Regression of left hyperschematia after prism adaptation: A single case study Julie Di Marco, Marine Lunven, Patrice Revol, Laure Christophe, Sophie Jacquin-Courtois, Giuseppe Vallar, Gilles Rode To cite this version: Julie Di Marco, Marine Lunven, Patrice Revol, Laure Christophe, Sophie Jacquin-Courtois, et al.. Regression of left hyperschematia after prism adaptation: A single case study. Cortex, 2019, 119, pp.128 - 140. �10.1016/j.cortex.2019.04.002�. �hal-03484620� HAL Id: hal-03484620 https://hal.science/hal-03484620 Submitted on 20 Dec 2021 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. 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Distributed under a Creative Commons Attribution - NonCommercial 4.0 International License Version of Record: https://www.sciencedirect.com/science/article/pii/S0010945219301571 Manuscript_ac9fd2b7a2c6f34fd3c74bddcad3ed18 Regression of left hyperschematia after prism adaptation: a single case study Di Marco J1, 2, Lunven M3, Revol P1, 2, Christophe L1, 2, Jacquin-Courtois S1, 2, Vallar G. 4, 5, Rode G1, 2. 1 INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon (CRNL), Equipe ImpAct, 16 avenue du doyen Lépine, Bron cedex, F-69676, France. 2 Service de médecine physique et réadaptation, hôpital Henry Gabrielle, Hospices Civils de Lyon, route de Vourles, 69230 Saint Genis Laval, France. 3 Laboratoire de Neuropsychologie Interventionnelle, Département d’études cognitives, ENS, PSL Research University, UPEC, Université Paris-Est, CNRS, Paris France 4 Dipartimento di Psicologia, Università degli studi di Milano-Bicocca, Milano, Italy 5 IRCCS Istituto Auxologico Italiano, Neuropsychological Laboratory, Milano, Italy Correspondence : Gilles Rode, Hôpital Henry Gabrielle 20 route de Vourles F-69230 Saint Genis Laval, France. gilles.rode@chu-lyon.fr. Phone: (0) 478 865 066. © 2019 published by Elsevier. This manuscript is made available under the CC BY NC user license https://creativecommons.org/licenses/by-nc/4.0/ 1 Abstract 2 3 Prism adaptation (PA) is a promising treatment in the rehabilitation of post-stroke cognitive 4 disorders such as unilateral spatial neglect or constructional deficits. Right brain damage can 5 bring about another representational spatial disorder, termed «hyperschematia», and defined 6 by a left-sided disproportionate expansion of drawings by copy and from memory, and by an 7 overestimation of left lateral extent when a leftward movement is required. This case study 8 aimed at evaluating the effect of PA induced by prismatic lenses creating a shift to the left on 9 hyperschematia signs. A 63-year-old woman with left hyperschematia, consecutive to a right 10 fronto-temporo-parietal hematoma, was exposed to a leftward optical deviation produced by 11 prismatic lenses. An anatomical MRI studied topography of the brain lesion; the patient’s 12 lesion was then mapped onto tractography reconstructions of white matter pathways. Results 13 showed that PA significantly reduced the left-sided expansion of drawing by copy and from 14 memory, and the overestimation of left lateral extent, immediately after prism removal and 4 15 days later, indicating a persistent long lasting cognitive effect. MRI showed a right hemisphere 16 disconnection of the posterior and long segments of the arcuate fasciculus, and of the inferior 17 longitudinal and fronto-occipital fasciculi. Overall, these findings suggest that: i) PA is effective 18 also in hyperschematia by re-orientating spatial attention towards the right side of space, 19 with a relative rightward PA-induced unbalance, and re-setting the spatial representation to 20 the left side of space, contralateral to the side of the lesion; ii) the left misrepresentation of 21 lateral extent may be related to a disconnection between visual coordinates and attentional 22 networks to the frontal lobe. 23 24 Key words: hyperschematia, prism adaptation, space representation, bottom-up. 25 2 1 1. Introduction 2 Prism adaptation (PA) is one of the most widely used and studied rehabilitation methods on a 3 large range of spatial neglect manifestations, including visual neglect (Pisella et al., 2006; 4 Rossetti et al., 1998), somatosensory and haptic neglect (Dijkerman et al., 2003), tactile 5 extinction (Maravita et al., 2003), hearing biases (Pochopien & Fahle, 2017), representational 6 neglect, numerical representations (Rode et al., 2001; Rossetti et al., 2004), and everyday 7 activities like writing or wheelchair driving (Jacquin-Courtois et al., 2008). The logic underlying 8 the utilization of PA to improve deficits such as spatial neglect consists in taking advantage of 9 the systematic leftward shift of visuomotor and proprioceptive responses induced during an 10 active exposure to a rightward optical deviation of the visual field. PA reorients behavior of 11 neglect patients toward the neglected side and produces a reduction of their deficits. These 12 effects have also been reported for neglect symptoms involving no visual or manual 13 components, such as representational neglect (Rode et al., 2001) suggesting that the effects 14 of PA extend to higher-level, supramodal representations of space (Jacquin-Courtois et al., 15 2013). 16 The common ground permitting to explain the improvement of neglect symptoms 17 remains debated. One possible candidate is the realignment of the visuo-motor space 18 through adaptation, which would lead to the simultaneous enlargement and shift of the 19 visuo-attentional space (Redding et al., 2005; Redding & Wallace, 2006; Rode et al., 2001; 20 Rossetti et al., 2004). In case of left spatial neglect, which associates a shift and a restriction of 21 the attentional field toward the ipsilesional side, such mechanism of action would stimulate 22 the regression of visuo-perceptive and visuo-motor symptoms (see review in Barrett et al., 23 2012; Rossetti et al., 2015). The reorientation of exogenous and endogenous attentional 24 components toward the pathological side may contribute to reduction of left-sided 25 behavioural bias, and a more symmetrical construction of 2D or 3D allocentric and egocentric 26 space representation. In representational neglect, such as neglect for the left side of an 27 imagined map of France (Rode et al., 2001; Rossetti et al., 2004), PA would increase the 28 capacity to find the topographic location. The re-orientation of the attentional bias towards 29 the left side of imagined space after PA may favour the building up of a more symmetrical 30 representation of space, and the access to topographic information in relation to that part of 3 1 space, as if the positive effects of PA on processes involved in spatial localization (‘where’) 2 facilitate the recall of semantic knowledge (‘what’) (Glize et al., 2017; Rode et al., 2004; 3 2010). 4 PA may also temporarily improve constructional deficits (Rode et al., 2006a), and 5 navigation and representation in virtual reality (Glize et al., 2017) in right brain-damaged 6 patients with left neglect, and postural imbalance in patients with left hemiparesis (Hugues et 7 al., 2015; Tilikete et al., 2001). PA may also reduce pathologic pain in the Complex Regional 8 Pain Syndrome (CRPS) (Bultitude & Rafal, 2010; Christophe et al., 2016; Sumitani et al., 2007). 9 Effects such as those on constructional abilities, independent of neglect, and on the CRPS 10 indicate that the effects of PA may be not confined to deficits of spatial attention and 11 representation contralateral to the side of the cerebral lesion, such as in the case of unilateral 12 spatial neglect (Bultitude et al., 2017; Legrain et al., 2012; Moseley et al., 2013). 13 In this study, we investigated the effects of PA on a representational spatial disorder 14 consecutive to a right brain damage, such as hyperschematia (Rode et al. 2006b, 2008, 2014). 15 Right-brain-damaged patients with left hyperschematia exhibit a left-sided disproportionate 16 expansion of drawings, both by copying and from memory, contralateral to the side of the 17 hemispheric lesion. In a series of 7 right-brain damaged patients with left hyperschematia, 18 this symptom-complex also included an overestimation of left lateral extent, when a leftward 19 movement was required, an unawareness of the disorder, and no unilateral spatial neglect; a 20 perceptual underestimation of the lateral extent of objects located in the left hand-side of 21 space was not a deficit present in all patients. This left-sided space expansion can be 22 interpreted in terms of a lateral leftward distortion of the representation of extra-personal 23 space, with a leftward anisometric expansion (relaxation) of the spatial medium. 24 Hence, the present study aimed at assessing this hypothesis, namely: whether PA can 25 reduce the left-sided disproportionate expansion of drawings, both by copying and from 26 memory, contralateral to the side of the hemispheric lesion, and the disproportionate 27 overestimation of left lateral extent, when a leftward movement is required in a patient with 28 left hyperschematia. We reasoned that, since left unilateral spatial neglect is ameliorated by 29 adaptation to prisms deviating the visual scene rightward, with leftward aftereffect, in the 30 case of a disproportionate leftward relaxation of the spatial medium, such as that taking place 4 1 in left hyperschematia, where patients «expand», rather than «neglect», the left side of 2 space, the appropriate adaptation was the one to prisms deviating the visual scene leftward, 3 with rightward aftereffect. 4 This reverse orientation of prisms is also described for rehabilitation of right neglect in 5 case of left-brain damaged patients. PA could temporarily improve right personal neglect 6 (Facchin et al., 2017). But even if patients adapted to prisms, rightward aftereffect was 7 reduced compared with right-brain-damaged patients (Magnani et al., 2011; Ronchi et al., 8 2018), underlying the role of the left hemisphere in mediating effect of PA. 9 10 In the seven right brain-damaged patients with left hyperschematia reported by Rode 11 and coworkers (2006b, 2008, 2014) evidence for a disproportionate expansion of the 12 representation of the left side of space was provided using the tasks of drawing objects (a 13 daisy) from memory and by copy, judging the lateral extent of two horizontal rectangles 14 (perceptual matching), and reproducing in the leftward and in the rightward direction 15 (namely, starting respectively from the leftward and the rightward endpoints of a line, aligned 16 with the mid-sagittal plane of the participant’s body) the lateral extent of horizontally 17 presented lines (line extension task). All patients with left hyperschematia showed evidence 18 for a disproportionate leftward expansion in the drawing tasks. Conversely, in the perceptual 19 matching task, while four patients exhibited a relative underestimation of the lateral extent of 20 the leftward rectangle (with scores being significantly different than the average of controls in 21 three patients) this was not the case for three patients, with one such patient exhibiting if 22 anything a significant underestimation of the rightward rectangle, as compared with control 23 participants. Overall, these findings suggest that the perceptual underestimation of the 24 leftward extension of objects is not likely to be a crucial mechanism underlying the 25 hyperschematic deficit in drawing (Rode et al., 2014). Finally, in the line extension task, group 26 analyses show in patients significant leftward, but not rightward, hyperextension, in 27 comparison with control participants. Based on this evidence, the effects of PA on drawing, 28 perceptual matching and line extension tasks were assessed in patient FV. 29 5 1 2. Case report 2 3 A 63-year-old right-handed woman (FV), with a middle school level (BTEC First Diploma), with 4 a history of arterial hypertension and essential thrombocythemia, was admitted to a 5 neurological unit for the sudden onset of left hemiparesis, left homonymous hemianopia, and 6 left spatial neglect, consecutive to a right fronto-temporo-parietal haematoma. One month 7 after stroke onset, the patient showed no left-sided motor or somatosensory deficits, 8 including tactile and proprioceptive sensation, and no tactile extinction to double 9 simultaneous stimulation (see Bisiach & Faglioni, 1974). There were neither motor nor 10 ideational apraxia, nor underutilization of the left-sided limbs. There were no dexterity 11 disorders. However a left lower quadrantanopia remained, with the patient being aware of 12 her visual deficit. Visual acuity was normal (10/10). The patient was alert and cooperative, 13 and showed an auditory extinction at a clinical exam, but no left spatial neglect. In a line 14 cancellation test the patient crossed out 40/40 lines (Albert, 1973). In a star cancellation test 15 the patient crossed out 55/56 targets, with one omission in the left side of the display (Wilson 16 et al., 1987). In a letter cancellation task (Diller et al., 1974), the patient crossed out 51/53 17 targets in the left-hand side, and 48/51 targets in the right-hand side of the sheet. In a line 18 bisection task (Schenkenberg et al., 1980) the patient scored +0.4%, within the normal range 19 (mean -0.7%, S.D. ±2.46, range -4.3 - +2.9), see Rode et al., 2006b. The patient was able to 20 read correctly short and long words, numbers, sentences, and passages of text, presented on 21 an A4 sheet, with the center of the stimulus being aligned with the midsagittal plane of the 22 patient’s trunk. The patient did not show constructional apraxia in drawing figures such as a 23 cube, a house, and a pyramid, both by copy, and from memory (table 1). However, in drawing 24 by copy, and from memory, the patient showed no evidence of spatial neglect but produced 25 symmetrical objects (a fir tree, a Christmas fir tree, a butterfly, a daisy) disproportionately 26 larger on the left-hand side (Figure 1), and was unaware of this deficit, as the 7 right-brain- 27 damaged patients reported by Rode et al. (2014). 28 The experimental procedure was applied 1 month post-onset of their stroke. Consent of 29 patient was obtained. 30 Control (C) data were provided by six right-handed neurologically unimpaired participants 31 [three females; mean age: 54.8 years (range 34–78); mean years of schooling: 12 (range 9– 32 18)] from previous studies (Rode et al., 2006b, 2008). 6 1 2 Insert here Table 1 3 Insert here Figure 1 4 5 3. Experimental study 6 7 3.1 Tests 8 9 The effectiveness of PA on hyperschematia was tested with four different tasks. 10 11 3.1.1 Drawing from memory 12 13 FV was required to draw from memory a daisy, on a 21 x 29.7 cm sheet of paper, placed in 14 front of her, with the centre of the sheet being aligned with the midsagittal plane of her body. 15 No model was provided, and no further specific instructions were given. The drawing was 16 repeated in three sessions: prior to prism exposure (pre-test), on prism removal (post-test) 17 and 4 days later (late-test). Six trials were given. FV showed no difficulties in executing the 18 task, and drew the pistil and the right-sided petals first. In order to measure the area and the 19 number of petals of the left-hand and of the right-hand sides, each drawn daisy was divided 20 into two sides by a vertical line passing through the centre of its pistil. Petals divided into 21 approximately equal parts by the vertical line were not considered in counting the number of 22 drawn petals. The areas of the two sides of each drawing were computed by a Leica imaging 23 system and Quantimet 500 software. For the left- and right-sided areas of each drawing, a 24 laterality index score (LI) was computed: (left-sided area minus right-sided area/left-sided 25 area plus right-sided area) × 100. A positive value of this LI indicated a greater left-sided area, 26 a negative LI a greater right-sided area. A similar laterality index score was computed for the 27 number of petals (PLI). 28 29 3.1.2 Drawing by copy 30 31 FV was asked to draw a daisy by copy. The drawing was repeated in three sessions: prior to 32 prism exposure (pre-test), on prism removal (post-test) and 4 days later (late-test). This test 7 1 differed from the previous one in that a symmetric daisy model was provided. The model was 2 printed in the centre of a 21 x 29.7 cm sheet. Six trials were given. The data were analyzed as 3 in the drawing from memory study, computing the LI and PLI scores. 4 Both tasks were performed at four time-points: two pre-tests at day -4 and day prior to 5 prism exposure, and two post-tests after intervention upon prism removal (0 h post-test), and 6 at 4 days thereafter (late-test). 8 ACCEPTED MANUSCRIPT 1 3.1.3 Perceptual matching task 2 3 This task assessed the patient’s ability to judge the lateral extent of two rectangles. The task 4 was repeated in two sessions: prior to prism exposure (pre-test) and after prism removal 5 (post-test). The stimuli were pairs of black rectangles 15 mm high. Twenty-five pairs of 6 rectangles were presented in a pseudorandom series, in order to measure the point of 7 subjective equality between patterns placed in the left and in the right visual half-spaces. The 8 distance between the right-hand side of the left-sided rectangle, and the left-hand side of the 9 right-sided rectangle was 8 cm. The centre of this distance was aligned with the midsagittal 10 plane of the patient’s body. In each pair, the length of one rectangle was fixed (8 cm), the 11 length of the other varied from 6.4 cm to 9.6 cm, in four 8 mm steps. In five trials the two 12 rectangles were equal in length (8 cm). In ten trials the right-sided rectangle was longer than 13 the left-sided segment, in ten trials vice-versa. The subject’s task on each trial was to report 14 verbally which was the longer out of the two rectangles. The scoring procedure of (Milner et 15 al., 1993) was used. Each error on a given trial was scored a value of n ± 1, where n was the 16 number of steps by which the patterns’ lengths differed on that trial. Rightward errors (i.e., 17 the right-sided rectangle judged as longer, when the left-sided rectangle was longer), were 18 given a positive score. Leftward errors (i.e., the left-sided rectangle judged as longer, when 19 the right-sided rectangle was longer) were given a negative score. Using this scoring method, 20 an identical pair of stimuli (n = 0) yielded a score of either +1 (rightward error), or –1 21 (leftward error). The larger was the difference in length between the two rectangles, the 22 greater the error score. The task was performed at two time-points pre-test at day prior to 23 prism exposure, and post-test after intervention upon prism removal. 24 25 3.1.4 Line extension task 26 27 The patient’ task was to reproduce the length of a horizontal black line in two conditions. In 28 the leftward movement condition, the line was placed in the right-hand side of the sheet, 29 with its left end being aligned with the midsagittal plane of the body of the participant, who 30 received instructions to reproduce the perceived length of the segment with a leftward 31 extension. In the rightward movement condition, the line was placed in the left-hand side of 32 the sheet, with its right end being aligned with the midsagittal plane of the body of the 9 1 participant, who received instructions to reproduce the perceived length of the segment with 2 a rightward extension. The stimuli were horizontal black lines, 1 mm in width, with three line 3 lengths (4, 6, and 8 cm). Each black line was printed on an A4 sheet. In each movement 4 condition, 24 lines were presented, eight per each length, in a random fixed order, for a total 5 of 48 lines. The length of the segment drawn by each subject on each trial was measured to 6 the nearest mm. For the extension of each line drawing, a Laterality Index score (LI) was 7 computed: (i) leftward extension (leftward extended length minus length of the right-sided 8 line/leftward extended length plus length of the right-sided line × 100); (ii) rightward 9 extension (rightward extended length minus length of the left-sided line/rightward extended 10 length plus length of the left-sided line × 100). A positive value of the LI indicated 11 overextension, a negative value underextension. The mean LIs were calculated for the two 12 conditions. The task was performed at two time-points pre-test at day prior to prism 13 exposure, and post-test after intervention upon prism removal. 14 15 3.2 Prism adaptation procedure 16 17 FV was exposed to a leftward optical deviation produced by prismatic lenses. Glacier goggles 18 (Julbo®, Lyon, France) were fitted with wide-field, point-to-point wedge lenses creating an 19 optical shift of 10° (www.optiquePeter.com, Lyon, France), affording wide binocular vision. 20 The exposure period consisted in 50 pointing responses to visual targets presented 10° to the 21 right or to the left of the objective body midline. During the prism exposure, FV was asked to 22 point at a fast but comfortable speed; the participant could see the target, the second half of 23 her pointing trajectory and her terminal error. The patient’s head was kept aligned with the 24 body’s sagittal axis by a chin-rest and controlled by the investigator (GR). During prism 25 exposure, the terminal errors of each movement were captured by means of the thimble and 26 converted into degrees of angular error with regard to the target. The total duration of this 27 exposure was about 3 min. 28 29 3.3 Open loop pointing task 30 31 The after-effects of PA were evaluated by means of open loop pointing (OLP) in the direction 32 of a visual target (n = 10), prior to prism exposure (pre-test), and on prism removal (post- 10 1 test). OLP accuracy measurement was carried out by asking FV to point with her right hand in 2 darkness to a target. A luminous visual target was aligned with FV’s sagittal axis. The 3 instruction given to FV was to place her right hand at the target drip-line, as precisely as 4 possible but without time constraint, the goal being to distance herself from the pointing 5 conditions employed during exposure, with the aim of obtaining measurements of sensory- 6 motor aftereffects. Pointing was measured using a contractor attached to a thimble threaded 7 into the index finger, atop a table covered with isoresistant carbon paper on which two 8 electrodes were applied, thereby delimiting a section at an angle of 50° and a depth of 70 cm 9 centered at the starting position near the torso. A direct 5 V current was generated between 10 the electrodes. When the finger touched the surface of the table, tension between the 11 thimble contact point and the reference electrode was measured as in a potentiometer. 12 Tension measurement enabled us to calculate the angular position in relation to the objective 13 sagittal axis, and this position could then be converted into degrees and conventionally signed 14 (negative on the left, positive on the right). Measurement precision was estimated at 0.5 15 degrees (see details in Rode et al., 2015). 16 Insert here Figure 2 17 18 3.4 19 Statistical analyses 20 In the drawings tasks (by memory or by copy) the patient’s LI, and PLI scores were compared 21 through different sessions using a one-way repeated measure ANOVA with scores as depend 22 variables and sessions as independent one. Planned comparisons were performed to assess 23 patient’s performances across sessions. Then patient’s scores were compared against the 24 mean score of control data set (Rode et al., 2006b) by t-tests (Crawford & Garthwaite, 2002; 25 Crawford & Howell, 1998) for each session, with scores of controls being considered as the 26 standard. Student t-test was used to compare the patient’s performance in pre-test and post- 27 test for the line extension task, as well as for Open Loop Pointing and Perceptual matching. 28 4 Neuroimaging 29 30 4.1 Imaging data acquisition 31 11 1 Six months post-onset, topography of the brain lesion was studied by an anatomical MRI and 2 diffusion weighted imaging (DWI), in order to objectify the different white matter tracts 3 impaired. 4 A sequence of Diffusion Weighted Imaging (DWI) with 32 diffusion with a b-value of 800 sec 5 mm−2 and one volume with no diffusion gradient were acquired on a 3T Ingenia Philips 6 medical system equipped with a 16-channel head coil (Philips Medical Systems, Erlangen, The 7 Netherlands). The acquisition sequence was fully optimized for tractography, providing 8 isotropic resolution (2 × 2 × 2 mm) and coverage of the whole brain. A three-dimensional axial 9 Gadolinium-enhanced T1 weighted covering the whole head was also acquired (160 slices, 10 voxel resolution = 0.5 × 0.5 × 1 mm, TE = 5.1, TR = 9.7). 11 12 4.2 Atlas-based analysis of disconnection 13 14 Lesion mask of the patient was first drawn on the native 3D T1 images by using the MRIcroN 15 software (Rorden et al., 2007). Registrations of the patient’s T1 MRI were performed using 16 BCBtoolkit 17 enantiomorphic approach (Nachev et al., 2008). During spatial normalization, the mask of the 18 lesion was replaced symmetrically by the healthy tissue of the contralateral hemisphere. T1 19 images were registered to the template (MNI152) using affine and diffeomorphic 20 deformations (Avants et al., 2011; Klein et al., 2009). Finally, patient’s lesion was manually 21 drawn a second time on the normalized images. (http://www.toolkit.bcblab.com, (Foulon et al., 2018). We used the 22 23 The patient’s lesion was mapped onto tractography reconstructions of white matter pathways 24 obtained from a group of healthy controls (Rojkova et al., 2016). Severity of the disconnection 25 was obtained by measuring the probability of the tract to be disconnected (Thiebaut de 26 Schotten et al., 2014), using Tractotron software as part of the BCBtoolkit (Foulon et al., 27 2018). In tracts with a minimum probability of 50% to be disconnected, we quantified the 28 severity of the disconnection by measuring the proportion of the tract to be disconnected 29 (Dalla Barba et al., 2018). 30 12 1 4.3 Disconnectome map approach 2 3 A second approach was chosen to identify brain areas deafferented by the lesion using a 4 disconnectome map approach using BCBtoolkit. This approach uses a set of 10 healthy 5 controls (Rojkova et al., 2016) diffusion weighted imaging datasets to track fibers passing 6 through the lesion of the patient. We registered the patient’s lesion in the MNI152 space to 7 each healthy control native space in order to use it as a seed for the tractography. We created 8 percentage overlap maps by adding the normalized visitation maps from each subject at each 9 point in the MNI space. Results were projected in a 3D rendering, using MRIcroN. 10 11 4.4 Tractography 12 13 We reconstructed fasciculi identified in our previous analysis (atlas-based analysis) in order to 14 confirm disconnections in the patient. In the first step, we corrected simultaneously diffusion 15 datasets 16 (http://www.exploredti.com, (Leemans & Jones, 2009). The tensor model was fitted to the 17 data using the Levenberg-Marquardt non-linear regression (Marquardt, 1963). Whole-brain 18 tractography was performed using Euler integration, that propagates from voxel to voxel 19 following a step size of 1 mm, and an angle threshold less than 45° (Dell’Acqua et al., 2013). 20 We excluded from the tractography voxel showing an FA value inferior to 0.2 (Jones, 2004). 21 This preprocessing was performed using Startrack (http://www.natbrainlab.co.uk). The whole 22 brain tractography was imported to “TrackVis” software (http://www.trackvis.org, (Wedeen 23 et al., 2008). ROIs were manually drawn on cerebral regions considered as an obligatory 24 trajectory for tracts of interest (Catani & Thiebaut de Schotten, 2008). for motion and geometrical distortions using ExploreDTI 25 13 1 5 Results 2 3 5.1 Open Loop pointing task 4 5 In pre-test, the mean OLP value was +0.98° (SD: 1.38). In post-test, the mean OLP value was 6 +9.86° (SD: 2.71), reflecting a significant sensori-motor after-effect directed toward the right 7 side induced by PA [t(1;18) = 9.6, p< 0.001]. 8 Insert here Table 2 9 10 11 5.2 Drawing from memory 12 13 One-Way ANOVA performed on patient’s LI, and PLI scores were significant (F(3,21)=6.58, 14 p<0.01 and F(3,21)=4.42, p<0.05 respectively) revealing that patient behaved differently 15 across session. In two pre-tests, the mean LIs were +11.74 (S.D. ±9.27) in Pre-test 1, and +6.4 16 (S.D. ±6.35) in Pre-test 2; (planned comparison F(1,21)=1.14, p=0.30), meaning larger left- 17 sided drawn areas; the mean PLIs were respectively +9.77 (S.D. ±7.64) in Pre-test 1, and +0.87 18 (S.D. ±7.98) in Pre-test 2; (planned comparison F(1,21)=1.24, p=0.28). A t-test comparing the 19 scores of the patient with the control data (-4.87; S.D. ±1.34 for the LI, and -2.39; S.D. ±4.04 20 for the PLI), showed a significant difference for both the LI (t = 11.76, p <0.001, for Pre-test 1; 21 t=7.83, p<0.001, for Pre-test 2), and the PLI in the first Pre test only (t = 2.79, p<0.05, for Pre- 22 test 1; t=0.75, p=0.24, for Pre-test 2). In post-test, the mean LI was significantly reduced (- 23 8.94, S.D. ±13.42, planned comparison with Pre-test 1 F(1,21)=17.13, p<0.001, and Pre-test 2 24 F(1,21)=8.74, p<0.001), showing a regression of left hyperschematia after prism adaptation, 25 with a significant lowest number of left petals (PLI= -12.28, S.D. ±14.49, planned comparison 26 with Pre-test 1 F(1,21)=12.93, p<0.001, and Pre-test 2 F(1,21)=5.33, p<0.05). In late test, the 27 mean LI and PLI were respectively -1.90 (S.D. ±4.22) and -4.61 (S.D. ±8.04) and significantly 28 reduced compared with the Pre-test 1 only (planned comparison F(1,21)=7.56, p<0.05 for LI 29 and F(1,21)=4.46, p<0.05 for PLI). Comparison of control data, and patient’s performance 30 immediately after prism adaptation (post-test), revealed a significant difference for LI (t= 31 2.28, p<0.05), and PLI (t= 2.27, p<0.05). As figure 3A shows, this statistical difference was due 32 to a greater right-sided area and a greater number of petals in the right side of the drawings, 14 ACCEPTED MANUSCRIPT 1 meaning a reduction of left hyperschematia after PA. Comparison of mean scores, before 2 (pre-test) and 4 days later (late-test) failed to revealed any significant difference for LI (t= 3 2.00, p=0.06) and PLI (t= 0.51, p=0.31), showing that the patient behaved as control 4 participants, as well as a persistent reduction of the left hyperschematia up to 96 h after PA 5 (Figure 3A). 6 5.3 Drawing by copy 7 8 One-Way ANOVA performed on patient’s LI and PLI scores were significant (F(3,21)=3.42, 9 p<0.05, and F(3,21)=4.03, p<0.05 respectively) showing that patient behaved differently 10 across session. In two pre-tests, the mean LIs were +15.29 (S.D. ±6.78) in Pre-test 1, and 11 +11.94 (S.D. ±14.12) in Pre-test 2; (planned comparison F(1,21)=0.28, p=0.60), meaning larger 12 left-sided drawn areas, as for the drawing from memory. In pre-tests, mean PLIs were +12.52 13 (S.D. ±9.29) in Pre-test 1, and +7.2 (S.D. ±14.56) in Pre-test 2 (planned comparison 14 F(1,21)=0.87, p=0.39). A t-test comparing the scores of the patient with the control data (- 15 3.94, S.D. ±3.18 for the LI; -4.43, S.D. ±8.17 for the PLI), showed significant differences for 16 both the LI (t= 5.59, p <0.01, for Pre-test 1; t= 4.62, p<0.01, for Pre-test 2), and the PLI only in 17 the first Pre-test (t= 1.93, p <0.05, for Pre-test 1; t= 1.32, p=0.12 for Pre-test 2). In post-test, 18 the mean LI was significantly reduced +0.99 (S.D. ±10.83) compared with Pre-test 1 only 19 (planned comparison F(1,24)=6.09, p<0.05), and did not differ from controls (t= 1.48, p=0.11), 20 showing a regression of left hyperschematia after prism adaptation with a significantly lowest 21 number of left petals (PLI= -6.70 SD. ± 12.16; planned comparison with Pre-test 1 22 F(1,24)=10.42, p<0.001 and Pre-test 2 F(1,24)=5.14, p<0.05)compared with controls (t = 0.26, 23 p=0.40), as for the drawing from memory. In late test, the mean LI was +3.80 (S.D. ±9.85), and 24 was not different from Pre-test sessions (planned comparison with Pre-test 1 F(1,24)=3.21, 25 p=0.09, and Pre-test 2 F(1,24)=1.53, p=0.23). The mean PLI was -0.34 (S.D. ±8.95) and was 26 significantly different only for Pre-test 1 (planned comparison with Pre-test 1 F(1,24)=5.08, 27 p<0.05 and Pre-test 2 F(1,24)=1.66, p=0.21, see Figure 3B). 28 29 Insert here Figure 3 30 31 Comparison of control data, and patient’s performance revealed a significant difference for LI 15 ACCEPTED MANUSCRIPT 1 (t= 2.26, p<0.05), but not for PLI (t= 0.46, p=0.33). So, four days after prismatic adaptation the 2 patient copied a daisy with a significantly larger right-sided area, compared with controls, but 3 with similar numbers of petals on the right side, suggesting some evidence of a persistent 4 reduction of the left hyperschematia after PA, as for the drawing from memory test. The 5 persistent after-effect of PA on left hyperschematia can be illustrated by the drawings of 6 butterfly from memory before and after PA (see Figure 4). 7 Insert here Figure 4 8 9 5.4 Perceptual matching task 10 11 In pre-test, the score was +0.80 (S.D. ±1.24), and similar to the mean score of the control 12 group (+0.91, S.D. ±0.11). In post-test, the score was (+0.85, S.D. ±1.29). Comparison by t-test 13 of scores before and after prism removal showed no significant difference (t= 0.13, p=0.85). 14 5.5 Line extension task 15 16 In pre-test, the mean leftward extension LIs were respectively +8.57 (S.D. ±3.21) for 4 cm, 17 +4.02 (S.D. ±3.25) for 6 cm and +3.94 (S.D. ±4.93) for 8 cm lines. The mean rightward 18 extension LIs were respectively +2.73 (S.D. ±5.08) for 4 cm, -1.27 (S.D. ±2.77) for 6 cm and - 19 0.66 (S.D. ±8.95) for 8 cm lines. The patient showed a leftward overextension for the three 20 lines. The performance of FV was similar to those of previously reported patients (Rode et al., 21 2006, 2008, 2014). Comparison of LIs before and after prism removal showed a significant 22 increase of the mean rightward extension LIs for the three lines lengths: +10.12 (S.D. ±4.83) 23 for 4 cm (t=2.98, p<0.05), +6.75 (S.D. ±4.48) for 6 cm (t=4.09, p<0.01), and +7.13 (S.D. ±4.40) 24 for 8 cm lines (t=2.21, p<0.05). There was no significant difference of the mean leftward 25 extension LIs for two lines lengths: LI= +9.73 (S.D. ±6.17) for 4 cm (t=0.47, p=0.65), and LI= 26 +6.01 (S.D. ±3.90) for 6 cm (t=1.07, p=0.31), and a significant difference for the 8 cm lines - 27 5.85 (S.D. ±3.43; t=4.61, p<0.001). Results showed that PA brought about a rightward 28 overextension for the three lines, associated to a reduction of the leftward overextension for 29 the longest line (8 cm), with no such effect on the 4 and 6 cm lines (see Figure 5). 30 31 Insert here Figure 5 16 ACCEPTED MANUSCRIPT 1 2 5 Anatomical correlates 3 4 3D T1 images showed that the lesion involved mostly the right temporo-parietal white 5 matter, the occipital (Brodmann areas BA 17, 18, 19, 41, 42), and temporal (BA 20, 21, 22, 37) 6 cortices, and both the angular and supramarginal gyri (BA 39, 40) of the inferior parietal 7 lobule (Figure 6A). 8 The atlas-based analysis of disconnection revealed that the lesion damaged 25% of the optic 9 radiations, 17% of the post and 16% of the long segments of the arcuate fasciculus, 11% of 10 the inferior longitudinal fasciculus and 10% the inferior fronto-occipital fasciculus. The lesion 11 damaged less than 5% of all other tracts. 12 The disconnectome map approach showed the high probability of deafferentation of the 13 inferior parietal lobule and of the temporal lobe (Figure 6B). 14 We conducted a tractography analysis to confirm the disconnection of previously identified 15 fasciculi using the atlas-based approach. Results demonstrated in our patient a disconnection 16 of the posterior and long segments of the arcuate fasciculus, of the inferior longitudinal and 17 fronto-occipital fasciculi and of optic radiations, in the right hemisphere. Posterior inter- 18 hemispheric connections were comparatively preserved (Figure 6C). 19 Insert here Figure 6 20 21 22 6 Discussion 23 24 The aim of the present study was to assess whether PA can reduce the left-sided 25 disproportionate expansion of drawings, both by copying and from memory, contralateral to 26 the side of the hemispheric lesion, and the overestimation of left lateral extent, when a 27 leftward movement is required in a patient with left hyperschematia, and without left 28 unilateral visual neglect. 29 30 6.1 Hyperschematia 31 32 Before prism exposure, FV exhibited a left spatial hyperschematia characterized by a 17 ACCEPTED MANUSCRIPT 1 disproportionate leftward expansion of drawings (with the addition of leftward details), both 2 by copy and from memory, overestimation of lateral extent, when a leftward movement was 3 required, but without perceptual underestimation of left-sided extent. As for the previous 4 seven cases reported patients by Rode et al., (2006b, 2014), the disorder was not associated 5 to a left visual neglect, but FV still suffered from a left auditory extinction, a deficit that may 6 occur independent of visuo-spatial neglect (Brozzoli et al., 2006; de Renzi et al., 1984). Lastly, 7 as for the previous cases (Rode et al., 2006b, 2008, 2014) , FV was not aware of her behaviour 8 in the drawing and line extension tasks. Since hyperschematia, and unawareness of it were 9 associated to a right hemispheric lesion, such an unawareness may be considered under the 10 rubric of anosognosia (see Mograbi & Morris, 2018) for components of the neglect, 11 specifically for the productive manifestation of “hyperschematia” (Vallar & Bolognini, 2014). 12 After the period of prismatic adaption to a leftward shift of the visual environment (10°), 13 towards which FV exhibited a disproportionate expansion of spatial representation and 14 attention in a number of visuo-motor tasks, the patient showed a significant after-effect 15 directed to the opposite side (right), as measured by the OLP task (mean amount: 8,88°). This 16 after-effect was associated to a dramatic reduction of the left-sided disproportionate 17 expansion of drawings, and added leftward details both in drawing from memory and by copy 18 tasks. These modifications remained unchanged four days later, meaning a persistent 19 cognitive effect on the spatial disorder affecting size representation of objects in extra- 20 personal space, along the horizontal dimension. One can speculate that the realignment of 21 the visuo-motor space through PA therefore leads to the building up of more symmetrical 22 representation of object space. In line with recent findings (Lunven et al., 2018), effects of PA 23 on space representation may be supported by intact inter-hemispheric connections. 24 Patient FV did not show a disproportionate perceptual underestimation of leftward extension. 25 This finding is in line with evidence from previously reported patients with leftward 26 hyperschematia, who may or may not show such biases, that, accordingly, do not represent a 27 core mechanism of the disorder (Rode et al., 2014). FV’s preserved performance in the task of 28 estimation of perceptual extent was not modulated by PA. This result may be considered with 29 reference to the evidence from studies in neurologically unimpaired participants, showing 30 directional effects of PA in a task broadly similar to the present one, namely the Landmark 18 1 task. Such effects mimic unilateral spatial neglect (Nijboer et al., 2010; Striemer & Danckert, 2 2010). Here, we do not find a modulation of a preserved performance, in a task assessing 3 perceptual biases largely unrelated to hyperschematia (Rode et al., 2014), by PA in a brain- 4 damaged patient. Seen in this perspective, these negative findings corroborate the conclusion 5 that the mere perceptual underestimation of leftward extent in the visual modality is not a 6 mechanisms of hyperschematia, where the disordered representation of the left hand-side of 7 space may also involve action components for leftward movements, and is not confined to 8 the visual modality [see Patient #1 of Rode et al. (2006b), who showed a leftward expansion 9 in drawing a daisy also in blindfolded conditions]. Future research using the present 10 perceptual matching task may further investigate the effects of PA in neurologically 11 unimpaired participants, although this is outside the aims of the present study. 12 Finally, in the line extension task, the significant effects of PA on FV’s leftward overextension 13 were confined to the longest, 8 cm, segment, while the average scores for the 6 and 4 cm 14 segments were, if anything, increased, although not significantly, further indicating that the 15 leftward overextension for these segments was not affected by PA. These findings may be 16 tentatively considered in the context of a result, showing that, at least in the line extension 17 task, FV’s performance is not made symmetrical by PA, but a rightward hyperextension is 18 produced. The tentative possibility may be then entertained that, in the case of the shortest 19 segments, where an extension in a part of space closer to the midline, and then to the right 20 hand side of space, is required, the spatial representation of extent is not normalized, with a 21 residual leftward (for 6 and 4 cm segments), and a rightward hyperextension involving all 22 segments, brought about by PA. 23 The hypothesis of a realignment of the visuo-motor space induced by PA has been proposed 24 in order to explain the reversibility after PA of the manifestations of the syndrome of 25 unilateral neglect, affecting the extrapersonal and imaginal spaces. In the case of left spatial 26 neglect (Vallar & Bolognini, 2014; Vallar & Calzolari, 2018), this realignment may involve the 27 simultaneous enlargement and reorientation of attentional components toward the 28 neglected side, contributing to the reduction of the right-sided behavioural bias, and resulting 29 in the construction of more symmetrical 2D and 3D allocentric and egocentric space 30 representations (see Figure 1D). In the case of left hyperschematia (Rode et al., 2006b, 2014; 19 1 Vallar & Rode, 2009), as shown by the present study, the realignment of visuomotor space 2 may conversely involve a reduction of the disproportionately leftward expanded visuo- 3 attentional space, with a more symmetrical orientation of voluntary attention toward either 4 side of space (Nijboer et al., 2008), contributing to a reduction of the left-sided 5 disproportionate expansion of drawings, and of the relevant spatial medium, ultimately 6 resulting in a more symmetrical construction of 2D or 3D allocentric and egocentric space 7 representations. 8 6.2 Imaging 9 10 In FV, the lesion involved mostly the right temporo-parietal white matter, the occipital 11 (Brodmann areas BA 17, 18, 19, 41, 42), and the temporal cortices (BA 20, 21, 22, 37), and the 12 inferior parietal lobule [angular and supramarginal gyri (BA 39, 40)], as for the previous seven 13 cases reported patients by (Rode et al., 2006b, 2014): accordingly, these cerebral regions 14 could support the processes involved in the representation of lateral extent. The patient 15 exhibited a disconnection between right attentional fronto-parietal networks, and the ventral 16 visual stream and a relative preservation of posterior callosal connections. The ILF and the 17 IFOF play an important role in spatial processing, executive function and attention (Urbanski 18 et al., 2008). Left misrepresentation of lateral extent may be related to a disconnection 19 between visual coordinates and attentional networks to the frontal lobe, brought about by 20 damage to these two fasciculi. By its role in “multimodal integration”, the IFOF plays an 21 important role for the perception of visuo-spatial information, and in the planning of visually- 22 guided movement (Aralasmak et al., 2006). Extending a line also requires participants to 23 orient attention to the leftward movement of the pencil and to continuously monitor their 24 spatially oriented movement (Perri et al., 2000). The temporo-parietal junction, which is 25 damaged in patient FV, is involved in shifting or maintaining spatial attention and 26 representation, in association with activity in the dorsolateral prefrontal cortex (Corbetta & 27 Shulman, 2002; Fan et al., 2005). In patient FV, the disconnection between right attentional 28 fronto-parietal networks may bring about an alteration in an internally driven intentional 29 system in the contralateral left side of space, resulting in the left-sided disproportionate 30 expansion of drawings and the hyperextension of lines, when a leftward movement is 31 required without any interruption by an external stimulus (Kim et al., 2016). 20 1 The pattern of white matter damage of patient FV is also compatible with an interpretation of 2 the disorder of size perception of left space in terms of a compensation mechanism of the left 3 visual neglect presented in the acute phase by the patient, based on the integrity of posterior 4 callosal connections and of the second and of the first branch of the SLF (Lunven et al., 2015; 5 Thiebaut de Schotten et al., 2014). In order to compensate for the alteration of space 6 representation and attention, disproportionately biased rightwards, an excessive leftward 7 extension with a comparatively reduced rightward extension of the spatial medium may take 8 place. This hypothesis could challenge the previously proposed explanation of 9 hyperschematia: a disordered representation of extrapersonal space, possibly involving a 10 contralesional relaxation of the spatial medium; a deficit which does not arise at the level of 11 retinotopic coordinate frames and considered as a distinct spatial disorder, which could 12 nevertheless co-occur with neglect following right brain damage (Rode et al., 2006b). It may 13 be relevant to note here that all reported patients with left hyperschematia had shown left 14 visuo-spatial neglect in the acute and subacute post-stroke phase (Rode et al., 2014). Be as it 15 may, the present single case study shows that PA with rightward aftereffects reduces the 16 leftward hyperschematic behavior. 17 18 6.3 Conclusion 19 20 PA appears then to be effective in disorders of spatial representation and attention, 21 featuring a contralateral deficit, such as unilateral spatial neglect: under these conditions, the 22 appropriate direction of the after-effects is towards the neglected side of space, since the 23 spatial representation of the neglected side is to be enhanced, and attention oriented 24 towards it. A similar directional approach holds for the CRPS (Christophe et al., 2016; Sumitani 25 et al., 2007). 26 With the limitations intrinsic to a single case observation, performed in early post- 27 stroke stage, that needs replication (Vallar, 1999), the present study shows that PA is also 28 effective in disorders of spatial representation and attention brought about by unilateral right 29 brain-damage, such as hyperschematia, featuring instead a disproportionately expanded 30 representation of the side of space contralateral to the side of the lesion: under these 31 conditions, the appropriate direction of the aftereffects is in a direction opposite to the 32 disproportionately expanded side of space, since such a “hyper-representation” needs to be 21 1 diminished. In both conditions, PA would operate re-setting more symmetrically the 2 orientation of spatial attention, and the spatial representation of both sides of space. 3 4 Declarations of interest: none 5 Funding. G.V. was supported in part by Ricerca Corrente Grants from the IRCCS istituto 6 Auxologico Italiano. 7 22 ACCEPTED MANUSCRIPT 1 References 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Albert, M. L. (1973). A simple test of visual neglect. Neurology, 23(6), 658–664. Aralasmak, A., Ulmer, J. L., Kocak, M., Salvan, C. V., Hillis, A. E., & Yousem, D. M. (2006). Association, commissural, and projection pathways and their functional deficit reported in literature. Journal of Computer Assisted Tomography, 30(5), 695–715. https://doi.org/10.1097/01.rct.0000226397.43235.8b Avants, B. B., Tustison, N. J., Song, G., Cook, P. A., Klein, A., & Gee, J. C. (2011). A reproducible evaluation of ANTs similarity metric performance in brain image registration. NeuroImage, 54(3), 2033–2044. https://doi.org/10.1016/j.neuroimage.2010.09.025 Barrett, A. M., Goedert, K. M., & Basso, J. C. (2012). Prism adaptation for spatial neglect after stroke: translational practice gaps. Nature Reviews. Neurology, 8(10), 567–577. https://doi.org/10.1038/nrneurol.2012.170 Bisiach, E., & Faglioni, P. (1974). Recognition of random shapes by patients with unilateral lesions as a function of complexity, association value and delay. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior, 10(2), 101–110. Brozzoli, C., Demattè, M. L., Pavani, F., Frassinetti, F., & Farnè, A. (2006). Neglect and extinction: within and between sensory modalities. Restorative Neurology and Neuroscience, 24(4-6), 217–232. Bultitude, J. H., & Rafal, R. D. (2010). Derangement of body representation in complex regional pain syndrome: report of a case treated with mirror and prisms. Experimental Brain Research, 204(3), 409–418. https://doi.org/10.1007/s00221-009-2107-8 Bultitude, J. H., Walker, I., & Spence, C. (2017). Space-based bias of covert visual attention in complex regional pain syndrome. Brain: A Journal of Neurology, 140(9), 2306–2321. https://doi.org/10.1093/brain/awx152 Catani, M., & Thiebaut de Schotten, M. (2008). A diffusion tensor imaging tractography atlas for virtual in vivo dissection. Cortex, 44, 1105–1132. Christophe, L., Chabanat, E., Delporte, L., Revol, P., Volckmann, P., Jacquin-Courtois, S., & Rossetti, Y. (2016). Prisms to shift pain away: pathophysiological and therapeutic exploration of CRPS with prism adaptation. Neural Plasticity, 2016, 1–21. https://doi.org/10.1155/2016/1694256 Corbetta, M., & Shulman, G. L. (2002). Control of goal-directed and stimulus-driven attention in the brain. Nature Reviews. Neuroscience, 3(3), 201–215. https://doi.org/10.1038/nrn755 Crawford, J. R., & Garthwaite, P. H. (2002). Investigation of the single case in neuropsychology: confidence limits on the abnormality of test scores and test score differences. Neuropsychologia, 40(8), 1196–1208. Crawford, J. R., & Howell, D. C. (1998). Comparing an Individual’s Test Score Against Norms Derived from Small Samples. The Clinical Neuropsychologist, 12(4), 482–486. https://doi.org/10.1076/clin.12.4.482.7241 Dalla Barba, G., Brazzarola, M., Barbera, C., Marangoni, S., Causin, F., Bartolomeo, P., & Thiebaut de Schotten, M. (2018). Different patterns of confabulation in left visuo-spatial neglect. Experimental Brain Research. https://doi.org/10.1007/s00221-018-5281-8 Dell’Acqua, F., Simmons, A., Williams, S. C. R., & Catani, M. (2013). Can spherical deconvolution provide more information than fiber orientations? Hindrance modulated orientational anisotropy, a true-tract specific index to characterize white matter diffusion. Human Brain Mapping, 34(10), 2464–2483. https://doi.org/10.1002/hbm.22080 23 ACCEPTED MANUSCRIPT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 de Renzi, E., Gentilini, M., & Pattacini, F. (1984). Auditory extinction following hemisphere damage. Neuropsychologia, 22(6), 733–744. https://doi.org/10.1016/0028-3932(84)90099-X Dijkerman, H. C., McIntosh, R. D., Milner, A. D., Rossetti, Y., Tilikete, C., & Roberts, R. C. (2003). Ocular scanning and perceptual size distortion in hemispatial neglect: effects of prism adaptation and sequential stimulus presentation. Experimental Brain Research, 153(2), 220– 230. https://doi.org/10.1007/s00221-003-1595-1 Diller, L., Weinberg, J., Gordon, W., Goodkin, R., Gerstman, L., & Ben-Yishay, Y. (1974). Studies in cognition and rehabilitation in hemiplegia. Facchin, A., Beschin, N., & Daini, R. (2017). Rehabilitation of right (personal) neglect by prism adaptation: A case report. Annals of Physical and Rehabilitation Medicine, 60(3), 220–222. https://doi.org/10.1016/j.rehab.2016.09.004 Fan, J., McCandliss, B. D., Fossella, J., Flombaum, J. I., & Posner, M. I. (2005). The activation of attentional networks. NeuroImage, 26(2), 471–479. https://doi.org/10.1016/j.neuroimage.2005.02.004 Foulon, C., Cerliani, L., Kinkingnéhun, S., Levy, R., Rosso, C., Urbanski, M., … Thiebaut de Schotten, M. (2018). Advanced lesion symptom mapping analyses and implementation as BCBtoolkit. GigaScience, 7(3), 1–17. https://doi.org/10.1093/gigascience/giy004 Glize, B., Lunven, M., Rossetti, Y., Revol, P., Jacquin-Courtois, S., Klinger, E., … Rode, G. (2017). Improvement of Navigation and Representation in Virtual Reality after Prism Adaptation in Neglect Patients. Frontiers in Psychology, 8, 2019. https://doi.org/10.3389/fpsyg.2017.02019 Hugues, A., Di Marco, J., Lunven, M., Jacquin-Courtois, S., Rossetti, Y., Bonan, I., & Rode, G. (2015). Long-lasting reduction in postural asymmetry by prism adaptation after right brain lesion without neglect. Cognitive Processing, 16(1), 371–375. https://doi.org/10.1007/s10339-015-0704-y Jacquin-Courtois, S., O’Shea, J., Luauté, J., Pisella, L., Revol, P., Mizuno, K., … Rossetti, Y. (2013). Rehabilitation of spatial neglect by prism adaptation: a peculiar expansion of sensorimotor after-effects to spatial cognition. Neuroscience and Biobehavioral Reviews, 37(4), 594–609. https://doi.org/10.1016/j.neubiorev.2013.02.007 Jacquin-Courtois, S., Rode, G., Pisella, L., Boisson, D., & Rossetti, Y. (2008). Wheel-chair driving improvement following visuo-manual prism adaptation. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior, 44(1), 90–96. https://doi.org/10.1016/j.cortex.2006.06.003 Jones, D. K. (2004). The effect of gradient sampling schemes on measures derived from diffusion tensor MRI: a Monte Carlo study. Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 51(4), 807–815. https://doi.org/10.1002/mrm.20033 Kim, G. H., Seo, S. W., Jung, K., Kwon, O.-H., Kwon, H., Kim, J. H., … Na, D. L. (2016). The neural correlates of motor intentional disorders in patients with subcortical vascular cognitive impairment. Journal of Neurology, 263(1), 89–99. https://doi.org/10.1007/s00415-015-79466 Klein, A., Andersson, J., Ardekani, B. A., Ashburner, J., Avants, B., Chiang, M.-C., … Parsey, R. V. (2009). Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. NeuroImage, 46(3), 786–802. https://doi.org/10.1016/j.neuroimage.2008.12.037 Leemans, A., & Jones, D. K. (2009). The B-matrix must be rotated when correcting for subject motion in DTI data. Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 61(6), 1336– 1349. https://doi.org/10.1002/mrm.21890 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 Legrain, V., Bultitude, J. H., De Paepe, A. L., & Rossetti, Y. (2012). Pain, body, and space: what do patients with complex regional pain syndrome really neglect? Pain, 153(5), 948–951. https://doi.org/10.1016/j.pain.2011.12.010 Lunven, M., Rode, G., Bourlon, C., Duret, C., Migliaccio, R., Chevrillon, E., … Bartolomeo, P. (2018). Anatomical predictors of successful prism adaptation in chronic visual neglect. https://doi.org/10.1101/144956 Lunven, M., Thiebaut De Schotten, M., Bourlon, C., Duret, C., Migliaccio, R., Rode, G., & Bartolomeo, P. (2015). White matter lesional predictors of chronic visual neglect: a longitudinal study. Brain: A Journal of Neurology, 138(Pt 3), 746–760. https://doi.org/10.1093/brain/awu389 Magnani, B., Oliveri, M., Mancuso, G., Galante, E., & Frassinetti, F. (2011). Time and spatial attention: Effects of prism adaptation on temporal deficits in brain damaged patients. Neuropsychologia, 49(5), 1016–1023. https://doi.org/10.1016/j.neuropsychologia.2010.12.014 Maravita, A., McNeil, J., Malhotra, P., Greenwood, R., Husain, M., & Driver, J. (2003). Prism adaptation can improve contralesional tactile perception in neglect. Neurology, 60(11), 1829– 1831. Marquardt, D. W. (1963). An Algorithm for Least-Squares Estimation of Nonlinear Parameters. Journal of the Society for Industrial and Applied Mathematics, 11(2), 431–441. https://doi.org/10.2307/2098941 Milner, A. D., Harvey, M., Roberts, R. C., & Forster, S. V. (1993). Line bisection errors in visual neglect: misguided action or size distortion? Neuropsychologia, 31(1), 39–49. Mograbi, D. C., & Morris, R. G. (2018). Anosognosia. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior, 103, 385–386. https://doi.org/10.1016/j.cortex.2018.04.001 Moseley, L. G., Gallace, A., Di Pietro, F., Spence, C., & Iannetti, G. D. (2013). Limb-specific autonomic dysfunction in complex regional pain syndrome modulated by wearing prism glasses. PAIN, 154(11). Retrieved from https://journals.lww.com/pain/Fulltext/2013/11000/Limb_specific_autonomic_dysfunction_i n_complex.29.aspx Nachev, P., Coulthard, E., Jäger, H. R., Kennard, C., & Husain, M. (2008). Enantiomorphic normalization of focally lesioned brains. NeuroImage, 39(3), 1215–1226. https://doi.org/10.1016/j.neuroimage.2007.10.002 Nijboer, T. C. W., McIntosh, R. D., Nys, G. M. S., Dijkerman, H. C., & Milner, A. D. (2008). Prism adaptation improves voluntary but not automatic orienting in neglect. Neuroreport, 19(3), 293–298. https://doi.org/10.1097/WNR.0b013e3282f4cb67 Nijboer, T., Vree, A., Dijkerman, C., & Van der Stigchel, S. (2010). Prism adaptation influences perception but not attention: evidence from antisaccades. Neuroreport, 21(5), 386–389. https://doi.org/10.1097/WNR.0b013e328337f95f Perri, R., Bartolomeo, P., & Gainotti, G. (2000). Lack of impairments on leftward and rightward line extension tasks in neglect patients. The International Journal of Neuroscience, 103(1-4), 101–113. Pisella, L., Rode, G., Farnè, A., Tilikete, C., & Rossetti, Y. (2006). Prism adaptation in the rehabilitation of patients with visuo-spatial cognitive disorders. Current Opinion in Neurology, 19(6). Retrieved from https://journals.lww.com/coneurology/Fulltext/2006/12000/Prism_adaptation_in_the_rehabilitation_of_patients.6.aspx Pochopien, K., & Fahle, M. (2017). Influence of Visual Prism Adaptation on Auditory Space 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 Representation. I-Perception, 8(6), 2041669517746701. https://doi.org/10.1177/2041669517746701 Redding, G. M., Rossetti, Y., & Wallace, B. (2005). Applications of prism adaptation: a tutorial in theory and method. Neuroscience and Biobehavioral Reviews, 29(3), 431–444. https://doi.org/10.1016/j.neubiorev.2004.12.004 Redding, G. M., & Wallace, B. (2006). Prism adaptation and unilateral neglect: review and analysis. Neuropsychologia, 44(1), 1–20. https://doi.org/10.1016/j.neuropsychologia.2005.04.009 Rode, G., Cotton, F., Revol, P., Jacquin-Courtois, S., Rossetti, Y., & Bartolomeo, P. (2010). Representation and disconnection in imaginal neglect. Neuropsychologia, 48(10), 2903–2911. https://doi.org/10.1016/j.neuropsychologia.2010.05.032 Rode, G., Lacour, S., Jacquin-Courtois, S., Pisella, L., Michel, C., Revol, P., … Rossetti, Y. (2015). Long-term sensorimotor and therapeutical effects of a mild regime of prism adaptation in spatial neglect. A double-blind RCT essay. Annals of Physical and Rehabilitation Medicine, 58(2), 40–53. https://doi.org/10.1016/j.rehab.2014.10.004 Rode, G., Michel, C., Rossetti, Y., Boisson, D., & Vallar, G. (2006b). Left size distortion (hyperschematia) after right brain damage. Neurology, 67(10), 1801–1808. https://doi.org/10.1212/01.wnl.0000244432.91915.d0 Rode, G., Pisella, L., Marsal, L., Mercier, S., Rossetti, Y., & Boisson, D. (2006a). Prism adaptation improves spatial dysgraphia following right brain damage. Neuropsychologia, 44(12), 2487–2493. https://doi.org/10.1016/j.neuropsychologia.2006.04.002 Rode, G., Revol, P., Rossetti, Y., & Vallar, G. (2008). 3D left hyperschematia after right brain damage. Neurocase, 14(4), 369–377. https://doi.org/10.1080/13554790802389154 Rode, G., Ronchi, R., Revol, P., Rossetti, Y., Jacquin-Courtois, S., Rossi, I., & Vallar, G. (2014). Hyperschematia after right brain damage: a meaningful entity? Frontiers in Human Neuroscience, 8(1), 1–8. https://doi.org/10.3389/fnhum.2014.00008 Rode, G., Rossetti, Y., & Boisson, D. (2001). Prism adaptation improves representational neglect. Neuropsychologia, 39(11), 1250–1254. Rode, G., Rossetti, Y., Perenin, M.-T., & Boisson, D. (2004). Geographic information has to be spatialized to be neglected: a representational neglect case. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior, 40(2), 391–397. Rojkova, K., Volle, E., Urbanski, M., Humbert, F., Dell’Acqua, F., & Thiebaut de Schotten, M. (2016). Atlasing the frontal lobe connections and their variability due to age and education: a spherical deconvolution tractography study. Brain Structure & Function, 221(3), 1751–1766. https://doi.org/10.1007/s00429-015-1001-3 Ronchi, R., Rossi, I., Calzolari, E., Bolognini, N., & Vallar, G. (2018). Exploring prism exposure after hemispheric damage: Reduced aftereffects following left-sided lesions. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior. https://doi.org/10.1016/j.cortex.2018.10.014 Rorden, C., Karnath, H.-O., & Bonilha, L. (2007). Improving lesion-symptom mapping. Journal of Cognitive Neuroscience, 19(7), 1081–1088. https://doi.org/10.1162/jocn.2007.19.7.1081 Rossetti, Y., Jacquin-Courtois, S., Calabria, M., Michel, C., Gallagher, S., Honoré, J., … Rode, G. (2015). Testing Cognition and Rehabilitation in Unilateral Neglect with Wedge Prism Adaptation: Multiple Interplays Between Sensorimotor Adaptation and Spatial Cognition. In K. Kansaku, L. G. Cohen, & N. Birbaumer (Eds.), Clinical Systems Neuroscience (pp. 359–381). Tokyo: Springer Japan. Retrieved from http://link.springer.com/10.1007/978-4-431-550372_20 26 ACCEPTED MANUSCRIPT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Rossetti, Y., Jacquin-Courtois, S., Rode, G., Ota, H., Michel, C., & Boisson, D. (2004). Does action make the link between number and space representation? Visuo-manual adaptation improves number bisection in unilateral neglect. Psychological Science, 15(6), 426–430. https://doi.org/10.1111/j.0956-7976.2004.00696.x Rossetti, Y., Rode, G., Pisella, L., Farné, A., Li, L., Boisson, D., & Perenin, M. T. (1998). Prism adaptation to a rightward optical deviation rehabilitates left hemispatial neglect. Nature, 395(6698), 166–169. https://doi.org/10.1038/25988 Schenkenberg, T., Bradford, D. C., & Ajax, E. T. (1980). Line bisection and unilateral visual neglect in patients with neurologic impairment. Neurology, 30(5), 509–517. Striemer, C. L., & Danckert, J. (2010). Dissociating perceptual and motor effects of prism adaptation in neglect. Neuroreport, 21(6), 436–441. https://doi.org/10.1097/WNR.0b013e328338592f Sumitani, M., Rossetti, Y., Shibata, M., Matsuda, Y., Sakaue, G., Inoue, T., … Miyauchi, S. (2007). Prism adaptation to optical deviation alleviates pathologic pain. Neurology, 68(2), 128–133. https://doi.org/10.1212/01.wnl.0000250242.99683.57 Thiebaut de Schotten, M., Tomaiuolo, F., Aiello, M., Merola, S., Silvetti, M., Lecce, F., … Doricchi, F. (2014). Damage to white matter pathways in subacute and chronic spatial neglect: a group study and 2 single-case studies with complete virtual “in vivo” tractography dissection. Cerebral Cortex (New York, N.Y.: 1991), 24(3), 691–706. https://doi.org/10.1093/cercor/bhs351 Tilikete, C., Rode, G., Rossetti, Y., Pichon, J., Li, L., & Boisson, D. (2001). Prism adaptation to rightward optical deviation improves postural imbalance in left-hemiparetic patients. Current Biology: CB, 11(7), 524–528. Urbanski, M., Thiebaut de Schotten, M., Rodrigo, S., Catani, M., Oppenheim, C., Touzé, E., … Bartolomeo, P. (2008). Brain networks of spatial awareness: evidence from diffusion tensor imaging tractography. Journal of Neurology, Neurosurgery, and Psychiatry, 79(5), 598–601. https://doi.org/10.1136/jnnp.2007.126276 Vallar, G. (1999). The methodological foundations of neuropsychology. In Handbook of clinical and experimental neuropsychology. (pp. 95–131). Hove, England: Psychology Press/Erlbaum (UK) Taylor & Francis. Vallar, G., & Bolognini, N. (2014). Unilateral spatial neglect. In Oxford Handbook of Attention (Oxford University Press, pp. 972–1027). A. C. Nobre & S. Kastner (Eds.). Retrieved from https://doi.org/10.1093/oxfordhb/9780199675111.013.012 Vallar, G., & Calzolari, E. (2018). Unilateral spatial neglect after posterior parietal damage. Handbook of Clinical Neurology, 151, 287–312. https://doi.org/10.1016/B978-0-444-636225.00014-0 Vallar, G., & Rode, G. (2009). Commentary on Bonnier P. L’aschématie. Rev Neurol (Paris) 1905;13:605-9. Epilepsy & Behavior: E&B, 16(3), 397–400. https://doi.org/10.1016/j.yebeh.2009.09.001 Wedeen, V. J., Wang, R. P., Schmahmann, J. D., Benner, T., Tseng, W. Y. I., Dai, G., … de Crespigny, A. J. (2008). Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers. NeuroImage, 41(4), 1267–1277. https://doi.org/10.1016/j.neuroimage.2008.03.036 Wilson, B., Cockburn, J., & Halligan, P. (1987). Development of a behavioral test of visuospatial neglect. Archives of Physical Medicine and Rehabilitation, 68(2), 98–102. 47 27 1 Captions to Figures 2 3 Figure 1. 4 Examples of drawings a daisy from memory (LI=+9,46; PLI=0) (1 1A), and by copy (LI=+44,3; 5 PLI=+23,8) (1 1C), and a house and trees (Gainotti et al., 1972) 1B), a Christmas tree (LI=+10,4) (1 6 (1 1D), by copy. In copying multiple-object arrays (1D), patient FV drew greater left-hand sides 7 of objects, also when they were located in the right hand-side of the model, indicating the 8 involvement of allocentric reference frames. LI: Laterality Index Score. PLI: Petal Laterality 9 Index Score. 10 11 Figure 2. 12 Description and time course of the experimental procedure. PA: Prism Adaptation; PMT: 13 Perceptual Matching Test; LET: Line Extension Task; OLP: Open Loop Pointing task. 14 15 3.. Figure 3 16 Scores for daisy drawing from memory (A A) and by copy (B B) in patient FV and in six control 17 participants. Mean Laterality Index scores, LIs (SEM), for drawn areas and mean Petal LIs (PLIs, 18 SEM) of patient FV, prior to PA (pre-test), immediately after PA (post-test), and after a delay 19 of about 96 h following PA (late-test). 20 21 Figure 4. 22 Effect of PA on drawing of an object (a butterfly) in patient FV, prior to PA (LI=+18), 23 immediately after PA (LI=+3,21), and after a delay of 4 days following PA (LI=-1,97). 24 25 Figure 5. 5. 26 Line extension task: mean (SEM) laterality indexes (LIs) of patient FV for rightward, and 27 leftward (L, R) extended lines, by line length (4, 6, and 8 cm), prior to PA and immediately 28 after PA. 29 30 Figure 6. 31 Lesion analysis of patient FV. Reconstruction of patient’s brain lesion (6 6A);; brain areas 32 6B) and tractography of the white matter identified by the disconnectome maps analysis (6 28 1 connections (orange: Inferior Fronto-occipital Fasciculus, blue: Inferior Longitudinal 2 Fasciculus, green: Optic radiations, red: Arcuate Fasciculus) (6 6C). 3 4 29 1 Tables Patient FV Age, years / gender Laterality Stroke localisation Neurological exam Line cancellation test (Albert) Star cancellation test (Wilson) Letter cancellation task (Diller) Line bisection task (Schenkenberg et al., 1980) MOCA test (Nasreddine et al., 2005) Other cognitive disorders FIM 63 / female Right-handed Right fronto-temporo-parietal haematoma Lower left quadrantanopia and left auditory extinction, no motor or somatosensory deficit 40/40 55/56 (one omission in the left side) 51/53 (2 omissions in the left side), 48/51 (3 omissions in the right side) +0.4% (normal range -4.3-+2.9, mean -0.7%, SD ±2.46) 20/30 Dysexecutive syndrome (dysfunction of sustained and divided attention, cognitive inflexibility) anosognosia, no constructional apraxia, no memory disorder. 126/126 2 3 Table 1. Neuropsychological and neurological profile of patient FV. 4 5 30 ACCEPTED MANUSCRIPT 1 Pre-test 1 (Day-4) Pre-test 2 (before PA) Post-test (after prism removal) Late-test (Day+4) Drawing from memory LI score 11.74 (9.27) # 6.4 (6.35) -8.94 (13.42) # -1.9 (4.22) PLI score 9.77 (7.64) # 0.87 (7.98) -12.28 (14.49) # -4.61 (8.04) Drawing by copy LI score 15.29 (6.78) # 11.94 (14.12) # 0.99 (10.83) 3.8 (9.85) PLI score 12.52(9.29) 7.2 (14.56) -6.7 (12.16) -0.34 (8.95) 0.8 (1.24) 0.85 (1.29) 8.57 (3.21) 4.02 (3.25) 3.94 (4.93) 2.73 (5.08) -1.27 (2.77) -0.66 (8.95) 9.73 (6.17) 6.01 (3.9) -5.85 (3.43) 10.12 (4.83) 6.75 (4.48) 7.13 (4.4) 0.98 (1.38) 9.86 (2.71) Perceptual matching task (LI) Line extension task Leftward LI (4cm) Leftward LI (6 cm) Leftward LI (8 cm) Rightward LI (4 cm) Rightward LI (6 cm) Rightward LI (8 cm) After-effect measurements OLP 2 # # Controls (n=6) -4.87 (SD±1.34, range -7.08 to -3.57) -2.39 (SD±4.04, range -8.13 to +3.89) -3.94 (SD±3.18, range -0.81 to -8.28) -4.43 (SD±8.17, range 0 to -20.8) +0.905 (SD±0.11, range +0.81 to +1.07) 3 Table 2. Mean (SD) values of the four different tasks testing the effectiveness of PA. After- 4 effects of PA were evaluated by means (SD) of open loop pointing task (OLP). 5 # FV’s scores significantly different from controls data. 31 A D B C CRediT author statement Julie Di Marco: Investigation, Writing- Original draft, Writing- Reviewing and Editing Marine Lunven : Software, Writing- Original draft, Writing- Reviewing and Editing Patrice Revol : Methodology, Formal analysis Laure Christophe : Investigation, Visualization Sophie Jacquin-Courtois : Investigation, validation Giuseppe Vallar : Writing- Original draft, Writing- Reviewing and Editing, Validation Gilles Rode : Conceptualization, Investigation, Writing- Original draft, Writing- Reviewing and Editing, Supervision