Keywords: Spatial neglect, Body neglect, Body schema, Lateropulsion, Pusher syndrome, Postural disorders, Gait disorders

Objective. Neglect is a complex disorder which occurs frequently in right-sided stroke, altering the functional recovery. Non-body neglect (NBN) has been reported associated with postural disorders. Although body neglect (BN) refers to the body schema, and therefore should have an impact on balance and gait disorders, this relationship has never been investigated. The objective of this study was to analyse effects of BN and NBN on balance and gait disorders at the subacute stage after the stroke.

Methods. This is a cohort study of 192 individuals assessed by 4 tests for each neglect domain (BN and NBN) and for lateropulsion (SCP), postural (PASS) and gait (mFMA) disorders, in the subacute stage after a first hemispheric stroke. Correlation and multiple regression analyses were made using composite scores of body and non-body neglect. Predictive analyses were made using the cut-offs of neglect tests and endpoints of SCP, PASS and mFMA.

Results. Multiple regression and partial correlation showed that lateropulsion was worse with NBN than with BN, with a positive interaction. Both domains worsened postural and gait disorders, with a positive interaction. In addition, a limited number of abnormal neglect tests (< 2) had a strong negative predictive value on the existence of impaired body orientation with respect to gravity, balance and abilities in daily life.

Conclusion.

This is the first study to investigate the effect of body neglect on lateropulsion, postural and gait disorders, using a series of 192 individuals tested with a battery of tests, at the subacute stage after a first hemispheric stroke. Non-body neglect magnified lateropulsion more than body neglect. This means that impaired body orientation with respect to gravity (lateropulsion) depends more on the allocentric frame of spatial neglect than on the egocentric one. Postural and gait disorders were better explained with two spatial neglect domains than only one. This study confirms our hypothesis that both BN and NBN must be assessed in routine, and not only NBN as usually performed. It reveals the link between NBN and lateropulsion, whereas balance and gait were associated to both forms, NBN again referring to an allocentric frame and BN referring to the body schema.

AVERTISSEMENT

Ce document est le fruit d'un long travail approuvé par le jury de soutenance.

La propriété intellectuelle du document reste entièrement celle du ou des auteurs. Les utilisateurs doivent respecter le droit d'auteur selon la législation en vigueur, et sont soumis aux règles habituelles du bon usage, comme pour les publications sur papier : respect des travaux originaux, citation, interdiction du pillage intellectuel, etc.

Il est mis à disposition de toute personne intéressée par l'intermédiaire de l'archive ouverte DUMAS (Dépôt Universitaire de Mémoires Après Soutenance).

Si vous désirez contacter son ou ses auteurs, nous vous invitons à consulter en ligne les annuaires de l'ordre des médecins, des pharmaciens et des sagesfemmes.

Contact à la Bibliothèque universitaire de Médecine Pharmacie de Grenoble : bump-theses@univ-grenoble-alpes.fr

L'UFR de Médecine de Grenoble n'entend donner aucune approbation ni improbation aux opinions émises dans les thèses ; ces opinions sont considérées comme propres à leurs auteurs.

[Données à caractère personnel]

Résumé

Introduction. La négligence est un trouble complexe fréquemment retrouvé après un AVC hémisphérique droit, qui altère la récupération fonctionnelle. La négligence extracorporelle a été décrite comme étant associée aux troubles de l'équilibre. Alors que la négligence corporelle, un trouble du schéma corporel, devrait avoir un impact sur les troubles de l'équilibre et de la marche, cette relation n'a jamais été investiguée. L'objectif de notre étude était d'analyser les effets de la négligence corporelle et extracorporelle sur les troubles de l'équilibre et de la marche à une phase subaiguë de l'AVC.

Méthode. Notre étude se base sur une cohorte de 192 individus, avec 4 tests de négligences pour chaque domaine de négligence (corporelle et extracorporelle) et une mesure de latéropulsion (SCP), d'équilibre (PASS) et de marche (mFMA), à une phase subaiguë d'un premier AVC hémisphérique. Des analyses de corrélations et en régression multiples ont été réalisées à l'aide de scores composites de négligences corporelle et extracorporelle, ainsi que des analyses prédictives en utilisant les valeurs seuils des tests de négligences et des mesures de SCP, PASS et mFMA.

Résultats. Les corrélations partielles et régression multiples ont montré que la latéropulsion était plus

altérée avec une négligence extracorporelle qu'avec une négligence corporelle, les deux ayant une interaction positive. Chaque domaine de négligence altérait également les troubles de l'équilibre et de la marche, avec toujours une interaction positive. De plus, un nombre limité de tests de négligence anormaux (< 2) avait une forte valeur prédictive négative sur la présence d'une orientation anormale du corps par rapport à la gravité, d'une station debout instable ou d'aides humaines à la marche.

Conclusion.

Cette étude est la première à investiguer les effets de la négligence corporelle et extracorporelle sur la latéropulsion et les troubles de la marche et de l'équilibre, avec une cohorte de 192 individus, testés avec quatre tests de négligence pour chaque domaine, à une phase subaiguë d'un premier AVC hémisphérique. La négligence extracorporelle aggravait plus la latéropulsion que la négligence corporelle. Ainsi, les troubles de l'orientation du corps par rapport à la gravité (latéropulsion) dépendaient plus de références allocentriques de la négligence que de références égocentriques. Les troubles de l'équilibres et de la marche étaient mieux expliqués par l'interaction des deux domaines. Nos résultats confirment notre hypothèse que les deux domaines de négligence devraient être mesurées plus systématiquement, et plus seulement la négligence extracorporelle qui est recherchée habituellement. Notre étude révèle aussi le lien entre la négligence extracorporelle et la latéropulsion, alors que les troubles de l'équilibre et de la marche sont associés aux deux formes, encore une fois, la négligence extracorporelle s'inscrivant dans un référentiel allocentrique et la négligence corporelle se référant aux troubles du schéma corporel.

Mots clés : Négligence spatiale, négligence personnelle, négligence corporelle, schéma corporel, latéropulsion, troubles de l'équilibre, troubles de la marche.

Mes très sincères remerciements

Au Professeur Dominic Pérennou, pour m'avoir permis de découvrir la recherche médicale, pour son aide aux différents travaux de recherche et pour tous ses conseils. A Olivier, mon frère, sans qui je ne serais jamais arrivé jusqu'ici, à Claire, ma soeur, pour son soutien constant malgré mes absences répétées et à mes parents pour avoir été toujours présents et m'avoir permis de réaliser ces études.

Au

A Emilie et Chloé. Merci de m'avoir supporté pendant ces mois de recherche. Merci pour tous ces moments de bonheur. Merci pour toutes ces belles aventures qui s'annoncent.

Table of contents

Introduction

Stroke is a major health issue with a high incidence in France, affecting around 150 000 patients every year. It is the first cause of acquired handicap in adults, the second cause of dementia and the third cause of mortality (Santé Publique France). Following stroke, 70% of patients will present sequelae and of these patients, half will have balance disorders [START_REF] De Peretti | Prévalence des accidents vasculaires cérébraux et de leurs séquelles et impact sur les activités de la vie quotidienne : apports des enquêtes déclaratives Handicap-santé-ménages et Handicap-santé-institution, 2008-2009[END_REF] and almost half won't be able to walk independently at chronic stage [START_REF] Veerbeek | Is Accurate Prediction of Gait in Nonambulatory Stroke Patients Possible Within 72 Hours Poststroke?: The EPOS Study[END_REF]. Postural disorders have a critical impact on the patients' ability to walk and decrease their independence in daily life. Furthermore, balance impairments are associated with an increased risk of falls [START_REF] Kim | Falls and Use of Assistive Devices in Stroke Patients with Hemiparesis: Association with Balance Ability and Fall Efficacy[END_REF][START_REF] Mackintosh | Balance Score and a History of Falls in Hospital Predict Recurrent Falls in the 6 Months Following Stroke Rehabilitation[END_REF][START_REF] Van Bloemendaal | Validity and reproducibility of the Functional Gait Assessment in persons after stroke[END_REF]. Balance and gait abilities are strongly correlated [START_REF] Huang | Postural Assessment Scale for Stroke Patients Scores as a predictor of stroke patient ambulation at discharge from the rehabilitation ward[END_REF], and are worsened by sensorimotor deficits [START_REF] Jørgensen | Recovery of walking function in stroke patients: The copenhagen stroke study[END_REF][START_REF] Michael | Reduced Ambulatory Activity After Stroke: The Role of Balance, Gait, and Cardiovascular Fitness[END_REF][START_REF] Patterson | Determinants of Walking Function After Stroke: Differences by Deficit Severity[END_REF] and also by spatial neglect [START_REF] Veerbeek | Is Accurate Prediction of Gait in Nonambulatory Stroke Patients Possible Within 72 Hours Poststroke?: The EPOS Study[END_REF][START_REF] Perennou | Postural disorders and spatial neglect in stroke patients: A strong association[END_REF][START_REF] Geurts | A review of standing balance recovery from stroke[END_REF][START_REF] Laufer | Standing Balance and Functional Recovery of Patients with Right and Left Hemiparesis in the Early Stages of Rehabilitation[END_REF][START_REF] Pérennou | Transcutaneous electric nerve stimulation reduces neglect-related postural instability after stroke[END_REF].

Spatial neglect is a post stroke disorder characterised by a "failure to report, respond, or orient to contralateral stimuli that is not caused by an elemental sensorimotor deficit" [START_REF] Heilman | Neglect and Related Disorders[END_REF]. Furthermore, positive symptoms can be observed mainly in the ipsilesional space [START_REF] Na | Motor perseverative behavior on a line cancellation task[END_REF]. Spatial neglect is a heterogeneous disorder because it can encompass different clinical subtypes, which might involve different frames of references (egocentric, allocentric), processing modalities (sensory, representational) or regions of space (personal, peripersonal, extrapersonal) [START_REF] Rode | Semiology of neglect: An update[END_REF].

While peripersonal and extrapersonal neglect refer to the non-body space, personal neglect refers to a form of hemi inattention where stroke patients show a "deficit relative to the side of the body contralateral to the lesion" [START_REF] Guariglia | Personal and extrapersonal space: A case of neglect dissociation[END_REF]. This means that in daily living activities patients with body neglect tend to ignore stimuli presented on the side of their body that is opposite to the brain damaged side, fail to use and recognize contralesional paretic limbs as their own, though a clinical examination may not be showing any motor deficit. Recent studies suggest that the neural bases of personal (i.e bodily domain) and extrapersonal (i.e non bodily domain) space awareness in humans are dissociated both from a functional and an anatomical point of view [START_REF] Beschin | Personal Versus Extrapersonal Neglect: A Group Study of their Dissociation Using a Reliable Clinical Test[END_REF][START_REF] Committeri | Neural bases of personal and extrapersonal neglect in humans[END_REF][START_REF] Committeri | Personal neglect: A comprehensive theoretical and anatomo-clinical review[END_REF]. However, definition of personal neglect still remains uncertain for several reasons.

Firstly, there is a relative absence of well-conducted studies evaluating personal neglect with a powerful battery of tests [START_REF] Caggiano | The 'Neglected' Personal Neglect[END_REF]. Secondly, this deficit is heterogenous, including motor and premotor neglect [START_REF] Sampanis | Motor Neglect and Future Directions for Research[END_REF], a lack of awareness of tactile and proprioceptive stimuli, and defective motor programming towards targets in the neglected sector of space [START_REF] Vallar | Spatial hemineglect in humans[END_REF]. Body (BN) and Non-body neglect (NBN) co-occur frequently [START_REF] Committeri | Neural bases of personal and extrapersonal neglect in humans[END_REF], however some studies report cases of dissociation [START_REF] Guariglia | Personal and extrapersonal space: A case of neglect dissociation[END_REF][START_REF] Beschin | Personal Versus Extrapersonal Neglect: A Group Study of their Dissociation Using a Reliable Clinical Test[END_REF][START_REF] Committeri | Neural bases of personal and extrapersonal neglect in humans[END_REF]. Recovery of NBN and BN doesn't differ. At 3 months, 54% of neglect-patients don't show asymmetry anymore, and about 30-40% of neglect patients still suffer from neglect after a year [START_REF] Iosa | Recovery of personal neglect[END_REF][START_REF] Nijboer | Time course of visuospatial neglect early after stroke: A longitudinal cohort study[END_REF].

The link between spatial cognition and postural disorders could take its origin in the vestibular cortex, which might represent the body in its environment by an internal model [START_REF] Barra | Humans use internal models to construct and update a sense of verticality[END_REF][START_REF] Lopez | The thalamocortical vestibular system in animals and humans[END_REF][START_REF] Yelnik | Perception of Verticality After Recent Cerebral Hemispheric Stroke[END_REF]. This vestibular cortex could build a 3D map [START_REF] Brandt Th | Vestibular cortex lesions affect the perception of verticality[END_REF], through an egocentric reference frame, based on the body scheme [START_REF] Barra | Asymmetric standing posture after stroke is related to a biased egocentric coordinate system[END_REF], and an allocentric reference frame, including graviception or visual information [START_REF] Howard | Visually Induced Reorientation Illusions[END_REF][START_REF] Isableu | Contrôle visuel de l'orientation et de l'équilibre[END_REF]. Body scheme disorders are correlated with postural disorders [START_REF] Barra | Asymmetric standing posture after stroke is related to a biased egocentric coordinate system[END_REF], in an egocentric reference frame, whereas NBN is correlated with postural disorders in an allocentric reference frame [START_REF] Embrechts | The association between visuospatial neglect and balance and mobility post-stroke onset: A systematic review[END_REF]. Furthermore, balance and gait abilities are predicted by lateropulsion which is a way of adjusting the body orientation to a wrong reference of verticality [START_REF] Dai | Balance, lateropulsion, and gait disorders in subacute stroke[END_REF][START_REF] Karnath | The origin of contraversive pushing: Evidence for a second graviceptive system in humans[END_REF]. and lateropulsion might correspond to a form of spatial neglect [START_REF] Dai | Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception[END_REF]. While the impact between NBN on postural and gait disorders is well-established, the impact of BN remains unclear. Our first hypothesis is that BN, by its egocentric reference frame, could play a role in lateropulsion, postural and gait disorders. The second hypothesis is that both BN and NBN are associated with these disorders.

Method Study design

This was a monocentric cross-sectional observational study, ancillary of the DOBRAS cohort (Determinants of Balance Recovery After Stroke; ClinicalTrials.gov NCT03203109), with participants comprehensively assessed in routine care (see [START_REF] Dai | Balance, lateropulsion, and gait disorders in subacute stroke[END_REF]. For the present study, we used the initial clinical assessments of DOBRAS participants, performed mostly within 3 days before or after day 30 (D30) after stroke, otherwise at 60 days (D60) or 90 days (D90) for those admitted lately in the rehabilitation ward. The novelty here was to analyse data related to neglect domain (BN or NBN) and lateropulsion, postural and gait disorders.

Protocol approvals, registrations, and patient consents

The DOBRAS cohort was approved by our institutional review board (CHU Grenoble Alpes) who validated the ClinicalTrials.gov registration (NCT03203109). The study was also registered at the National Committee for Informatics and Freedom (Commission Nationale Informatique et Liberté; CNIL-No.2014874-v1) and was performed in accordance with the Helsinki Declaration. According to French law, observational studies do not require approval by an ethics committee, provided that participants have been informed of the specific research and are not opposed to use of their data. All eligible individuals were informed of the DOBRAS study (orally and in writing) and those who did not want to participate signed an opposition form.

Participants

Between January 2012 and August 2019, we included 192 individuals (Figure 1), eligible for this study if they met common criteria of the DOBRAS cohort (18 years or older; first-ever unilateral stroke limited to one hemisphere confirmed by MRI or CT). Exclusion criteria were : patients over 80 years old or under 18 years old; recurrent stroke; complication at the acute stage (malignant infarct, cerebral herniation, subarachnoid haemorrhage, and hydrocephalus); dementia; previous disability interfering with balance, gait or vestibular disorders; unstable medical conditions or psychiatric problems; and inability to speak French. These conditions were obtained from the hospital electronic file describing the history of every patient, by interviewing patients and relatives, and by a systematic clinical examination. For the ancillary study, individuals with less than 3 tests evaluating BN and less than 3 tests evaluating NBN or individuals without lateropulsion, postural or gait disorder assessments were excluded.

Participants of the DOBRAS study, similarly to all patients admitted to our department, followed a personalized rehabilitation program, taking into account deficits and activity limitations. According to their abilities, they had 2 physiotherapy and 1 occupational therapy sessions per day (total 1h30), plus, if needed, sessions with a speech therapist, neuropsychologist, psychologist, or orthoptist. Rehabilitation sessions included weight shifting exercises, balance and gait training.

Neglect assessments

To assess spatial neglect, nine main tests were performed by neuropsychologists and one by an occupational therapist in both BN space and NBN space (see Additional materials) One test evaluated both domains:

-The ecological Catherine Bergego Scale was used for the two domains in activities of daily living [START_REF] Azouvi | Behavioral assessment of unilateral neglect: Study of the psychometric properties of the Catherine Bergego Scale[END_REF]. The result is considered "normal" if the score is < 2.

Three tests evaluated non-body neglect:

-The Bells test: a cancelation task with 7 columns, each containing 5 targets (bells) and distractors. The result was considered "normal" if the number of omissions was ≤ 6.

(39) -A copying test (the Gainotti copy): for which the result was considered abnormal if any omissions were observed. [START_REF] Gainotti | Qualitative analysis of unilateral spatial neglect in relation to laterality of cerebral lesions[END_REF] -A reading test [START_REF] Azouvi | A battery of tests for the quantitative assessment of unilateral neglect[END_REF]: for which the result was considered abnormal if one omission was observed.

Three other tests evaluated body neglect:

-The Bisiach test: a simple task that assess the ability to reach the contralesional hand with the ipsilesional arm with eyes closed. The result was considered "abnormal" if the score was higher than 0. ( 42) -The Fluff test: in which the blindfolded patient has to remove 24 targets attached to his clothes in a time limit of 2 mn, with no targets placed on the non-paretic arm. Result was considered "normal" if ≥ 13/15 targets were detached. [START_REF] Cocchini | The Fluff Test: A simple task to assess body representation neglect[END_REF] -The comb and razor/compact test: in which patient is asked firstly to comb the hair for 30sec and secondly to shave (for men) or to make up (for women) for 30 sec. The difference in strokes between the two sides of the head or the face was recorded. A score > 11% indicated a BN. [START_REF] Beschin | Personal Versus Extrapersonal Neglect: A Group Study of their Dissociation Using a Reliable Clinical Test[END_REF][START_REF] Mcintosh | Improving the Clinical Diagnosis of Personal Neglect: A Reformulated Comb and Razor Test[END_REF] We analysed the severity of spatial neglect by computing composite scores for each spatial domain (BN and NBN). The raw scores of all neglect tests were first normalized to a range from 0 to 100, then averaged by spatial domain to obtain composite BN and NBN scores, both averaged to give a global neglect score. For the Comb and Razor test, raw instead of normalized scores were used in the calculation to avoid inflating the BN scores. To avoid negative values, the distribution of the BN scores was finally normalized between 0 and its maximal value.

In addition to the severity of spatial neglect evaluated by the composite scores, we analysed participants in terms of absence or presence of spatial neglect. Participants with 2 or more pathological tests in BN space were considered to have a BN, likewise for the NBN space. This cut-off was chosen to avoid false positives [START_REF] Azouvi | A battery of tests for the quantitative assessment of unilateral neglect[END_REF][START_REF] Jehkonen | How to detect visual neglect in acute stroke[END_REF]. If participants presented both BN and NBN, they were considered to have a transmodal neglect. If one domain was pathological without the other, we retained an isolated BN or an isolated NBN.

Lateropulsion, balance and gait disorder assessment

Lateropulsion, which represents a contralesional tilt in a sitting or standing position, was assessed by physiotherapists using the Scale for Contraversive Pushing (SCP) with a score ranging from 0 to 6 [START_REF] Karnath | The neural representation of postural control in humans[END_REF]. Individuals were categorized as: "upright" (SCP score ≤ 0.5) or "lateropulsion" (SCP ≥ 0.75).

Balance disorders were assessed by physiotherapists with the Postural Assessment Scale for Stroke (PASS), which is used to assess static and dynamic balance of stroke patients evaluating ability to maintain or change a given lying, sitting, or standing posture [START_REF] Benaim | Validation of a Standardized Assessment of Postural Control in Stroke Patients: The Postural Assessment Scale for Stroke Patients (PASS)[END_REF]. PASS demonstrates high inter-and intra-rater reliability [START_REF] Benaim | Validation of a Standardized Assessment of Postural Control in Stroke Patients: The Postural Assessment Scale for Stroke Patients (PASS)[END_REF], and high test retest reliability [START_REF] Mao | Analysis and Comparison of the Psychometric Properties of Three Balance Measures for Stroke Patients[END_REF]. It is easy to administer in a clinic, and is suitable for all patients, even those with poor postural performance [START_REF] Benaim | Validation of a Standardized Assessment of Postural Control in Stroke Patients: The Postural Assessment Scale for Stroke Patients (PASS)[END_REF]. This scale includes 12 items scored from 0 to 3, for a total score from 0 to 36. Participants were categorized in two groups with an endpoint set as the stable erect stance [START_REF] Laufer | Standing Balance and Functional Recovery of Patients with Right and Left Hemiparesis in the Early Stages of Rehabilitation[END_REF], as follows:

-PASS score ≥ 28 meant that the participants had a "satisfactory erect stance".

-PASS score < 28 meant that the participants were "not able to stand independently without any help".

Gait independence was evaluated with the modified Fugl-Meyer gait Assessment (mFMA) [START_REF] Lindmark | Evaluation of functional capacity after stroke as a basis for active intervention. Presentation of a modified chart for motor capacity assessment and its reliability[END_REF]. This walking scale is specifically dedicated to stroke and evaluate patient performances depending on the degree of assistance with scores ranging from 0 (no walking) to 6 (normal walking). Participants were categorized as follows:

-"non-functional gait" (mFMA ≤ 2) if they were not able to walk or if they were able to walk with human assistance, and as having a "functional gait" (mFMA ≥ 3) if they were able to walk without human assistance.

Other clinical characteristics

Deficits analysed in this study were quantified at the first systematic assessment available, D30, D60 or D90.

Deficits were evaluated by a battery of well validated tests and scales, assessing motor command, spasticity, sensory loss, visual field defect and language disorders.

Motor command was assessed by physiotherapists with the Medical Research Council scale which involves testing muscles against gravity and the examiner's resistance [START_REF] Held Jp | Devenir des hemiplegies vasculaires par atteinte sylvienne en fonction du cote de la lesion[END_REF]. Scores range from 0 (no contraction) to 5 (full range of motion against gravity with maximal resistance).

Eight key muscle groups (hip flexors and extensors, hip abductors and adductors, knee flexors and extensors, ankle flexors and extensors) of the paretic lower limb were tested with a total score from 0 to 40 (normal strength).

Spasticity was assessed by physiotherapists with the Ashworth Scale (51). Scores range from 0 (no increase in tone) to 4 (limb rigid) depending on the increase in muscle tone during a passive movement. Five key muscle groups (hip flexors and adductors, quadriceps and hamstrings, triceps sural and tibialis posterior) of the lower paretic limb were tested with a total score from 0 to 20.

Hypoesthesia was evaluated by occupational therapists with the Semmes-Weinstein

Monofilament test on the paretic lower limb using a set of monofilaments that vary in thickness and diameter. Each filament was identified by the logarithm of the force produced expressed in milligrams. Participants were classified into 4 classes: "no hypesthesia", "light hypoesthesia", "moderate hypoesthesia" and "severe hypoesthesia", from 3 to 0.

The presence of hemianopia has been clinically investigated by physicians.

Handedness before stroke was evaluated by occupational therapists through interviews (patient, relatives) to assess the Edinburgh Handedness Inventory [START_REF] Oldfield | The assessment and analysis of handedness: The Edinburgh inventory[END_REF]. Scores range from -1 to +1, and a score ≥ 0.4 categorized the patient as right-handed.

Height and weight were collected to calculate Body Mass Index (BMI).

Aphasia was evaluated by speech therapists with the Boston Diagnostic Aphasia Examination to appreciate the severity of the language disorder. The presence of aphasia was considered if the score was ≤ 4 [START_REF] Howard | Visually Induced Reorientation Illusions[END_REF].

Statistics

Statistical analyses were done with RStudio (Version 1.2.5042), except Multiple imputation which was performed with SPSS (Version 21.0). For descriptive analysis, data were presented as numbers, as odds ratios in the tables, as percentages for categorical variables and as median [quartile 1-3 (Q1-Q3)] for continuous variables. The Mann-Whitney test or the Kruskal-wallis test were used to compare age, spasticity, motor command, hypoesthesia, FIM and NIHSS between BN, NBN and Transmodal Neglect individuals. Chi-square test was used to compare gender, handedness, stroke side, aphasia and hemianopia between groups.

To test our first hypothesis, that BN could play a role in lateropulsion, postural and gait disorders, we used Pearson correlations between neglect domain (BN and NBN) and lateropulsion (SCP) and functionals outcomes (PASS, mFMA). Pearson's partial correlations were used to measure the degree of association between a neglect domain, controlling the other neglect domain, using the package "ppcor" (53) of the R statistical software. If necessary, the difference between two overlapping correlation coefficients (i.e. with one variable in common) was assessed by the test of Zou's confidence interval (2007) provided by the package "cocor" [START_REF] Diedenhofen | cocor: A Comprehensive Solution for the Statistical Comparison of Correlations[END_REF]. Before using parametric statistics, a gaussian transformation of BN and NBN scores was run using the "BestNormalize" package in Rstudio, which selects the best transformation according to the Pearson P statistic (divided by its degrees of freedom), as calculated by the "nortest" package. Gaussian transformations were tested using a Kolmogorov Smirnov test.

Multiple regression analysis was used to test our second hypothesis, that BN could play a role in association with NBN, using as independent variables the Normalized BN score and NBN score, the interaction between both domains, and the severity of stroke (NIHSS), and as dependant variables the SCP, the PASS and the mFMA.

Because of inclusion criteria, a few participants had 1 missing test regardless of the neglect domain (i.e., 3 on 4 tests for BN or NBN). Thus, Multiple imputation method was performed with SPSS 21.0, to fill missing data by plausible values.

Finally, contingency analysis explored how BN and NBN were predictive for an upright position, a stable erect stance or the need for technical aid.

Results

Participants

We analysed 192 individuals of the DOBRAS cohort (figure 1). Excluded participants were in majority due to language disorders. The median age was 67 [START_REF] Rorden | Allocentric neglect strongly associated with egocentric neglect[END_REF][START_REF] Reeves | Combining Multiple Indicators of Clinical Quality: An Evaluation of Different Analytic Approaches[END_REF][START_REF] Bowen | Reasons for Variability in the Reported Rate of Occurrence of Unilateral Spatial Neglect After Stroke[END_REF][START_REF] Halligan | Visuospatial neglect : underlying factors and test sensitivity[END_REF][START_REF] Stone | The Incidence of Neglect Phenomena and Related Disorders in Patients with an Acute Right or Left Hemisphere Stroke[END_REF][START_REF] Caggiano | Personal Neglect Following Unilateral Right and Left Brain Damage[END_REF][START_REF] Appelros | Neglect and Anosognosia After First-Ever Stroke: Incidence and Relationship to Disability[END_REF][START_REF] Katz | Functional disability and rehabilitation outcome in right hemisphere damaged patients with and without unilateral spatial neglect[END_REF][START_REF] Kollen | Predicting Improvement in Gait After Stroke: A Longitudinal Prospective Study[END_REF][START_REF] Spaccavento | Effect of subtypes of neglect on functional outcome in stroke patients[END_REF][START_REF] Vossel | Anosognosia, neglect, extinction and lesion site predict impairment of daily living after right-hemispheric stroke[END_REF][START_REF] Suchan | Neglect severity after left and right brain damage[END_REF][START_REF] Vallar | A fronto-parietal system for computing the egocentric spatial frame of reference in humans[END_REF][START_REF] Corbetta | Control of goal-directed and stimulus-driven attention in the brain[END_REF][START_REF] Doricchi | White matter (dis)connections and gray matter (dys)functions in visual neglect: Gaining insights into the brain networks of spatial awareness[END_REF][START_REF] Heilman | Right hemisphere dominance for attention: The mechanism underlying hemispheric asymmetries of inattention (neglect)[END_REF][START_REF] Lunven | Attention and spatial cognition: Neural and anatomical substrates of visual neglect[END_REF][START_REF] Mesulam | The functional anatomy and hemispheric specialization for directed attention: The role of the parietal lobe and its connectivity[END_REF] years old, there were 125 males (65%), mostly right-handed (n= 155, 81% with a score > 0.6) according to the Edinburgh inventory [START_REF] Oldfield | The assessment and analysis of handedness: The Edinburgh inventory[END_REF], mostly with a cerebral infarct (n = 157, 82%) and often right sided brain damage (n = 99, 52%) (Table 2). Participants were assessed at 30 days post-stroke (D30, n=163, 85%), 60 days post-stroke (D60, n=25, 13%) or 90 days post-stroke (D90, n=4, 2%).

Each patient performed a minimum of six BN or NBN tests, and had a postural, gait and lateropulsion assessment.

Missing data

There were 267/5568 (4.8%) missing data in the whole dataset. As for the two primary outcomes (both aggregated by four subtests), the scores of BN and NBN had 66/192 (34%) and 49/192 (26%) missing data, respectively. Concerning the origins of missing data, the missing data of score of BN mainly resulted from the missing data of Fluff test, which was introduced later in our battery (since 2014) and was missing in 58/192 individuals (30%); while the missing data of score of NBN mainly resulted from the missing data of reading, which was caused by aphasia and was missing in 42/192 individuals (22%). Apart from Fluff and reading tests, the other six secondary outcomes had few missing data: both 6 (3%) in body and non-body CBS, 2 (1%) in Bisiach test, and 1 (1%) in Bell test, none in Gainotti and Comb & Razor tests. Other missing data are presented in Table 1.

Spatial neglect

The original global neglect score ranged from 0% to 74% with a median of 14% [8; 25]. The original BN scores ranged from 0% to 66% with a median of 21% [13; 35] The global neglect score was highly correlated with both BN (r = 0.95, p < 10 -6 ) and NBN (r = 0.85, p < 10 -6 ) scores, and the latter were also correlated (r= 0.70, p < 10 -6 ).

Among the 192 individuals, 79 (41%) did not show any form of spatial neglect, 104 (54%) showed a BN, 71 (37%) a NBN, and 62 (32%) a transmodal neglect. Forty-two individuals (22%) showed an isolated BN, whereas only nine (5%) showed an isolated NBN. Figure 3 presents the overlaps and dissociations of neglect forms. Clinical characteristics of individuals of different neglect forms are detailed in table 2. Both BN and NBN individuals had more rightsided lesions. They present more frequently a hemianopia. Deficits in motor command and sensibility were more severe. Finally, functional outcomes were decreased by the presence of any form of neglect. Individuals showing an isolated BN and NBN are compared in table 3.

There were more right-sided lesions in individuals with transmodal neglect. Isolated BN was equally found in both right and left-sided stroke, while isolated NBN was found more frequently in left sided stroke. Individuals with isolated NBN and transmodal neglect showed more hemianopia. Motor deficit tended to be more severe in individuals with isolated BN than those with an isolated NBN. A hypoesthesia was found for both isolated neglect domains. Neglect severity increased with isolated BN or NBN by a factor 2, thus with both neglect domain by a factor 4. Functional outcome was decreased by the presence of a form of isolated neglect, and further decreased with both form of neglect.

To sum up, BN was more frequent in our study than NBN, and isolated BN appeared more often than isolated NBN. Regardless of the domain involved, neglect was associate with more motor and sensibility deficits, and was more frequent and severe in right sided lesions.

Interestingly, hemianopia was found more frequently in isolated NBN, as was weakness in isolated BN. Isolated neglect was not found to be more frequent in right sided lesion.

Transmodal neglect was the most frequent form of neglect, the most severe form and was found more frequently in right-sided lesion.

Postural and gait disorders

The SCP ranged from 0 to 6 (/6) with a median of 0 [0; 1.25]. The PASS ranged from 0 to 36 (/36) with a median value of 32 [24; 35]. The modified Fugl Meyer Gait assessment mFMA ranged from 0 to 6 (/6) with a median of 4 [2; 6]. As for endpoints, 59 individuals (31%) showed lateropulsion, 65 (34%) had an unstable erect stance, and 130 (68%) were able to walk without human help.

Relationship between spatial neglect and lateropulsion

Correlations analyses

We first tested parametric correlation between neglect domains and lateropulsion (SCP). SCP was moderately correlated with the global neglect (r = 0.58, p < 10 -6 ) and the NBN (r = 0.58, p < 10 -6 ) and tended to be less correlated with BN (r = 0.54, p < 10 -6 ), without significant difference between these two latter correlations (Delta = 0.4, CI 95%: [-0.05, 0.13]).

Partial correlations showed an interaction between neglect domain, with a decreased correlation between neglect domain and lateropulsion, when controlled by other neglect domains.

Moreover, partial correlation between BN and SCP (r = 0.24, p < 10 -3 ) was lower than the partial correlation between NBN and SCP (r = 0.33, p < 10 -6 ).

The best fitted linear multiple regression model for lateropulsion (SCP), was an interaction between BN and NBN, controlled with NIHSS (Adjusted R-squared: 0.44; F-statistic: 39.19 on 4 and 187 DF; p-value: < 10 -6 ). Estimate of NBN was stronger (β = 0.61, p < 10 -4 ) than the estimate of BN (β = 0.38, p = 0.006). Interaction was also significant with an intermediate estimate (β = 0.53, p < 10 -6 ). Interestingly, NIHSS was not statistically significant (β = 0.02, p = 0.356)

Predictive analyses

Data are presented in Table 4. Lateropulsion was found more frequently in NBN individuals (n= 46, 65%) than in those with BN (n= 49, 47%; χ-squared = 4.62; p = 0.03). NBN was more specific (81%) whereas BN was more sensitive (83%). There were also few individuals with a lateropulsion but without BN or NBN. Thus, negative predictive values were high: 89% both for BN and NBN. This means that individuals who had less than 2 tests considered pathological in any form of neglect had a low probability of showing lateropulsion. Moreover, when an individual showed no lateropulsion, the probability of having a NBN was low. We noticed that specificity and predictive negative value were comparable for the transmodal neglect (86% and 88% respectively).

To sum up, lateropulsion was independently and moderately correlated with both forms of neglect, and their interaction worsened it. NBN was more strongly associated with lateropulsion than BN.

Relationship between spatial neglect and balance disorders

Correlations analyses

Postural ability (PASS) was moderately correlated with global neglect (r = -0.56, p < 10 -6 ), BN (r = -0.53, p < 10 -6 ) and NBN (r = -0.55, p < 10 -6 ).

Partial correlations confirmed that each neglect domain was independently correlated with postural abilities (BN: r = -0.25, p < 10 -3 , and NBN: r = -0.29, p < 10 -4 ).

The best multiple regression model to explain postural abilities from spatial neglect was that including BN, NBN, and their interaction, controlled with NIHSS (Adjusted R-squared: 0.40, F-statistic: 33.41 on 4 and 187 DF, p-value: < 10 -6 ). Both neglect domains contributed to independently explain postural abilities: BN (β = -2.07, p = 0.005) and NBN (β = -2.42, p = 0.001), as well as their interaction (β = -2.01, p < 10 -3 ) and as stroke severity (β = -0.31, p = 0.004).

Predictive analyses

As presented in Table 4, the erect stance was as frequently non acquired in individuals with BN than in those with NBN (52/52 [50%] vs 29/42 [41%]; χ-squared = 1.078, p = 0.299).

NBN was more specific (77%) whereas BN was more sensitive (80%). There were also few individuals with an unstable erect stance but without BN or NBN. Thus, negative predictive values were high: 85% for BN and 81% for NBN. This means that individuals who had less than 2 tests considered pathological in any form of neglect had a low probability of showing an unstable erect stance. Moreover, when an individual showed a satisfactory erect stance, the probability of having a NBN was low. We noticed that specificity and predictive negative value were comparable for the transmodal neglect (80% and 82% respectively).

To summarize, postural disorders were independently and moderately correlated with both forms of neglect, and their interaction worsened them. No form of neglect prevailed.

Relationship between spatial neglect and gait disorders

Correlations analyses

Gait disorders (mFMA) were moderately correlated with global neglect (r = -0.50, p < 10 -6 ), BN (r = -0.48, p < 10 -6 ) and NBN (r = -0.48, p < 10 -6 ).

Partial correlations confirmed that each neglect domain was independently correlated with gait disorders (r = -0.23, p = 0.001, r = -0.23, p = 0.001 for BN and NBN).

For the gait disorders, the best model for multiple regression analyses also admitted an interaction between the BN and the NBN, controlled with NIHSS (Adjusted R-squared: 0.36, F-statistic: 28.17 on 4 and 187 DF, p-value = 10 -6 ). Both neglect domains contributed to independently explain gait disorders: BN (β = -0.44, p-value = 0.019) and NBN (β = -0.38, pvalue = 0.042). We noticed that NBN was very close to the insignificant p-value threshold.

Interaction was also significant (β = -0.35, p-value = 0.011) as was the severity of stroke (β = -0.13, p-value < 10 -5 ).

Predictive analyses

Table 4 shows that walking without human aid was as frequently not acquired in individuals with BN than in those with NBN (55/104 [53%] vs 29/71 [41%]; χ-squared = 1.9917, df = 1, pvalue = 0.158).

NBN was more specific (78%) whereas BN was more sensitive (79%). Most individuals walked without human aid, when BN or NBN were absent. Thus, negative predictive values were high with: 85% for BN and 83% for NBN. This means that individuals who had less than 2 tests considered pathological in any form of neglect had a low probability of walking with human aid. Moreover, when an individual walked with technical aid or without any aid, the probability of having a NBN was low. We noticed that specificity and predictive negative value were comparable for the transmodal neglect (82% and 82% respectively).

To summarize, gait disorders were independently and moderately correlated with both forms of neglect, and their interaction worsen them. No form of neglect prevailed.

Discussion

To the best of our knowledge, this is the first cross-sectional study investigating the specific relationship of both BN and NBN with postural and gait disorders. A large series and the use of several neglect tests per domain ensure robust results. We found more BN participants than NBN, and more isolated BN than NBN. Transmodal neglect was the most prevalent form of neglect, despite a dissociation between both domains. NBN was more correlated with lateropulsion than BN. Both domains were equally negatively correlated with postural and gait abilities. The interaction of both domains further decreased these abilities.

Statistical analyses

Composite scores were based on an Indicator Average method which is the easiest way to aggregate indicators. Many other indicator aggregate methods are known in literature, for instance: "Center of Cancellation" [START_REF] Rorden | Allocentric neglect strongly associated with egocentric neglect[END_REF], "All-or-none", "Patient average", etc. [START_REF] Reeves | Combining Multiple Indicators of Clinical Quality: An Evaluation of Different Analytic Approaches[END_REF]. Center of Cancellation wasn't used because we rated scores by omissions. Indicator Average method was chosen because of its simplicity and because the impact of weighting systems is particularly transparent with this method. ( 56)

Spatial neglect

In our study, half the participants presented BN and a third NBN. Isolated BN was found in 22% of patients and only 9 patients showed isolated NBN. While this distribution, with an higher prevalence of BN, was described before by Committeri (20), this strong difference was not known. However, prevalence of neglect has often been discussed in literature, and is generally due to including criteria, lesion localization, and nature or timing of assessment [START_REF] Jehkonen | How to detect visual neglect in acute stroke[END_REF][START_REF] Bowen | Reasons for Variability in the Reported Rate of Occurrence of Unilateral Spatial Neglect After Stroke[END_REF][START_REF] Halligan | Visuospatial neglect : underlying factors and test sensitivity[END_REF][START_REF] Stone | The Incidence of Neglect Phenomena and Related Disorders in Patients with an Acute Right or Left Hemisphere Stroke[END_REF]. In our study, both domains were evaluated by four tests, which was motivated by many papers recommending a battery of tests [START_REF] Committeri | Personal neglect: A comprehensive theoretical and anatomo-clinical review[END_REF][START_REF] Azouvi | A battery of tests for the quantitative assessment of unilateral neglect[END_REF][START_REF] Jehkonen | How to detect visual neglect in acute stroke[END_REF][START_REF] Halligan | Visuospatial neglect : underlying factors and test sensitivity[END_REF]. In most studies evaluating BN and NBN, there are more NBN assessments than BN [START_REF] Caggiano | The 'Neglected' Personal Neglect[END_REF]. Increased prevalence of isolated BN, compared to isolated NBN, might be the result of an increased sensitivity induced by using a battery of four BN tests, as it has been described before for NBN [START_REF] Jehkonen | How to detect visual neglect in acute stroke[END_REF]. That being said, some studies investigating BN report prevalence similar to ours, between 40 to 70%, with one or two tests [START_REF] Committeri | Neural bases of personal and extrapersonal neglect in humans[END_REF][START_REF] Iosa | Recovery of personal neglect[END_REF][START_REF] Caggiano | Personal Neglect Following Unilateral Right and Left Brain Damage[END_REF]. One could hypothesize that NBN is rare, and is partially encompassed in Transmodal neglect, whereas BN plays a role of its own. With a balance distribution of BN and NBN tests, we expected a dissociation between BN and NBN as has been described before [START_REF] Guariglia | Personal and extrapersonal space: A case of neglect dissociation[END_REF][START_REF] Beschin | Personal Versus Extrapersonal Neglect: A Group Study of their Dissociation Using a Reliable Clinical Test[END_REF][START_REF] Committeri | Neural bases of personal and extrapersonal neglect in humans[END_REF]. Our study highlights these two forms of neglect and their dissociation. Interestingly, transmodal neglect was the most represented and the most severe form, which is consistent with some studies showing NBN is associated with poor functional outcomes [START_REF] Appelros | Neglect and Anosognosia After First-Ever Stroke: Incidence and Relationship to Disability[END_REF][START_REF] Katz | Functional disability and rehabilitation outcome in right hemisphere damaged patients with and without unilateral spatial neglect[END_REF][START_REF] Kollen | Predicting Improvement in Gait After Stroke: A Longitudinal Prospective Study[END_REF][START_REF] Spaccavento | Effect of subtypes of neglect on functional outcome in stroke patients[END_REF][START_REF] Vossel | Anosognosia, neglect, extinction and lesion site predict impairment of daily living after right-hemispheric stroke[END_REF]. Probably, most studies evaluating visual neglect were blind to BN. This asserts the need for a well-assessed BN which is strongly associated with NBN, resulting in poor deficits and functional outcomes.

Among individuals with isolated BN, there were the same ratio in right and left-sided stroke patients. This is consistent with studies evaluating personal neglect in left and right sided lesions in subacute stroke [START_REF] Azouvi | A battery of tests for the quantitative assessment of unilateral neglect[END_REF][START_REF] Caggiano | Personal Neglect Following Unilateral Right and Left Brain Damage[END_REF] and highlights the necessity to assess left-sided stroke patients.

However, these results question the neural basis and mechanisms of neglect disorders. In our study, isolated BN and NBN were not found more frequently in right-sided stroke patients, whereas it was the case for transmodal neglect. This is consistent with a study that reported the same ratio between left and right-sided stroke patients, but a more severe neglect in right-sided stroke patients [START_REF] Suchan | Neglect severity after left and right brain damage[END_REF]. Many studies have shown that the right hemisphere is the key localisation for spatial cognition [START_REF] Committeri | Neural bases of personal and extrapersonal neglect in humans[END_REF][START_REF] Brandt Th | Vestibular cortex lesions affect the perception of verticality[END_REF][START_REF] Vallar | A fronto-parietal system for computing the egocentric spatial frame of reference in humans[END_REF], probably because of a high-order internal system preferentially in the right hemisphere [START_REF] Lopez | The thalamocortical vestibular system in animals and humans[END_REF]. Moreover, spatial neglect is also an attentional disorder, which is described as being lateralized in right-sided lesions of white matter interesting the ventral attentional network [START_REF] Corbetta | Control of goal-directed and stimulus-driven attention in the brain[END_REF][START_REF] Doricchi | White matter (dis)connections and gray matter (dys)functions in visual neglect: Gaining insights into the brain networks of spatial awareness[END_REF][START_REF] Heilman | Right hemisphere dominance for attention: The mechanism underlying hemispheric asymmetries of inattention (neglect)[END_REF][START_REF] Lunven | Attention and spatial cognition: Neural and anatomical substrates of visual neglect[END_REF][START_REF] Mesulam | The functional anatomy and hemispheric specialization for directed attention: The role of the parietal lobe and its connectivity[END_REF]. Thus, isolated forms of neglect, that follow both right or left-sided stroke, might be due to a lesion disrupting the function of the remaining intact internal system of spatial cognition, a phenomenon known as diaschisis [START_REF] Feeney | Diaschisis[END_REF]. In left-sided stroke, it might also be due to a lesion involving a spatial network which is not dominant, with a compensatory mechanism in the right hemisphere [START_REF] Mesulam | The functional anatomy and hemispheric specialization for directed attention: The role of the parietal lobe and its connectivity[END_REF]. Recently, Doricchi proposed the hypothesis that functional disruption of different networks could be associated with different neglect signs. This could depend on selective lesions of different white matter fasciculi, on the localisation of the disconnection at different points along the same fasciculus and on the combination of these pathophysiological factors with damage of different cortical modules or efferents from these modules [START_REF] Doricchi | White matter (dis)connections and gray matter (dys)functions in visual neglect: Gaining insights into the brain networks of spatial awareness[END_REF]. Thereby, isolated BN and NBN might be due to slight lesions in white matter involved in spatial cognition.

Individuals with isolated BN tended to have more motor deficits than individuals with isolated NBN, while isolated NBN individuals tended to have more hemianopia than isolated BN individuals. Poor outcomes have been described before in right brain damaged patients, regardless of neglect domain [START_REF] Sterzi | Hemianopia, hemianaesthesia, and hemiplegia after right and left hemisphere damage. A hemispheric difference[END_REF]. This difference between domains could be explained by associated neglect disorders (hypokinesia, akinesia, motor neglect, motor impersistence, etc.) described before by Heilman [START_REF] Heilman | Neglect and Related Disorders[END_REF], and by the difference in clinical and anatomical mechanisms between BN and NBN. In fact, BN is more associated with body scheme disorders and is found in patients with lesions in the somatosensory cortex (supramarginal and post-central gyri), motor cortex and posterior supra temporal gyrus [START_REF] Committeri | Personal neglect: A comprehensive theoretical and anatomo-clinical review[END_REF][START_REF] Rousseaux | Neuroanatomy of space, body, and posture perception in patients with right hemisphere stroke[END_REF], while NBN is associated with lesions involving the frontal lobe (inferior precentral and medio-frontal gyri) and temporal lobe (anterior and middle supra temporal gyrus).

Correlations between neglect domains and lateropulsion, postural and gait disorders

Approximately a third of individuals showed lateropulsion, postural and gait disorders, which is consistent with previous studies [START_REF] Bergmann | Robot-assisted gait training to reduce pusher behavior[END_REF][START_REF] Krewer | Time Course and Influence of Pusher Behavior on Outcome in a Rehabilitation Setting: A Prospective Cohort Study[END_REF][START_REF] Perennou | Lateropulsion, pushing and verticality perception in hemisphere stroke: a causal relationship?[END_REF]. Some studies found an interaction between neglect and lateropulsion [START_REF] Karnath | The origin of contraversive pushing: Evidence for a second graviceptive system in humans[END_REF][START_REF] Dai | Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception[END_REF][START_REF] Perennou | Understanding the Pusher Behavior of Some Stroke Patients With Spatial Deficits: A Pilot Study[END_REF][START_REF] Vaes | Contraversive neglect? A modulation of visuospatial neglect in association with contraversive pushing[END_REF]. Two of these studies investigated neglect as NBN [START_REF] Karnath | The origin of contraversive pushing: Evidence for a second graviceptive system in humans[END_REF][START_REF] Vaes | Contraversive neglect? A modulation of visuospatial neglect in association with contraversive pushing[END_REF] and two explored both BN and NBN in a composite score [START_REF] Dai | Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception[END_REF][START_REF] Perennou | Understanding the Pusher Behavior of Some Stroke Patients With Spatial Deficits: A Pilot Study[END_REF]. Our study reveals that lateropulsion is explained by both BN and NBN, but is worse with NBN than with BN, and by the interaction between these domains.

One hypothesis is that lateropulsion could be a high-order disruption known as graviceptive neglect [START_REF] Dai | Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception[END_REF][START_REF] Perennou | Lateropulsion, pushing and verticality perception in hemisphere stroke: a causal relationship?[END_REF][START_REF] Perennou | Understanding the Pusher Behavior of Some Stroke Patients With Spatial Deficits: A Pilot Study[END_REF]. The gravity frame of reference is allocentric, as is the visual frame of reference, and is dependent of multi-sensory integration including otolith organs, tactile receptors, and proprioceptors [START_REF] Howard | Visually Induced Reorientation Illusions[END_REF]. Moreover, lateropulsion is composed of a body tilt, which is its cardinal sign, and a contralesional visual vertical bias [START_REF] Dai | Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception[END_REF]. We reinforced this hypothesis with a model in which lateropulsion was better explained by NBN, which encompasses a visual bias and an allocentric disorder. Thus, pushers might actively adjust their body posture to a subjective vertical which leans towards the contralesional side, as well as turn their visual exploration according to a subjective horizontal deviated to the ipsilateral side. Therefore, the active behaviour seen in patients with pusher syndrome, a severe form of lateropulsion, could be consistent with active and positive symptoms in the ipsilesional side in neglect patients [START_REF] Na | Motor perseverative behavior on a line cancellation task[END_REF]. These latter hypothesis could be consistent with the hypothesis of 3D maps as internal models, rather than just a mosaic of 2D representations [START_REF] Brandt Th | Vestibular cortex lesions affect the perception of verticality[END_REF][START_REF] Dai | Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception[END_REF], with biased horizontal and vertical perceptions. Furthermore, it's consistent with previous neural basis studies, which hypothesized that lateropulsion might be due to a lesion in the temporo-parietal junction [START_REF] Pérennou | The polymodal sensory cortex is crucial for controlling lateral postural stability: evidence from stroke patients[END_REF] or in the inferior parietal lobe [START_REF] Babyar | Lesion Localization of Poststroke Lateropulsion[END_REF]. In fact areas of allocentric integration, assessed by subjective visual vertical, overlapped with areas linked to lateropulsion, with lesions encompassing the parieto-insular vestibular cortex and the posterior part of the inferior parietal lobule [START_REF] Rousseaux | Neuroanatomy of space, body, and posture perception in patients with right hemisphere stroke[END_REF]. Another study evaluating allocentric and egocentric integration found that persistent allocentric neglect was associated with angular gyrus lesions. Persistent egocentric neglect was associated with the posterior section of the superior temporal gyrus, at the junction with and extending into the supramarginal gyrus [START_REF] Chechlacz | The Prognosis of Allocentric and Egocentric Neglect: Evidence from Clinical Scans[END_REF]. Both egocentric and allocentric neglect were associated with a lesion in the temporo parietal junction [START_REF] Chechlacz | The Prognosis of Allocentric and Egocentric Neglect: Evidence from Clinical Scans[END_REF]. Thus, lateropulsion could take its origin in the temporoparietal junction with an extension into the inferior parietal lobule.

Our findings suggest the possibility of reducing lateropulsion with interventions used for visuospatial neglect, such as prism adaptation. It was already known that prism adaptation reduced postural instability [START_REF] Tilikete | Prism adaptation to rightward optical deviation improves postural imbalance in left-hemiparetic patients[END_REF], probably because visual information is most relevant for postural disorders after hemispheric stroke [START_REF] Bonan | Reliance on visual information after stroke. Part I: balance on dynamic posturography[END_REF] and could bias the perception of gravity [START_REF] Howard | Visually Induced Reorientation Illusions[END_REF].

Moreover, two studies report that robot gait training seems to persistently reduce pusher behaviour, possibly by recalibrating the disturbed postural vertical reference, which is a clinical measure of the graviceptive reference frame [START_REF] Bergmann | Robot-assisted gait training to reduce pusher behavior[END_REF][START_REF] Krewer | Immediate effectiveness of singlesession therapeutic interventions in pusher behaviour. Gait Posture[END_REF]. Both recalibration of visual and postural vertical references could be used in rehabilitation [START_REF] Odin | Modulating the internal model of verticality by virtual reality and body-weight support walking: A pilot study[END_REF]. This highlights the complexity of lateropulsion, which encompasses a postural vertical and a visual vertical tilt [START_REF] Perennou | Lateropulsion, pushing and verticality perception in hemisphere stroke: a causal relationship?[END_REF], and in our study, a body and a non-body horizontal tilt.

Concerning postural disorders and gait disorders we found an independent and moderate correlation with both BN and NBN, and the interaction of both domains worsened the disorders.

Global neglect was already known to be a poor prognostic factor of gait recovery [START_REF] Kollen | Predicting Improvement in Gait After Stroke: A Longitudinal Prospective Study[END_REF], probably because of the interaction between both forms, while only visuospatial neglect was investigated in this study. A disturbed egocentric reference frame was found to be correlated with postural disorders in an upright position [START_REF] Barra | Asymmetric standing posture after stroke is related to a biased egocentric coordinate system[END_REF]. Interestingly this study didn't find any interaction between visual biases (i.e., allocentric reference frame) and postural disorders. Our findings bring a new insight, in which disturbed egocentric and allocentric reference frames decrease postural and gait abilities. This could be due to the association between lateropulsion, which is a form of neglect, and gait or balance disorders [START_REF] Dai | Balance, lateropulsion, and gait disorders in subacute stroke[END_REF][START_REF] Krewer | Time Course and Influence of Pusher Behavior on Outcome in a Rehabilitation Setting: A Prospective Cohort Study[END_REF]. Another study evaluating independent gait recovery found that both motor deficit and sitting trunk balance were predictors at 6-month post stroke [START_REF] Veerbeek | Is Accurate Prediction of Gait in Nonambulatory Stroke Patients Possible Within 72 Hours Poststroke?: The EPOS Study[END_REF]. Sitting trunk balance could also imply spatial cognition [START_REF] Pérennou | The polymodal sensory cortex is crucial for controlling lateral postural stability: evidence from stroke patients[END_REF].

Our study highlights the effect of BN, which is rarely evaluated [START_REF] Caggiano | The 'Neglected' Personal Neglect[END_REF], as a cause of postural and gait disorders, and its association with NBN (i.e., Transmodal neglect) which worsens them.

Thus, studies evaluating rehabilitation programs should include body neglect rehabilitation.

Predictive analyses

A battery of 4 tests for each domain was used to made predictive analysis on the presence or absence of upright stance, stable erect stance, and walking without human aid.

BN and NBN showed a strong negative predictive value for this endpoint, with moderate prevalence of neglect in our sample of patients (54% for BN and 37% for NBN). This is consistent with studies reporting that neglect plays a role in the recovery of an independent gait [START_REF] Geurts | A review of standing balance recovery from stroke[END_REF][START_REF] Laufer | Standing Balance and Functional Recovery of Patients with Right and Left Hemiparesis in the Early Stages of Rehabilitation[END_REF]. Thus, individuals who had less than 2 tests considered pathological in any form of neglect had a low probability of walking with human aid, of being unstable in an erect stance or of showing lateropulsion. Interestingly, negatives predictive values were similar between BN and NBN for lateropulsion. This could be because of loss of information due to use of categorical variables and because BN and NBN were partially included in Transmodal neglect.

That being said, a systematic battery of tests for both neglect domains could help clinical examinators to distinguished patients who are at risk of presenting postural and gait disorders at D30.

Limits of the study

The first limit of our study was the exclusion of many severe aphasic patients (n = 39), due to the limits of neglect assessments which require a minimal comprehension and participation. This limit is known and could partly explain the prevalence of right-sided stroke patients with neglect, because of the dominance for language skills in the left-sided hemisphere [START_REF] Tzourio-Mazoyer | Multi-factorial modulation of hemispheric specialization and plasticity for language in healthy and pathological conditions: A review[END_REF].

However a previous study showed that, even if the prevalence of neglect was balanced between both hemispheres, left-sided stroke patients are less severe than right-sided [START_REF] Suchan | Neglect severity after left and right brain damage[END_REF]. Moreover, in our study we report some isolated left-sided stroke patients with BN or NBN, but the interaction of both was mostly found in right-sided stroke patients.

Composite scores were rated by omission tests, which were at risk of including some attentional disorders, principally for the Bell test [START_REF] Suchan | Neglect severity after left and right brain damage[END_REF]. This choice was made so as to give the same dimension to all tests, before aggregating them by indicators average. Then we chose to assess BN and NBN as principally and respectively personal tests and peripersonal tests. We didn't use tests specifically made for allocentric or egocentric neglect [START_REF] Rorden | Allocentric neglect strongly associated with egocentric neglect[END_REF][START_REF] Marsh | Dissociation between egocentric and allocentric visuospatial and tactile neglect in acute stroke[END_REF], which limits interpretation of NBN as an allocentric reference frame test. Furthermore, clinical and anatomical mechanisms of BN or NBN and egocentric or allocentric neglect do not strictly overlap [START_REF] Committeri | Neural bases of personal and extrapersonal neglect in humans[END_REF][START_REF] Rorden | Allocentric neglect strongly associated with egocentric neglect[END_REF][START_REF] Vallar | A fronto-parietal system for computing the egocentric spatial frame of reference in humans[END_REF][START_REF] Rousseaux | Neuroanatomy of space, body, and posture perception in patients with right hemisphere stroke[END_REF][START_REF] Chechlacz | The Prognosis of Allocentric and Egocentric Neglect: Evidence from Clinical Scans[END_REF].

Missing data were replaced with substituted values, using a multiple imputation for neglect assessments. As the replaced data were not dependent variables and the missing values counted for 5 to 40% of the sample size and were "missing at random", multiple imputation was a better method than complete case analysis [START_REF] Jakobsen | When and how should multiple imputation be used for handling missing data in randomised clinical trials -a practical guide with flowcharts[END_REF].

Considering multiple regression analysis, the strong correlation between BN and NBN could induce statistical biases due to multicollinearity, which could affect the interpretation of individual predictors. In our study, the principal outcome was to assess if BN or NBN were predictors of lateropulsion, balance or gait disorders, and we had to include both variables in the model. However, as we already discussed, BN and NBN were not exactly correlated, and partial correlation presented the same results as multiple regression with the specific portion of variance explained by eliminating the effect of the other variable [START_REF] Kim | ppcor: An R Package for a Fast Calculation to Semi-partial Correlation Coefficients[END_REF].

Conclusion

Our study confirms that body and non-body neglect are two dissociated forms of neglect which must be individualized. They may appear in isolation or be associated, for right and left hemisphere stroke, with a right predominance. Transmodal spatial neglect (BN+NBN) was overall found after right-hemisphere stroke, with more severe signs of spatial neglect. Nonbody neglect magnified lateropulsion more than body neglect. This means that impaired body orientation with respect to gravity (lateropulsion) depends more on the allocentric frame of spatial neglect than on the egocentric one. Both domains worsened postural and gait disorders, with a positive interaction. Therefore, postural and gait disorders are better explained with two spatial neglect domains than only one. In addition, a limited number of abnormal neglect tests (< 2) had a strong negative predictive value on the existence of impaired body orientation with respect to gravity, balance and abilities in daily life. This study confirms our hypothesis that both BN and NBN must be assessed in routine, and not only NBN as usually performed. It reveals the link between NBN and lateropulsion, whereas balance and gait were associated to both forms, NBN again referring to an allocentric frame and BN referring to the body schema.

Tables

  corporelles et extracorporelles de la négligence sur l'équilibre après un AVC en phase subaiguë THÈSE PRÉSENTÉE POUR L'OBTENTION DU TITRE DE DOCTEUR EN MÉDECINE DIPLÔME D'ÉTAT Jean BERTRAND THÈSE SOUTENUE PUBLIQUEMENT À LA FACULTÉ DE MÉDECINE DE GRENOBLE Le: 02/04/2021 DEVANT LE JURY COMPOSÉ DE Président du jury: Monsieur le Professeur Dominic PERENNOU, PUPH Institut de Rééducation CHU Grenoble Alpes Membres du jury: Madame la Professeure Monica BACIU Monsieur le Professeur Marc HOMMEL Monsieur le Maître de Conférence David GASQ Madame le Docteur Anne CHRISPIN

  Professeur Monica Baciu, pour m'avoir accepté dans son laboratoire et m'avoir soutenu dans mon master de recherche, pour avoir très gentiment accepté d'être membre de mon jury de thèse. Au Professeur Marc Hommel et au Dr David Gasq, pour avoir très gentiment acceptés d'être membres de mon jury de thèse. Au Dr Anne Chrispin, pour m'avoir transmis sa rigueur et son sens clinique dans la prise en charge rééducative de l'AVC, pour toute sa bienveillance, et pour avoir très gentiment accepté d'être membre de mon jury de thèse. A Louis Dai, pour tout son travail initial sur les données, pour ses conseils et ses interventions statistiques, et pour son aide précieuse sur ma thèse. A Rémi Lafitte, pour avoir donné un temps considérable à des itératives réunions zoom afin de m'aider au mieux dans ma thèse. A Céline Piscicelli, pour avoir transmis son savoir sur la négligence. A l'équipe d'Aix les Bains et plus particulièrement aux Drs Lamotte, Cantalloube et Grange pour leurs accueils en début et en fin d'internat, pour m'avoir transmis leurs nombreuses connaissances, pour leur soutien, et pour leur chaleureuse bienveillance. A mes professeurs de contrebasse, Jean Marie Verne et Patrick Lauvernet, à qui je dois ce goût du travail, tous les deux partis trop tôt et qui auraient surement aimé être présents ce jour. A Christophe Rulh, pour tes cours sur l'épaule et le bassin, pour la transmission de ton savoir sur la vie, et pour tes conseils littéraires. Au Pr Detante, pour ses débats parfois plus philosophiques que médicaux, pour ses conseils sur la vie et sur la médecine, et pour la transmission de toutes ses connaissances cliniques et scientifiques. Merci également aux neurologues du CHU, tous toujours bienveillants et riches autant humainement que cliniquement. Au Dr Bourg, pour son apprentissage clinique et plus particulièrement pour les comptines, un savoir nécessaire en rééducation pédiatrique. A Rémi Gimat, pour son soutien inconditionnel, pour sa gentillesse, pour ses précieux conseils, distillés et vieillis en fût de chêne. A Adélie et Ophélie, pour avoir partagé nos difficultés dans le master. Tout était bien parti, et puis la quiche est tombée par terre, la sncf s'est mise en grève… Merci à toutes les deux pour votre soutien, pour vos relectures, pour avoir été toujours présentes et pour avoir tenu jusqu'au bout. A Loïc et Pomme, pour avoir partagé ces 3 mois intenses (pour moi) en neurologie vasculaire et pour votre bonne humeur au milieu des thrombolyses et thrombectomies. A Gauthier et Florent, l'amicale du welsh, pour m'avoir fait goûter un plat exquis. A Lucie, Hélène, Adeline, amies indéfectibles. Merci pour votre présence et pour tous ces moments partagés tout au long de ces années.

  Résumé .................................................................................................................................................... Abstract ................................................................................................................................................... Mes très sincères remerciements ........................................................................................................... Introduction ........................................................................................................................................... Method .................................................................................................................................................. Study design ...................................................................................................................................... Protocol approvals, registrations, and patient consents .................................................................. Participants ........................................................................................................................................ Neglect assessments .........................................................................................................................

Functional

  outcomes were evaluated by occupational therapist with the Functional Independence Measure (FIM), which assesses six areas of function (Self-care, Sphincter control, Transfers, Locomotion, Communication and Social cognition) Stroke severity was evaluated by the National Institutes of Health Stroke Scale (NIHSS), assessed in the intensive stroke unit at entry.

  figures 2 A, B, C. Their transformed Gaussian distributions are displayed in figures 2 D, E, F.

FiguresFigure 1 :

 1 Figures

Figure 2 :Figure 3 :

 23 Figure 2: Histogram of Body, Non body neglect and Global neglect scores.

  Lateropulsion, balance and gait disorder assessment ...................................................................... Other clinical characteristics ............................................................................................................. Statistics ............................................................................................................................................ Results ................................................................................................................................................... Participants ........................................................................................................................................ Missing data ...................................................................................................................................... Spatial neglect ................................................................................................................................... Postural and gait disorders ................................................................................................................ Relationship between spatial neglect and lateropulsion .................................................................. Predictive analyses ........................................................................................................................ Relationship between spatial neglect and balance disorders ........................................................... Correlations analyses..................................................................................................................... Predictive analyses ........................................................................................................................ Relationship between spatial neglect and gait disorders ................................................................. Correlations analyses..................................................................................................................... Predictive analyses ........................................................................................................................ Discussion .............................................................................................................................................. Statistical analyses ............................................................................................................................. Spatial neglect ................................................................................................................................... Correlations between BN and NBN and lateropulsion, postural and gait disorders ........................ Predictive analyses ............................................................................................................................ Limits of the study ............................................................................................................................. Conclusion ............................................................................................................................................. Tables .................................................................................................................................................... Figures ...................................................................................................................................................

	Correlations analyses.....................................................................................................................

Table 1 : Missing values before multiple imputation Summary of variables ,b

 1

		Missing		N valid	Mean	Sd
	N	Percent
	BN score	66	34,4%	126	16,4252	14,65312
	Fluff test	58	30,2%	134	2,63	3,446
	NBN score	49	25,5%	143	11,2816	17,86170
	Reading test	42	21,9%	150	7,19	21,752
	Apraxia	11	5,7%	181	10,62	2,367
	Motor command	9	4,7%	183	28,06	11,865
	Spasticity	7	3,6%	185	1,54	2,452
	ECB BN	6	3,1%	186	3,228	3,2470
	ECB NBN	6	3,1%	186	2,120	3,0237
	FIM	5	2,6%	187	88,78	27,426
	Hypoesthesia	3	1,6%	189
	HLH	2	1,0%	190
	Bisiach	2	1,0%	190	,27	,608
	Bell Test	1	0,5%	191	6,54	8,222
	Aphasia	0	0,0%	192
	Delay	0	0,0%	192	35,10	12,821
	Comb Razor test	0	0,0%	192	10,7839	21,75225
	Gainotti	0	0,0%	192	,336	,9025
	Independent Gait	0	0,0%	192
	mFMA	0	0,0%	192	3,53	2,253
	SCP	0	0,0%	192	1,0104	1,78157
	Single Limb Stance	0	0,0%	192
	PASS	0	0,0%	192	28,00	9,262
	Edinburgh	0	0,0%	192	,7669	,56871
	Stroke Side	0	0,0%	192
	a. Maximal number of variables displayed : 25
	b. Minimum percentage of missing values to include for the variable: 0,0%

Hypoesthesia (0 -3)

Additional materials

The postural assessment scale for stroke (PASS)

The modified Fugl-Meyer Assessment for gait (mFMA)

The Scale for contraversive pushing (SCP)

Non-body Neglect assessments A B

Body neglect assessments

The fluff test with the distribution of post it on the body

Ecological neglect assessment

Ecological Catherine Bergego Scale with 10 items