prism adaptation affects neglect could lead to a better understanding of the neglect syndrome Elsevier Science Ltd. All rights reserved. Keywords: Double-dissociation; Egocentric reference; Hemispatial neglect; Plasticity; Prism adaptation; Space representation 1. Introduction The syndrome of unilateral neglect is frequently observed in right-handed patients following right hemisphere brain damage. This condition can be defined as a loss of visual awareness for contralesional stimuli despite residual implicit processing [10,24]. Typically, the patient fails to report, respond to or orient toward left-sided stimuli [15,18], or tends to underestimate it [28]. Neglect symptoms have been described to range from sensori motor levels [17,26] to mental representations of space [4,31]. In addition, neglect is responsible for poor functional recovery and is resistant to treatment [12]. * Corresponding author. Fax: address: pisella@psych.unimelb.edu.au (L. Pisella). Orienting in space requires an integration of retinal, eye-position and head-position signals, together with vestibular information. These signals are classically considered to be further transformed to build a unitary egocentric reference, aligned with the sagittal body axis (review in [21]). This hypothesis draws on the notion that spatially-directed behaviour from perception to action has to be coded in a supramodal coordinate system. One of the classical manifestations of hemispatial neglect is an alteration of the egocentric reference, which can be tested by requiring the subject to point straight-ahead in the dark [20,44]. Patients often produce subjective mid-line demonstrations deviated to the right [7,16]. Along this line, a reference-shift hypothesis of neglect has been proposed, according to which all the orienting biases observed in neglect patients [1,13,17,26,27] are /01/$ - see front matter 2001 Elsevier Science Ltd. All rights reserved. PII: S (01)

2 328 L. Pisella et al. / Neuropsychologia 40 (2002) due to an illusory rotation of the egocentric reference, somewhat as if the subject felt being constantly rotated toward the lesion side [19]. Postulating that the rightward shift of the egocentric reference constitutes the anchor of the neglect syndrom [23], this hypothesis predicts that a restoration of the centred straight-ahead demonstration should produce an improvement in performance on other neglect tests. Support for this hypothesis was found in the temporary improvement of neglect patients after different types of physiological manipulation [5,22,30 32,37,41] that compensate for the pathological shift of the egocentric reference, and hence afford an improvement of the patient s behaviour in the left hemispace [23]. More recently, however, Chokron and Bartolomeo [6], Farnè et al. [11] and Bartolomeo and Chokron [2] studied two, 23 and 18 neglect patients respectively and challenged this reference shift theory of hemispatial neglect by showing that not all patients exhibited a rightward shift of the egocentric reference. In those three studies, a total of 43 patients were examined, and only 27 of them exhibited a deviation of the manual straight-ahead to the right. In addition, Farnè et al. [11] showed that the same proportion of right brain-damaged patients without neglect exhibited a similar trend. In a previous investigation, we studied 16 neglect patients with the aim of testing the effects of the adaptation to an optical deviation towards the ipsilesional side on their spatial deficit through two experiments [34]. In the first experiment, the effect of prism adaptation was tested on manual straight-ahead demonstration with eyes closed. After adaptation, all patients exposed to the optical shift of the visual field (n=8) showed an improvement on this task. In the second experiment, the effect of prism adaptation on clinical manifestations of neglect was tested on six patients, as assessed by classical neuropsychological tests. The battery included the line bisection task, line cancellation task, drawing from memory, copying and reading. Upon removal of the prisms, each of the six patients (four with hemianopia and two without hemianopia) showed an improvement in performance on each of these five tests, showing that prism adaptation improves symptoms of spatial neglect [34]. A control group of six neglect patients performing the pointing procedure with neutral goggles exhibited no significant improvement. By contrast with the other physiological manipulations [5,22,30 32,37,41], this improvement was maintained 2 h after the prism exposure [34]. The first question raised by these former results involved the potential duration of the benefits induced by prism adaptation. We therefore followed the performances of two neglect patients over a testing period of 1 week on two continuous and sensitive tests adapted to repeated measures: straight-ahead demonstration and line bisection. This longitudinal study allowed us to assess a secondary question about the reference shift hypothesis of neglect. In our previous study [34], the three neglect patients who took part in the two experiments were improved on both the straight-ahead demonstration (Exp. 1) and the classical neuropsychological tests (Exp. 2). This conjunction may support the view that the core of neglect is indeed a deviation of the internally represented midsagittal plane of the body [23]. If this view is correct, a covariation should be expected for the two types of performance. Alternatively, if the deviation of the egocentric reference and the visual neglect symptoms rely on separate mechanisms, it should be possible to selectively alter one of them without affecting the other (simple dissociation) and vice versa (double-dissociation). If no correlation is observed between the two tested variables, then at least two different and independent mechanisms have to be advocated, each being responsible for a particular neglect symptom. Hence, we also compared the effects of prism adaptation on straight-ahead demonstrations (evaluating the egocentric reference) and on line bisection (one of the most sensitive tests of neglect) in these two neglect patients. A lack of correlation between the egocentric reference and a cancellation task has been obtained recently with a group analysis [11]. It should be emphasised here that the lack of an inter-individual correlation (as obtained by [11] or [2]) does not rule out the possibility for an intra-individual link between the two variables explored. Only longitudinal studies can distinguish changes over time within individuals from differences among people in their baseline levels (cohort effect); Cross-sectional studies cannot [9]. Repeated observations of individuals enable a direct study of change in parameters A and B. These changes can be used to assess the link between A and B in a more sensitive manner. The advantages of using prism adaptation is that it allowed us to compare the temporal evolution of the two parameters within-subject (as well as between subjects), assuming that prism adaptation will trigger alterations in at least one of the tested parameters. If the two parameters were to show the same evolution over time, it would be compatible with the hypothesis that the prismatic effect on cognitive symptoms is mediated by an alteration of the egocentric reference. 2. Methods 2.1. Cases description Two right-handed females [SA (56) and PE (47)] showing left unilateral neglect consecutive to a damage of the right hemisphere participated in the study. Both had been admitted to a neurological rehabilitation unit for severe left hemiplegia. Clinical features are de-

3 L. Pisella et al. / Neuropsychologia 40 (2002) Table 1 SA Delay post onset 3 weeks 8 weeks Left hemiparesis Present Absent b Left hemianesthesia Present Absent Left hemianopia Present Present Head and gaze deviation Anosognosia a Present 1 Present 0 Left auditory extinction Aethiology Present Haemorrhagic Present Ischemic Site lesions (C.T. Basal ganglia, Frontal, temporal scan data) caudate Paraventricular Paraventricular white white matter matter Internal capsule Internal capsule a Assessed by the four point scale of Bisiach et al., 1986 [3]: score 0, the deficit was spontaneously reported or mentioned by the patient following a general discussion about his complaints; score 1, the disorder was reported only following a specific question about the strength of the patient s left limbs; score 2, the disorder was acknowledged only after its demonstration through routine techniques of neurological examination and score 3, no acknowledgement of the disorder could be obtained from the patient. b The left hemiparesis of patient PE resolved during her stay and was not present at the time of testing. scribed in Table 1. The two patients showed a rather extensive unilateral brain lesion, which was documented by CT-scan (Fig. 1). Patients had no past history of stroke and did not suffer from impaired vigilance, confusion, general mental deterioration or psychiatric disorders. The two patients showed severe neglect affecting extrapersonal and personal space. They were included in the study following a neurospychological screening based on a routine protocol [32]. PE scored PE 10 left on the Albert cancellation test, 3+1 on the Gainotti copying test (following the scoring procedure described in [34]) and drew nine petals on the right versus one on the left on the daisy drawing test. SA scored 10 left on the Albert cancellation test, 3+2 on the Gainotti copying test and drew nine petals on the right versus 1on the left on the daisy drawing from memory Experimental set up and procedure The two patients were tested during five consecutive days. The effect of prism adaptation on the straightahead pointing and line bisection test was repeatedly evaluated over ten sessions within this time period. These two tests were administered 1 day before ( 24 h), just before ( 1 h), just after (0 h) and every 2 h after a short prism-adaptation session during Day 1 (+2, +4 and +6 h), then again over the next 3 days [Day 2 (+24 h, +30 h), Day 3 (+48 h) and Day 4 (+72 h)] Straight-ahead pointing test Patients were blindfolded and seated in front of a box that allowed pointing location to be recorded with an accuracy of 0.1. They were required to make free pointings straight-ahead from a starting position near their sternum, with their eyes closed. After every trial, subjects returned their hand to the starting position. Throughout the task, their head was kept aligned with the body sagittal axis using a chin-rest. Ten trials were performed in order to obtain a reliable average value. The pointing error was measured as the angle between the pointing position and the objective body midline and carried a minus sign for leftward pointing and a plus sign for rightward pointing Line bisection test Patients were asked to mark the midline of 20 horizontal lines presented in the right, centre and left part of the same testing sheet [38]. This sensitive test allowed us to compute a score reflecting the bias in line bisection. This score was calculated as proposed by Schenkenberg et al. [38]. It expresses the mean percentage of horizontal deviation in line bisections, towards the right (signed positive) or towards the left (signed negative). Fig. 1. Reconstruction of the lesions of patients PE and SA, based on cranial MRI scans. Horizontal sections show large right-sided subcortical (SA) and cortico-subcortical (PE) lesions (depicted in black) Prism-adaptation procedure The exposure period consisted of 50 pointing trials made by right hand towards visual targets presented at 10 to the right and to the left of the body midline in a cm box (as in [34]). During this pointing session patients were asked to point at a normal speed. They could see the target and only the second half of their pointing trajectory, as well as their terminal error. The

4 330 L. Pisella et al. / Neuropsychologia 40 (2002) Fig. 2. Temporal evolution of the performance of the two patients in the straight-ahead pointing task. Positive values correspond to right deviations, and negative ones to left deviations. The shadowed area represents the Pretesting period gathering the two sessions realised by the patients before the single prism adaptation procedure. The X-axis zero corresponds to the experimental testing performed just after adaptation (upon prism removal). left-based wedge prisms used in this experiment were wide field glasses inserted into light goggles. With these goggles on, the visual field was uniformly shifted by 10 to the right. In normal subjects, rapid adaption usually occurs to resolve the visuo-motor discrepancy. By contrast to a previous study which used a leftward prismatic shift to draw attention to the neglected field [36], our experiment was designed to test whether the compensatory after-effects of adaptation to a rightward prismatic shift could improve neglect [34]. Hence, subjects were always tested without prisms, both before (pretest) and after (post-test) the adaptation procedure Statistical analysis A one way ANOVA was used to investigate the effects of Subject and Period of testing. 3. Results 3.1. Straight-ahead demonstration In the pretests, both patients exhibited a shift of the straight-ahead pointing towards the right side (Fig. 2). Just before the prism exposure, the mean deviations of patients PE and SA were evaluated to 3.8 and 14.9 respectively. During the initial stage of the post-tests (day 1), the mean deviation of both SA and PE was reduced. The two patients followed a similar pattern of evolution. Just after adaptation to the 10 rightward optical deviation, the straight-ahead demonstration was shifted about 9 leftward in the two patients. This immediate aftereffect gradually decreased in both patients during the first 4 h following prism adaptation. After this short-term effect, the evolution of the mean deviations began to differ between the two patients. Four hours after the adaptation, the straight-ahead demonstration of patient PE was correct (ie close to 0 ) whereas the deviation of patient SA was back to the value of the second pretest. In the late-tests, the performance of patient PE seemed to be stabilised around the normal value. By contrast, patient SA did not show a long-term improvement with respect to the demonstration performed prior to prism adaptation Line bisection test In the pretests, both patients exhibited positive deviation scores, that is that their bisection of horizontal lines was shifted to the right of the objective centre, independently of the location of the line in the testing sheet (Fig. 3). Just before prism adaptation, the deviation scores of SA and PE were 50.5 and 12.4% respectively, ie both were above the liminar value of 11% used by Schenkenberg et al. [38] to define a pathological deviation. In the post-tests, the score of SA was dramatically reduced, whereas the score of PE remained unchanged. Immediately after the prism exposure, the deviation score of SA was reduced to the value of 24%. Two hours after, the performance of SA was further improved up to normal values and the effect seems to be durable throughout the late-tests. By contrast, no improvement was observed for Patient PE, either in the short-term or in the long-term.

5 L. Pisella et al. / Neuropsychologia 40 (2002) Statistical analysis In order to investigate more precisely the effect of prism adaptation, an analysis of variance contrasting the pretest and the post-test periods was performed (one way ANOVA, two periods). For patient SA, measures made during these two periods were significantly different for straight-ahead pointing (F(1,92) =85.2; P 0.001) and for the Schenkenberg test (F(1,190)= 23.4; P 0.001). For patient PE, a significant difference between these two periods was only found for straightahead pointing (F(1,102) 116.9; P 0.001) and not for the Schenkenberg test (F(1,190)=0.66; P 0.1). In order to distinguish in more detail between transient and long-lasting improvement after prism adaptation (as described in the qualitative analysis), we divided the post-test period into two parts: measures performed on the 1st day of the prism exposure (day 1) and measures performed during the following 3 days (late-test). For each patient, an additional ANOVA was performed with contrasts in order to compare the three defined periods by pairs (planned comparisons between pretests, day 1 and late-tests) Straight-ahead pointing The pretests were significantly different from day 1 (F(1,102) 111; p 0.01) and from the Late-tests (both Fs(1,102) 86; P 0.001) for patient PE. Furthermore, day 1 and late-tests were not significantly different (F(1,102) 3; P 0.05). These results showed a durable effect of prisms on straight-ahead pointing task for patient PE. A significant difference was found between performances of patient SA measured 24 h before and just before the prism adaptation (Post Hoc test Scheffé P 0.005). For the sake of carefulness, the contrast analysis performed for patient SA excluded this first measure (24 h before prism adaptation). Even the single measure made just before prism adaptation was significantly different contrasting with all eight measures made after it (F(1,92)=10.4; P 0.005). A significant difference was found contrasting the measure made just before prisms (preperiod) and those made in day 1 (F(1,92)=18.9; P 0.005), although it was not contrasting pre and late periods (F(1,92)=3.1; P 0.05). Furthermore, day 1 and late periods were found to be significantly different (F(1,92)=17; P 0.001). These results reflect only a transient effect of prisms on straight-ahead pointing task for patient SA Schenkenberg test No difference between the three periods was found for patient PE [pre vs day 1 (F(1,190)=0.05; P 0.8), pre vs late (F(1,190)=1.6; P 0.2) and day 1 vs late (F(1,190)=1.6; P 0.2)), which indicated that prism adaptation had no significant effect on line bisection task for this patient. By contrast, performances of patient SA were significantly different between pre and day 1 periods (F(1,190)=17.5; P 0.001) as well as between pre and late (F(1,190)=21.6; P 0.001). No significant decrease of the adaptation effect was found between day 1 and late (F(1,190)=0.3; P 0.5). Prism exposure thus produced a durable effect on patient SA. Interestingly, no significant correlation was found between the results of the straight-ahead and the Schenkenberg tests whether the analysis was performed with both patients together (R 2 =0.15; F(1,18)=0.53; P 0.6) or for each patient separately (R 2 =0.16; F(1,8)=1.21; P 0.2 for patient SA and R 2 =0.89; F(1,8)=0.88; P 0.4 for patient PE) This result is compatible with the absence of a causal link between Fig. 3. Temporal evolution of the performance of the two patients in the line bisection task (Schenkenberg test). The deviation score (%) is calculated as in Schenkenberg et al. (1980) [38]. Same legend as in Fig. 2.

6 332 L. Pisella et al. / Neuropsychologia 40 (2002) the egocentric reference bias and the other symptoms of neglect Subjecti e manifestations In patient SA surprisingly, the improvement of neglect, as assessed by the line bisection test, was accompanied by a negative change in mood. Whereas the patient was anosodiaphoric in the pre-tests period, the lack of awareness of her left motor deficit disappeared in the late-tests period (day 2) and raised a catastrophic reaction with deep anxiety and depression. A psychotropic treatment had to be administered from day Discussion Our previous results showed that a substantial improvement of both straight-ahead pointing and line bisection tasks can be obtained in neglect patients exposed to base-left wedge prisms and that this improvement is maintained for at least 2 h [34]. The main aim of the present study was to further investigate the effects of prism adaptation on hemispatial neglect over a longer testing period. In addition, this longitudinal study turned out to be appropriate to investigate the link between the two variables explored using a withinsubject design. Our study yielded three main results. First, both patients adapted easily to the optical deviation, as shown by the important immediate after-effects found on straight-ahead demonstration. Second, the effects of prism adaptation on neglect symptoms can be maintained over 4 days. Third, a clear double-dissociation between subjects was demonstrated on long-term effects. Initially, both patients exhibited a rightward bias on the two tasks (straight-ahead demonstration and line bisection) in the pre-exposure phase, with one patient showing a more severe neglect (SA). This different level of severity may be in accordance with the time postonset of the two patients (see Table 1). However, this difference was not crucial to our comparisons, because we did not compare the performances of the two present patients but the presence, the duration and the evolutive pattern of the effects of prism adaptation. After the prism adaptation, both patients showed an immediate leftward after-effect on straight-ahead pointing. Its amplitude was about 9 (for a 10 prismatic deviation). This important effect is comparable to the one observed in a group of eight neglect patients, and is about twice the effect obtained with normal subjects in the same condition [34]. In addition, the effect of adaptation on straight-ahead was maintained here for at least 2 h, which again contrasts with the after-effect observed in normal subjects which is cancelled after a few trials performed under visual feed-back [43]. These first results demonstrate that both patients had no problem developing an adaptation to the optical deviation. The second important result is the observation of long lasting improvement of line bisection in SA and of straight-ahead demonstrations in PE. As in our previous study, these long-term effects contrast with the short duration of our adaptation procedure (about 5 min). Once the effect of prisms was maintained for 4 h after the prism adaptation procedure, we did not observe any return to the initial pathological deviations over the 4-day follow-up period. As the benefit seems to be durably gained, one may assume that an important step has been made in the recovery process. This longterm effect implies a central action of prism adaptation, that can be based on active processes triggering plastic neuronal changes rather than a simple orthesis effect [see 34]. Furthermore, in both cases the improvement consisted of a sudden quasi-normalisation of the parameter studied. In SA, the sudden remission of visuo spatial neglect may explain the negative modification of mood. One may hypothesise that prism adaptation restored a symmetrical conscious representation of peripersonal and personal space, increasing the perceptive awareness of her left hemibody hence of her hemiplegia. This supports the idea that prism adaptation can act on cognitive levels in both neglect patient [31,33,34] and healthy subjects [8]. It is important to note that such a reduction of deficit awareness could not be achieved when the patient had been repeatedly invited to look at his left paretic hemibody. The third interesting result obtained here is that during the late phase following prism adaptation (days 2 4) the effects on the two symptoms were double-dissociated between the two patients. No bias in line bisection reappeared in SA, whereas after 4 h the rightward shift of the egocentric reference was comparable with the pretests. Patient PE exhibited the mirror dissociation: the shift of the egocentric reference remained improved during the follow-up period, whereas line bisection performance was not affected by the adaptation procedure. These results confirm that the benefit of prism adaptation on spatial cognition is not mediated by a modification of the egocentric reference. These two symptoms probably depend on distinct mechanisms in different, though neighbouring, brain structures. In reference to this point a recent functional brain imaging study by Vallar and colleagues [40] is of great interest. These authors asked normal subjects to make subjective judgements of their body midline by stopping a vertical bar moving along the horizontal plane. Results showed that the angular gyrus (area 39), especially in the right hemisphere, was the most activated cortical area during the execution of this task. In another study of 110 right-handed stroke patients, Val-

7 L. Pisella et al. / Neuropsychologia 40 (2002) lar and Perani [42] showed that in the subgroup of 29 patients showing severe neglect, the lesions surimpose in the supramarginal gyrus of the inferior parietal lobule. Therefore, the focus area responsible for midline computation and estimation (area 39) may lie just adjacent to the main focus of the composite contour maps drawn for the lesions responsible for neglect, that is the supramarginal gyrus (fronto temporo parieto junction or area 40) [42]. This anatomo functional dissociation is likely to explain the several dissociations recently found between neglect and the rightward bias in straight-ahead demonstration, suggesting that these two phenomena are not causally related [2,6,11]. Our study further demonstrates on the basis of a within-subject design that these biases rely upon two different brain mechanisms. This result is fully compatible with the growing evidence that hemispatial neglect cannot be understood as a unitary disturbance [14,25,29]. Lastly, with respect to the classical use of double-dissociation in neuropsychological studies (see [35]), the present study has provided a new type of double-dissociation. Because the positive and negative behavioural consequences of a given restricted lesion may be partially explained by the reorganisation of surrounding intact brain tissue, the specificity of the effect of a single lesion is often questionable. A more reliable indicator of the separation between two processes is provided by a double-dissociation, where a lesion of structure X will specifically disrupt function A while sparing function B, and a lesion of Y will specifically affect B while A would remain intact [[39], review in [35]]. It is particularly interesting that the two neglect symptoms studied here were not dissociated in the pretest between SA and PE. 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