MSc Fiora Martinelli
email: mfiora13@gmail.com

PHD Céline Perez

PHD Florent Caetta
email: f.caetta@gmail.com

MD Michaël Obadia
email: mobadia@for.paris

MD Julien Savatovsky
email: jsavatovsky@gmail.com

PHD Sylvie Chokron
email: sylvie.chokron@gmail.com

NEUROANATOMIC CORRELATES OF VISUAL HALLUCINATIONS IN POST-STROKE HEMIANOPIC PATIENTS

Keywords: Hemianopia, Visual Hallucinations, Stroke, Occipital, Temporal

Homonymous hemianopia (HH) is the most frequent visual-field defect after a stroke. Some of these patients also suffer from visual hallucinations which origin and frequency remain largely unknown.

Objectives:

(1) Determine the occurrence of visual hallucinations among post-stroke hemianopic patients in function of the location (Brodmann areas) of the brain lesion, as determined by MRI. (2) Study the neuroanatomic correlates of these hallucinations by nature, frequency and type.

Methods: 116 HH patients that had suffered a stroke in the posterior region, including the occipital lobe participated in the study. We evaluated the frequency and nature of visual hallucinations with the Q3H questionnaire. The volume of each patient's brain lesion was modeled in 3D.

Results:

Of 116 patients with a homonymous hemianopia from a cortical infarction, 85 were excluded due to confounding factors associated with hallucinations. In the final cohort of 31 patients, matched for lesion location and etiology, 58% had experienced hallucinations. A significant inverse correlation between lesion size and the frequency of visual hallucinations emerged. The presence of visual hallucinations in post-stroke hemianopic patients requires a relatively small lesion that includes, at the very least, loss of the striate cortex, but that spares BA19, BA20 and BA37.

Conclusion:

Our results suggest that visual hallucinations might be due to complex interactions between damaged areas and intact areas of the visual cortex. We discuss these findings regarding models of perception and of visual recognition. Our results also have implications for clinical care of HH patients that have suffered a stroke.

INTRODUCTION

Homonymous hemianopia (HH) is the most frequent clinical manifestation of visual-field defects following a retrochiasmatic lesion. [START_REF] Holmes | Disturbances of vision by cerebral lesions[END_REF][START_REF] Pambakian | Can visual function be restored in patients with homonymous hemianopia?[END_REF] Apart from implicit visual capabilities defined as blindsight [START_REF] Pöppel | Residual Visual Function after Brain Wounds involving the Central Visual Pathways in Man[END_REF][START_REF] Weiskrantz | Visual capacity in the hemianopic field following a restricted occipital ablation[END_REF] , hemianopic patients can also experience simple or complex visual hallucinations in their blind contralesional visual field [START_REF] Seguin | A clinical study of lateral hemianopsia[END_REF][START_REF] Chokron | Behavioral Consequences and Cortical Reorganization in Homonymous Hemianopia[END_REF] typically defined as the perception of objects or scenes in the absence of external stimuli [START_REF] Ey | Traité des hallucinations[END_REF][START_REF] Blom | A dictionary of hallucinations[END_REF] . They can accompany diverse psychiatric and neurologic pathologies [START_REF] Collerton | The neuroscience of visual hallucinations[END_REF][START_REF] Yoshida | Complex visual hallucination and mirror sign in posterior cortical atrophy[END_REF] as well as ophthalmologic disorders. Charles Bonnet Syndrome (CBS) is thus defined as an association between a decrease in visual acuity and the onset of visual hallucinations. [START_REF] Teunisse | Visual hallucinations in psychologically normal people: Charles Bonnet's Syndrome[END_REF] However, hemianopic patients are sometimes mixed in with patients suffering from ophthalmologic deficits and CBS. [START_REF] Franke | Challenges of diagnosing and treating Charles Bonnet syndrome[END_REF][START_REF] Mcnamara | Visual hallucinations in blindness: the Charles Bonnet syndrome[END_REF][START_REF] Dodd | Visual hallucinations associated with Charles Bonnet Syndrome : an ever increasing diagnosis[END_REF] Visual hallucinations have been mostly reported in patients with cortical blindness [START_REF] Wunderlich | Visual hallucinations in recovery from cortical blindness: Imaging correlates[END_REF] , occasionally in hemianopia [START_REF] Penfield | Epilepsy and the functional anatomy of the human brain[END_REF] and in epileptic patients. [START_REF] Manford | Complex visual hallucinations. Clinical and neurobiological insights[END_REF][START_REF] Boyer | Rare and rarer: co-occurrence of stroke-like migraine attacks after radiation therapy and Charles Bonnet syndromes[END_REF] Winton-Brown et al. [START_REF] Winton-Brown | Distinguishing neuroimaging features in patients presenting with visual hallucinations[END_REF] proposed that visual hallucinations occur either by deafferentation in the retino-geniculo-striate pathway 20,[START_REF] Burke | The neural basis of Charles Bonnet hallucinations: a hypothesis[END_REF] or by suppression of regulatory inhibition in the ascending pathways [START_REF] Abrams | Anatomic and functional topography of the dorsal raphe nucleus[END_REF] or finally through a defect in the thalamo-cortical loops. [START_REF] Grieve | The primate pulvinar nuclei: vision and action[END_REF] According to neuroimaging studies 24,25, complex visual hallucinations (faces and objects) are associated to heightened activity in the occipital cortex suggesting that they can be caused by a lesion of the occipital and parietal lobes. [START_REF] Wunderlich | Visual hallucinations in recovery from cortical blindness: Imaging correlates[END_REF][START_REF] Kölmel | Complex visual hallucinations in the hemianopic field[END_REF] Visual hallucinations in hemianopic patients have been reported mostly in case studies [START_REF] Seguin | A clinical study of lateral hemianopsia[END_REF][START_REF] Franke | Challenges of diagnosing and treating Charles Bonnet syndrome[END_REF][START_REF] Boyer | Rare and rarer: co-occurrence of stroke-like migraine attacks after radiation therapy and Charles Bonnet syndromes[END_REF][START_REF] Michel | Palinopsia cerebral localization with computed tomography[END_REF][START_REF] Mancusa | Visual manifestations of occipital lobe infarction in three patients on a geriatric psychiatry unit[END_REF][START_REF] Benson | Formed hallucination in the hemianopic field[END_REF][START_REF] Anderson | Hallucinations following occipital lobe damage: the pathological activation of visual representations[END_REF][START_REF] Vaphiades | Positive spontaneous visual phenomena limited to the hemianopic field in lesions of central visual pathways[END_REF][START_REF] Kasten | Chronic visual hallucinations and illusions following brain lesions. A single case study[END_REF][START_REF] Cole | When the left brain is not right the right brain may be left: report of personal experience of occipital hemianopia[END_REF][START_REF] Beniczky | Complex hallucinations following occipital lobe damage[END_REF] , which unfortunately do not enable assessment of their frequency or neuroanatomic bases.

Our objective was to assess the neuroanatomic bases of visual hallucinations in a cohort of poststroke hemianopic patients, in function of lesion side and location (i.e. Brodmann area).

MATERIALS & METHODS

Participants

One-hundred-and-sixteen post-stroke HH patients whose stroke involved the posterior cerebral artery were originally considered for inclusion in the study. The patients ranged in age from 21 years to 92 years old (mean: 58.19 years ± 16.97 years) and were divided equally by lesion side (58 left HH and 58 right HH). Using the Q3H questionnaire (Questionnaire for Hallucinations in Homonymous Hemianopia) [START_REF] Perez | Hémianopsie latérale homonyme : amputation du champ visuel, perception implicite et hallucinations visuelles[END_REF] specifically designed to ascertain the frequency and nature of visual hallucinations, we interviewed these patients to assess their possible experiences with visual hallucinations. [START_REF] Chokron | Behavioral Consequences and Cortical Reorganization in Homonymous Hemianopia[END_REF] Among the 116 patients, 48 had experienced visual hallucinations (26 left HH and 22 right HH) and 68 had not (32 left HH and 36 right HH). However, to obtain a homogenous study cohort from the initial one of 116 patients, we excluded those patients (n=85) that had diencephalic or frontal lesions as these had already been shown to be sufficient to cause visual hallucinations [START_REF] Vaphiades | Positive spontaneous visual phenomena limited to the hemianopic field in lesions of central visual pathways[END_REF][START_REF] Kasten | Chronic visual hallucinations and illusions following brain lesions. A single case study[END_REF][START_REF] Cole | When the left brain is not right the right brain may be left: report of personal experience of occipital hemianopia[END_REF][START_REF] Beniczky | Complex hallucinations following occipital lobe damage[END_REF][START_REF] Perneczky | Cerebral metabolic dysfunction in patients with dementia with Lewy bodies and visual hallucinations[END_REF] as well as those who underwent medical treatment or had already presented with positive visual phenomena before the stroke. Application of these exclusion criteria to the initial cohort of 116 patients yielded a final cohort of 31 patients (11 women; 35%), ranging in age from 24 years to 88 years old (mean: 57.03 years ± 17.80 years), all of whom had exhibited HH following a unilateral stroke affecting the occipital lobe (28 ischemic strokes and 3 hemorrhagic strokes) and all of whom were right-handed. These 31 patients were divided into two groups: those who experienced visual hallucinations (n = 18; 8 right HH and 10 left HH) and those who did not (n = 13; 5 right HH and 8 left HH). Each patient's HH was evaluated by visualfield testing (Figure 1 A), either automated (Humphrey) or manual (Goldmann). All patients had normal visual acuity (corrected or uncorrected), did not exhibit any neuropsychological impairments and had not previously experienced any neurologic or troubles, other than their stroke. Relevant to the present study, no patient in the experimental group presented any sign of psychiatric disorder or delirium. This research was approved by the local ethical committee and patients gave their consent to participate in the study.

For lesion reconstruction, MRI images were acquired on a Philips 3 Tesla unit, in the 3D FLAIR (Fluid-Attenuated Inversion Recovery) 8000 sequence (Time to repetition: 8000 ms; Echo time: 365 ms; Matrix size: 240 x 243 pixels; Reconstruction size: 240 x 243 pixels; Field of view: 240 x 240 mm; Flip angle: 90°; Voxel size range: from 0.9 mm to 1.25 mm). Anatomic slices (Figure 1B) were recovered in DICOM format for subsequent 3D visualization using OsiriX Medical Imaging software (OsiriX MD, Pixmeo, Genava, Switzerland). The lesion contours were manually delineated in each 2D slice, thereby enabling reconstruction of a volume of interest (VOI; in cm 3 ). To determine the anatomic extent of the lesions, each damaged Brodmann area was individually identified with the help of Brain Voyager software (Brain Innovation, Maastricht, The Netherlands) and checked by a neuroradiologist.

/Insert Figure 1/ 2. Q3H (Questionnaire for Hallucinations in Homonymous Hemianopia [START_REF] Chokron | Behavioral Consequences and Cortical Reorganization in Homonymous Hemianopia[END_REF][START_REF] Perez | Hémianopsie latérale homonyme : amputation du champ visuel, perception implicite et hallucinations visuelles[END_REF] Visual hallucinations in hemianopic patients have not been systematically researched perhaps, in part, because there is a lack of specific and standardized questionnaire that could be easily used by practitioners. Recognizing this need, our group has developed such a questionnaire for hemianopic patients and more generally, for patients with cortical visual impairment, which was named the Questionnaire for Hallucinations in Homonymous Hemianopia Patients (abbreviated as the "Q3H" questionnaire) [START_REF] Perez | Hémianopsie latérale homonyme : amputation du champ visuel, perception implicite et hallucinations visuelles[END_REF] . For a given patient, this questionnaire enables characterization of their hallucinations (i.e. type, frequency, etc.), including determining the extent to which they are aware of the phenomenon.

Data Analysis

Difference between groups was assessed using Mann-Whitney U test. The degree of association between visual hallucinations (presence/absence) and lesions in Brodmann areas (extent of lesions or presence/absence) was measured with the point biserial and phi coefficients.

Data statement availability:

The present behavioural and neuroimaging data are available.

RESULTS 1 Questionnaire for Hallucinations in Homonymous Hemianopia (Q3H)

Only one of the 18 patients with hallucinations reported a hallucinatory episode; for all other patients, hallucinations were perceived several times at different times. For 67% of patients, hallucinations were often or very often perceived. Hallucinations lasted from a few seconds to a few minutes in 50% of patients, while they lasted more than 5 minutes in 11% of patients and were perceived continuously in 39% of patients. With respect to critical judgment, 33% of hemianoptic patients believed that their hallucinations were true perceptions, while 67% could criticize them. For all hemianoptic patients (100%), visual hallucinations have always appeared in the blind controlesional visual field, with no temporal regularity. For 78% of patients, visual hallucinations were simple perceptions (lights) while they were complex for 22% of patients (objects, shapes, people). 67% of patients reported hallucinations that were always the same, while 28% of patients reported the same forms with some variations. In only 6% of cases, the hallucinations varied over time. For 94% of patients, hallucinations were grey (like shadows) and colored for only 6% of patients. For 92% of patients, movement was associated with hallucination, while it was a static perception for 18% of patients. For most patients (67%), hallucinations were considered neutral or pleasant, while in 33% of cases, they were perceived as frightening. Finally, for 22% of patients, there were strong similarities between hallucination and a dream, and for 39% of patients these perceptions were quite similar to mental imagery.

A correlation between the items was performed and showed that the frequency of visual hallucinations is positively correlated with their duration (rsp=0.63; p <.01). Considering the responses to Q3H by lesion side, patients with right HH (left brain-damaged patients) reported greater variability in their hallucinations (U = 18, p <0.05) and less similarity to a real visual experience (U=63; p <0.05) than patients with left HH (roght brain-damaged).

Neuro-anatomical correlates of visual hallucinations in hemianopic patients

Neuroanatomic analysis of the lesions in the study cohort of 31 patients revealed a significant inverse correlation between lesion size and the occurrence of visual hallucinations (rpb = 0.47; p<0.1). Thus, the mean lesion volume was significantly smaller (U=54; p<.05) among the eighteen patients that experienced visual hallucinations (Mdn= 9.46; m = 14.11 cm 3 , sd = 12.59 cm 3 ) than among the thirteen patients that had not experienced hallucinations (Mdn= 27.93; m=37.02 cm 3 ; sd = 30.34 cm 3 ).

/Insert Figure 2/ 1.1. Visual hallucinations: relationship to damage in Brodmann areas (BA)

The occurrence of visual hallucinations was significantly linked to the presence or absence of damage in specific Brodmann areas. For example, in all eighteen (100%) of the patients that had experienced hallucinations, BA20 was spared (p = 0.023; ϕ = -0.453); and in sixteen (89%) of these patients, BA37 was spared (p = 0.002; ϕ = -0.599). Contrariwise, in all of the thirteen patients that did not experience hallucinations (100%), BA19 was damaged (p = 0.003; ϕ = -0.544) (Figure 2).

/Insert Figure 3/

Among the eighteen patients that had experienced visual hallucinations, all (100%) of them had suffered an occipital lesion and nine (50%) of them exhibited the same exact lesion profile, in which BA17 and BA18 were both damaged but BA19, BA20 and BA37-39 were all spared.

Likewise, the second most frequent lesion profile among these patients, found in six (33%) of them, was that of damage to BA17-19. Interestingly, among the patients that had not experienced hallucinations, six (46%) had a lesion encompassing BA17-19 and BA37. Finally, the presence of a temporal lesion correlated significantly to the absence of visual hallucinations (p < 0.001; ϕ = -0.87). In other words, it seems that for visual hallucinations to occur, the temporal lobe must remain intact. Indeed, sixteen (89%) of the patients that experienced hallucinations did not have a temporal lesion, whereas all (100%) of the thirteen patients that did not experience hallucinations did have a temporal lesion (BA 20, BA 37 or BA 38).

Unfortunately, as presented in Table 1, only two patients with visual hallucinations were proposed an EEG. However, interestingly, in these two patients, the EEG recording was perfectly normal.

DISCUSSION

Previous groups reported only a minor occurrence of visual hallucinations among HH patients, ranging from 2.4% 30 to 15% [START_REF] Kölmel | Complex visual hallucinations in the hemianopic field[END_REF] . In contrast to those findings, in the present study we found that 41% of our initially considered study population of post-stroke HH patients and 58% of our study cohort had experienced hallucinations. The incongruence between previous findings and our own is most likely due to the strict inclusion and exclusion criteria that we used, especially in terms of lesion location and etiology, as well as to the specificity of the Q3H questionnaire. In a study on patients with visual defects unrelated to any ocular pathology, Menon et al. [START_REF] Menon | Complex visual hallucinations in the visually impaired : A structured historytaking approach[END_REF] affirmed that 63% of patients that had been asked about visual hallucinations reported having experienced them, whereas none of them had spontaneously admitted to having experienced hallucinations and only 7% of them alluded to hallucinations on an indirect questionnaire. Crucially, the occurrence of visual hallucinations among HH patients can frequently be underestimated due to the anxiety that they cause patients: not only due to the social stigmas attached to hallucinations, but also because patients may simply be unaware that perceptions in their blind visual field are actually hallucinatory. Indeed, patients consider perceptions in their contralesional visual field to be a sign of restoration of their visual function. Accordingly, only when using another sensory function (e.g. touch) to assess the perception, do they realize that they are actually hallucinating.

The difficulty with which patients become cognizant of their hallucinations most certainly explains why so few patients complain about this issue and why so few clinicians seem interested in it.

Neuroanatomic correlates and neurophysiologic mechanisms underlying visual hallucinations in hemianopic patients

Neuroanatomic analysis revealed a significant inverse correlation between lesion size and the occurence of visual hallucinations. As a matter of fact, based on a highly accurate lesion study, our results suggest that the occurrence of visual hallucinations in post-stroke hemianopic patients requires a relatively small lesion that includes, at the very least, loss of the striate cortex, but that spares BA19, B20 and B37. Nevertheless, although the question of lesion volume has been addressed in previous studies [START_REF] Manford | Complex visual hallucinations. Clinical and neurobiological insights[END_REF] , to date, researchers had attributed the occurrence of visual hallucinations to the presence of the lesion but had scarcely studied the potential influence of damage to specific brain areas. Given that BA19, BA20 and BA37, which are located at the beginning of the ventral pathway, are directly connected to the primary visual cortex and to the temporal lobe, and consequently, to construction of perception of place [START_REF] Foerster | The cerebral cortex in man[END_REF] , the idea that they are required for occurrence of visual hallucinations makes sense.

Our results confirm the findings of earlier case studies that reported visual hallucinations among hemianopic patients who suffered lesions that were either limited to the occipital lobe [START_REF] Michel | Palinopsia cerebral localization with computed tomography[END_REF][START_REF] Mancusa | Visual manifestations of occipital lobe infarction in three patients on a geriatric psychiatry unit[END_REF][START_REF] Benson | Formed hallucination in the hemianopic field[END_REF][START_REF] Anderson | Hallucinations following occipital lobe damage: the pathological activation of visual representations[END_REF][START_REF] Vaphiades | Positive spontaneous visual phenomena limited to the hemianopic field in lesions of central visual pathways[END_REF][START_REF] Kasten | Chronic visual hallucinations and illusions following brain lesions. A single case study[END_REF][START_REF] Cole | When the left brain is not right the right brain may be left: report of personal experience of occipital hemianopia[END_REF][START_REF] Beniczky | Complex hallucinations following occipital lobe damage[END_REF] or that affected the occipito-parietal lobe. [START_REF] Kölmel | Complex visual hallucinations in the hemianopic field[END_REF][START_REF] Critchley | Types of visual perseveration: palinopsia and illusory visual spread[END_REF][START_REF] Lance | Simple formed hallucinations confined to the area of a specific visual field defect[END_REF] Moreover, the present findings are further corroborated by several f-MRI studies that revealed activation of the occipital and temporal cortices during visual hallucinations. [START_REF] Ffytche | The anatomy of conscious vision: an fMRI study of visual hallucinations[END_REF][START_REF] Ffytche | The hodology of hallucinations[END_REF] The mechanisms underlying the origin of visual hallucinations among hemianopic patients may be linked to perturbation of cortico-thalamic projections after an occipital lesion, as well as to activation of the adjacent visual association cortex, which would generate percepts. [START_REF] Rushmore | Functional impact of primary visual cortex deactivation on subcortical target structures in the thalamus and midbrain[END_REF] Visual hallucinations would then result from deafferentation due to a loss of cortico-cortical input between the damaged striate cortex and the spared areas of the ventral pathway. The occurrence of visual hallucinations suggests pathologic activation of the feedback signaling from the associated visual areas adjacent to the damaged striate cortex [START_REF] Vaphiades | Positive spontaneous visual phenomena limited to the hemianopic field in lesions of central visual pathways[END_REF][START_REF] Cole | When the left brain is not right the right brain may be left: report of personal experience of occipital hemianopia[END_REF] , where the neurons, once deprived of their cortical afferent signals, would be more likely to spontaneously fire. [START_REF] Lance | Simple formed hallucinations confined to the area of a specific visual field defect[END_REF] Studies on visual hallucinations in hemianopic patients should be based on a larger patient cohort and should incorporate functional neuroimaging to enable better identification of the underlying neuroanatomy and neurophysiologic mechanisms. We should also improve our understanding of the mechanisms that underpin visual hallucinations in HH to enable improved clinical care of these patients.

Figures Legend

Figure 1 :

 1 Figure 1 : Visual-field plot and stroke lesions for four patients

Figure 2 :

 2 Figure 2 : Brodmann area damage and visual hallucinations

Figure 3 :

 3 Figure 3 : Lesion reconstruction in patients with (3A) or without (3B) visual hallucinations

Acknowledgments: This study was approved by the Ethical Committee of the Fondation Ophtalmologique Adolphe de Rothschild.


PhD Sylvie Chokron
email: sylvie.chokron@gmail.com

PhD Carole Peyrin

PhD Céline Perez

Carlo Marzi

Petra Stoerig

Guido Gainotti

Ian Roberstson

M Rizzo

Ipsilesional Deficit of Selective Attention in Left homonymous hemianopia and Left Unilateral spatial

Keywords: Homonymous hemianopia, Unilateral spatial neglect, sighblindness, hemispheric specialization, selective attention Homonymous hemianopia, Unilateral spatial neglect, sighblindness, hemispheric specialization, selective attention

Aims. Patients with homonymous hemianopia may present a subtle ipsilesional deficit, recently referred to as 'sightblindness' in addition to the contralesional visual field defect. We recently demonstrated that this deficit could be worse in right brain-damaged patients with left hemianopia than in left brain-damaged patients with right hemianopia, confirming right hemisphere dominance for visuo-spatial and attentional capacities. In the present study we investigate whether this ipsilesional deficit could be attentional in nature and to what extent it is comparable in right brain-damaged (RBD) patients with left hemianopia and in RBD patients with left neglect. The study was also conducted in RBD patients with neither left hemianopia nor left neglect signs in order to test if a right hemisphere lesion per se could be responsible for subtle ipsilesional attentional deficit. To reach this aim, we tested selective attentional capacities in both visual fields of 10 right brain-damaged patients with left neglect (LN), 8 right braindamaged patients with left homonymous hemianopia (LHH), 8 right braindamaged patients with no signs of left neglect or left hemianopia (RBD controls), and 17 healthy age-matched participants (Normal controls). Method. A lateralized letter-detection task was used to test if rightbrain damaged patients with LN or LH may present a deficit of selective attention in their right, ipsilesional visual field, in comparison to Normal and RBD controls. Participants were asked to detect a target letter in either a single large stimulus (low attentional load) or a small stimulus surrounded by flankers (high attentional load). Stimuli were displayed either in the left or in the right visual field. Accuracy and reaction times were recorded. Results. Results on accuracy showed that both LN and LH patients exhibited lower correct responses than Normal controls in their ipsilesional right visual field, suggesting an attentional deficit in their ipsilesional, supposed healthy visual field. More specifically, LH patients exhibited a specific deficit for processing single large stimuli, but not for processing flanked stimuli, relative to normal controls. LN patients exhibited lower correct responses for processing all types of stimulus than normal controls, but also than right brain damaged controls, in both visual fields suggesting a non-lateralized deficit not only due to the right hemisphere lesion. Furthermore, this deficit is more pronounced for flanked small stimuli, requiring higher attentional load. Conclusions The present results bring further evidence that patients with left homonymous hemianopia or left unilateral neglect both present a weaker but significant ipsilesional deficit in addition to their wellknown massive contralesional deficit. The presence of a specific attentional deficit in the right ipsilesional visual field of left hemianopic and left neglect patients is discussed regarding the hypothesis of hemispheric specialization for selective spatial attention and may have clinical implications for both conditions.

Reviewer #1: Authors responded to all my comments and now the paper is ready to be published.

We are glad the reviewer considers that the the paper is ready to published.

Reviewer #2: Chokron and colleagues submitted a study on patients with neglect and hemianopia to investigate the presence of additional ipsilesional deficits (sight-blindness) and their putative attentional nature. A lateralized letter section task is used, with low or high attentional load and in either left or right visual field. Accuracy and reaction times show that right-hemisphere damaged patients with neglect and/or hemianopia have lower accuracy for ipsilesional targets. It is concluded that patients with left homonymous hemianopia or left unilateral neglect both present a weaker but significant ipsilesional deficit in addition to their well-known massive contralesional deficit.

The study is interesting and well-written, generally well performed. Analyses are (now) sound, and the topic clearly fits well with the special issue honoring Larry Weiskrantz. I did not review the original submission of the paper, but only this revised version. In retrospect, I agree with most of the previous comments, especially on the necessity to add data on the performance in the left visual field. As far as I can see this and other concerns have been addressed carefully and cogently in this revised version.

The paper thus looks in good shape for publication.

I only have a relatively minor, though relevant, comment to offer. There is a longstanding issue about whether attentional functions as well as implicit functions in neglect and/or blindsight entail a re-balancing of inter-hemispheric interaction. This issue seems particularly relevant for the present case, and I elaborate this further hoping to provide a context that authors may briefly mention. For example, inter-hemispheric transmission has been proved to be asymmetric from right-to-left rather than leftto-right (e.g., Marzi et al., 1991 Neuropsychologia). More specifically, whether visual functions damaged after hemianopia and blindsight can be subserved by the intact hemisphere by taking over and plasticity has come under renewed scrutiny. There is indeed recent support for this option from fMRI+DTI (e.g., Celeghin et al., 2017 PNAS); TMS (Silvanto et al., 2007 Exp Brain Res); and behavioral studies (Celeghin et al., 2015 Cons & Cogni). Therefore, in addition to the well-documented and extensively investigated extra-geniculate intra-hemispheric pathways subserving spared functions (e.g., reviewed recently in Tamietto & Morrone 2016 Curr Biol); this mechanism of inter-hemispheric compensation has come to the forefront. This may well be relevant for the present effect and its asymmetrical nature may provide a likely additional basis for the interpretation of the sight-blindness reported here. I would therefore invite the authors to refer to this literature and comment, if anything speculatively, on this option We thank Reviewer 2 for his comments, all the suggested references were added in the discussion section of the revised version of the manuscript (see new sections in blue).

Responses to reviewers

Reviewer #1: Authors responded to all my comments and now the paper is ready to be published.

We are glad the reviewer considers that the the paper is ready to published.

Reviewer #2: Chokron and colleagues submitted a study on patients with neglect and hemianopia to investigate the presence of additional ipsilesional deficits (sight-blindness) and their putative attentional nature. A lateralized letter section task is used, with low or high attentional load and in either left or right visual field. Accuracy and reaction times show that right-hemisphere damaged patients with neglect and/or hemianopia have lower accuracy for ipsilesional targets. It is concluded that patients with left homonymous hemianopia or left unilateral neglect both present a weaker but significant ipsilesional deficit in addition to their well-known massive contralesional deficit.

The study is interesting and well-written, generally well performed. There is a longstanding issue about whether attentional functions as well as implicit functions in neglect and/or blindsight entail a re-balancing of inter-hemispheric interaction. This issue seems particularly relevant for the present case, and I elaborate this further hoping to provide a context that authors may briefly mention. For example, inter-hemispheric transmission has been proved to be asymmetric from right-to-left rather than leftto-right (e.g., Marzi et al., 1991 Neuropsychologia). More specifically, whether visual functions damaged after hemianopia and blindsight can be subserved by the intact hemisphere by taking over and plasticity has come under renewed scrutiny. There is indeed recent support for this option from fMRI+DTI (e.g., Celeghin et al., 2017 PNAS); TMS (Silvanto et al., 2007 Exp Brain Res); and behavioral studies (Celeghin et al., 2015 Cons & Cogni). Therefore, in addition to the well-documented and extensively investigated extra-geniculate intra-hemispheric pathways subserving spared functions (e.g., reviewed recently in Tamietto & Morrone 2016 Curr Biol); this mechanism of inter-hemispheric compensation has come to the forefront. This may well be relevant for the present effect and its asymmetrical nature may provide a likely additional basis for the interpretation of the sight-blindness reported here. I would therefore invite the authors to refer to this literature and comment, if anything speculatively, on this option We thank Reviewer 2 for his comments, all the suggested references were added in the discussion section of the revised version of the manuscript (see new sections in blue).

Introduction

Participants suffering from left unilateral neglect are usually described as being impaired in responding to stimulation in the hemispace controlateral to the brain lesion [START_REF] Heilman | Mechanisms underlying hemispatial neglect[END_REF]; for a review, see [START_REF] Bartolomeo | Levels of impairment in unilateral neglect[END_REF]. In addition, it has been repeatedly demonstrated that patients do not simply neglect left objects but are also attracted by right ones [START_REF] Mark | Hemispatial neglect affected by non-neglected stimuli[END_REF][START_REF] Marshall | When right goes left: an investigation of line bisection in a case of visual neglect[END_REF]. This behaviour has been interpreted as a 'rightward attentional capture' and indeed several experiments have demonstrated that reducing visual salience in the right hemispace may decrease left neglect signs [START_REF] Mark | Hemispatial neglect affected by non-neglected stimuli[END_REF][START_REF] Marshall | Neuropsychology. Imagine only the half of it[END_REF][START_REF] Chokron | The role of vision in spatial representation[END_REF]. The hypothesis of a rightward attraction of attention increasing left neglect behavior raises an important question: does the rightward bias reflect enhanced attention to the right hemispace? This assumption would fit several attentional models such as Kinsbourne's model (1970) predicting that there is a bias towards orienting attention in the rightward, ipsilesional hemispace of left neglect patients due to the release of left hemisphere from right hemisphere inhibition (see for discussion, [START_REF] Bartolomeo | Orienting of attention in left unilateral neglect[END_REF]. Along those lines, [START_REF] Làdavas | The deployment of visual attention in the intact field of hemineglect patients[END_REF], and subsequently [START_REF] Natale | Abnormally speeded saccades to ipsilesional targets in patients with spatial neglect[END_REF], found that right brain-damaged patients with left neglect may respond faster to ipsilesional targets than right brain-damaged patients without neglect or may even outperform healthy participants (in the latter study). More recently, Vossel and Fink (2016) found that in right brain-damaged patients, the presence of a distractor in the contralesional hemifield expedited ipsilesional (i.e., right) target detection. This effect was significantly related to lesions in the anterior middle temporal and temporoparietal cortex, external and internal capsule, as well as the superior longitudinal fascicle (SLF). The authors thus suggested that damage to the temporal and temporoparietal cortex and white matter tracts may transform contralesional stimulation into an unspecific saliency signal contributing to facilitating information processing in ipsilesional space. However, rather than being interpreted Ipsilesional Attention Deficit 5 in terms of facilitation, the rightward orientation of attention could be seen as a deficit in neglect patients. Indeed, according to Viken et al. (2014), the ipsilesional capture of attention in left neglect patients could be a predictor of chronic deficit. Indeed, these authors demonstrated that the most important predictors assessed early after stroke were presence of ipsilesional bias for dependency at 3 months and visual processing speed for dependency at 2 years after stroke. In this manner, the increase in rightward orientation of attention could be seen as a core deficit of unilateral spatial neglect.

Contrasting with the idea of a rightward facilitation, Bartolomeo and Chokron (1999), as well as Bartolomeo et al. (1999), found that left neglect patients were slower than normal controls when responding to left, but also to right, ipsilesional stimuli. This finding can be interpreted based on [START_REF] Heilman | Right hemisphere dominance for attention: the mechanism underlying hemispheric asymmetries of inattention (neglect)[END_REF] hypothesis that the left hemisphere attends only to contralateral space whereas the right attends to both contralateral and ipsilateral hemispaces. Thus, left hemispheric damage could be compensated for by right hemispheric attentional mechanisms, thereby only rarely provoking right neglect. Conversely, right cerebral damage would cause left neglect because the left hemisphere is unable to attend to the left hemispace. An essential corollary of this hypothesis is that right hemisphere lesions should determine a severe deficit in attention for the contralateral hemispace, but also a milder ipsilesional deficit, because fewer attentional resources could now be deployed in the right hemispace. Consistently, Bartolomeo and Chokron (1999) and Bartolomeo et al. (1999), found that left neglect patients were also impaired in their right hemispace. In addition, the authors demonstrated that this ipsilesional slowing of reaction times does not simply reflect a nonspecific arousal deficit, but is strictly related to the severity of left neglect. In addition, they demonstrated that the capacity to inhibit successive responses to right-sided events could predict performance on the left side of paper and pencil neglect tests (Bartolomeo et al., 1999).

The rightward attentional bias in left neglect patients can thus take the form of a facilitation for simple detection as mentioned above or a deficit in more complex attentional tasks. Therefore, it seems to be one of defective, and not enhanced, attention, but the nature of this deficit is still unclear.

On the one hand, according to [START_REF] Robertson | The relationship between lateralised and non-lateralised attentional deficits in unilateral neglect[END_REF][START_REF] Robertson | Do we need the "lateral" in unilateral neglect? Spatially nonselective attention deficits in unilateral neglect and their implications for rehabilitation[END_REF], unilateral neglect would be very strongly associated with a fundamental loss of attentional capacity that may not be confined to one region of space, but could also involve the right ipsilesional space, meaning a nonlateralized attentional deficit. In this view, neglect patients suffer from a spatially nonselective component of attentional deficit that may be some form of basic arousal dysfunction. On the other hand, the attentional deficit in the ipsilesional field of left neglect patients could merely involve selective attention such as filtering processing. Indeed, using a 'flanker task' (e.g., the identification of a central stimulus flanked on both sides by task-irrelevant flankers), [START_REF] Snow | Goal-driven selective attention in patients with right hemisphere lesions: how intact is the ipsilesional field?[END_REF] clearly demonstrated that right brain-damaged patients with left unilateral neglect or extinction have a specific impairment in the ability to selectively inhibit taskirrelevant information within the ipsilesional visual field (IVF). Thus, according to these authors, in addition to the deficit of spatial orientation of attention present in left neglect patients, selective attention in IVF might more accurately be viewed as 'dysfunctional' rather than 'intact', as previously thought (for review, see [START_REF] Snow | Goal-driven selective attention in patients with right hemisphere lesions: how intact is the ipsilesional field?[END_REF]. Indeed, it has to be noted that although the orientation of attention in space has been extensively studied in left neglect patients (for review, see [START_REF] Bartolomeo | Orienting of attention in left unilateral neglect[END_REF], relatively few studies have focused on selective attention. When they did, these studies mainly focused on the deficit in the left, contralesional hemispace (see for example, [START_REF] Rapcsak | Selective attention in hemispatial neglect[END_REF][START_REF] Lavie | The role of perceptual load in neglect: rejection of ipsilesional distractors is facilitated with higher central load[END_REF][START_REF] Robertson | Do we need the "lateral" in unilateral neglect? Spatially nonselective attention deficits in unilateral neglect and their implications for rehabilitation[END_REF], but not on the behaviour in the right, ipsilesional space. Interestingly, regarding visual field defects consecutive to retrochiasmatic unilateral damage (V1), the same conclusion can be drawn.

Ipsilesional Attention Deficit 7

Indeed, most studies focused on the contralesional visual field, either on the deficit per se or on the residual, implicit capacities, referred to as 'blindsight ' (Weiszkrantz, 2004).

However, contrary to the case of blindsight, which has been extensively studied in hemianopic patients, vision quality in the central visual field and in the IVF of these patients has scarcely been assessed, and moreover, has traditionally been assumed to be fully preserved. Yet, regarding visuo-attentional capacities in the IVF of hemianopic patients, [START_REF] Hess | Spatial and temporal contrast sensitivity in hemianopia. A comparative study of the sighted and blind hemifields[END_REF] proposed that spatial and temporal sensitivities were lower than in control subjects. [START_REF] Rizzo | Bilateral effects of unilateral visual cortex lesions in human[END_REF], followed by [START_REF] Poggel | Time will tell: deficits of temporal information processing in patients with visual field loss[END_REF], confirmed that hemianopic patients can exhibit lower sensitivity to signals, compromised processing of temporal information and longer reaction times in both contralesional and ipsilesional visual fields, as compared to control participants. By studying a patient one week before and six months after a surgical intervention (embolization of an arteriovenous malformation in the right occipital lobe), we directly addressed the role of the right visual cortex on local analysis (based on the high spatial frequency content of scene stimuli) and global analysis (based on the low spatial frequency content) of visual information in scenes (Peyrin et al., 2006b). Results confirmed that damage to the right primary visual cortex (V1) induces a decrease in performance in the right IVF. In fact, the patient was found even before surgery to perform with lesser accuracy and higher reaction times in the right IVF for all types of scenes compared to performance in healthy controls and presented an additional deficit for global analysis (based on low spatial frequencies) in her right IVF after surgery. This study led us to hypothesize that the right occipital lobe could be involved in the processing of the global aspects of a visual scene (low spatial frequencies) in both visual fields. The right temporo-parietal junction has already been hypothesized to be involved in global processing [START_REF] Fink | Neural mechanisms involved in the processing of global and local aspects of hierarchically organized visual stimuli[END_REF][START_REF] Fink | Hemispheric asymmetries in global local processing are modulated by perceptual salience[END_REF].

Regarding visual detection and analysis, [START_REF] Paramei | Contour-integration deficits on the intact side of the visual field in hemianopia patients[END_REF] reported that hemianopic patients exhibited diminished ability to detect fragmented targets among a noisy Ipsilesional Attention Deficit 8 background in the IVF, whereas [START_REF] Schadow | Impairments of Gestalt perception in the intact hemifield of hemianopic patients are refected in gamma band EEG activity[END_REF] found deficits in the early and late visual processing of Gestalt patterns in the IVF. More recently, Bola et al. (2013a) confirmed these findings and reported processing-speed deficits in a simple detection task in the IVF. The authors termed this phenomenon sightblindness, as the reverse situation of blindsight (Bola et al. 2013b): the former refers to visuo-attentional deficits in the IVF, whereas the latter refers to residual (although implicit) visual abilities in the controlateral visual field (CVF) that are highlighted in forced-choice tasks (e.g., Weiskrantz et al., 1974;[START_REF]Primary visual cortex: awareness and blindsight[END_REF]. Along those lines, and as recently suggested, neither the central visual field [START_REF] Cavézian | Specific impairments in visual processing following lesion side in hemianopic patients[END_REF]2015;[START_REF] Perez | An FMRI investigation of the cortical network underlying detection and categorization abilities in hemianopic patients[END_REF] nor the IVF of hemianopic patients (Bola et al., 2013a;2013b;Sanchez-Lopez et al., in press) actually appear to be fully intact or functional. In line of these findings, it was also demonstrated that cortical reorganization may be observed not only in the lesioned but also in the healthy hemisphere after a unilateral occipital damage acquired in childhood (Mikellidou et al., in press). Moreover, as we proposed, the nature of the task and the type of stimulus may determine the central and ipsilesional visual deficit and the pattern of cortical activation of hemianopic patients [START_REF] Cavézian | Specific impairments in visual processing following lesion side in hemianopic patients[END_REF][START_REF] Cavézian | Hemisphere-dependent ipsilesional deficits in hemianopia: Sightblindness in the 'intact' visual field[END_REF][START_REF] Perez | An FMRI investigation of the cortical network underlying detection and categorization abilities in hemianopic patients[END_REF][START_REF] Chokron | Behavioral Consequences and Cortical Reorganization in Homonymous Hemianopia[END_REF]. As a matter of fact, recently, we specifically investigated the effect of lesion side on the nature and severity of the ipsilesional deficit [START_REF] Cavézian | Hemisphere-dependent ipsilesional deficits in hemianopia: Sightblindness in the 'intact' visual field[END_REF]. In this study, five left and five right hemianopic patients were presented filtered (high or low spatial frequencies) as well as non-filtered scenes in their IVF during a detection and a categorization task. Right braindamaged patients with left hemianopia made more errors for categorizing scenes in their IVF than did their matched controls, regardless of the spatial frequency content of scene. In contrast, left brain-damaged patients with right hemianopia made more errors than did the controls only when categorizing high spatial frequency scenes. Interestingly, in both tasks (detection and categorization), the right brain-damaged patients performed worse in their IVF than did the left brain-damaged patients.

Ipsilesional Attention Deficit 9

Together, these studies among right brain-damaged patients suffering either from left neglect or left homonymous hemianopia raise the question of the integrity of selective attention processing in the ipsilesional healthy right visual field. However, most of the studies among both LN patients and LH patients focused mainly on selective attention in the contralesional and not ipsilesional visual field. Indeed, authors focused either on the disentangling between LH and LN (Walker et al., 1991;[START_REF] Nadeau | Gaze-dependent hemianopia without hemispatial neglect[END_REF][START_REF] Ferber | Size perception in hemianopia and neglect[END_REF][START_REF] Müller-Oehring | Neglect and hemianopia superimposed[END_REF] or on the additive effect of LN and LH in processing stimuli in the contralesional field [START_REF] Doricchi | Misrepresentation of horizontal space in left unilateral neglect: role of hemianopia[END_REF][START_REF] Barton | Ocular search during line bisection. The effects of hemi-neglect and hemianopia[END_REF][START_REF] Saj | Influence of spatial neglect, hemianopia and hemispace on the subjective vertical[END_REF], whereas other studies aimed to investigate how these two types of patients react to nonvisual stimuli [START_REF] Kerkhoff | Contrasting spatial hearing deficits in hemianopia and spatial neglect[END_REF]1999;[START_REF] Bolognini | Multisensory integration in hemianopia and unilateral spatial neglect: Evidence from the sound induced flash illusion[END_REF]. Only a few studies were interested in comparing the behavior of LN and LH patients in their ipsilesional visual field [START_REF] Barrett | Ipsilateral neglect versus hemianopic compensation[END_REF][START_REF] Tant | Grey scales uncover similar attentional effects in homonymous hemianopia and visual hemi-neglect[END_REF][START_REF] Gainotti | The influence of distracters, stimulus duration and hemianopia on first saccade in patients with unilateral neglect[END_REF][START_REF] Doricchi | Causes of crossover in unilateral neglect: between-group comparisons, within-patient dissociations and eye movements[END_REF].

The aim of the present study was thus to investigate the presence, the nature and the severity of a selective spatial attention deficit in the ipsilesional visual field of both LN and LH patients and to understand to which extent the nature of the deficit in the contralesional visual field (attentional or visual) could determine the nature of the ipsilesional attentional deficit. The concept of selective spatial attention usually refers to the ability to focus on areas of visual space to facilitate target detection [START_REF] Posner | The attention system of the human brain[END_REF]. According to many authors, the key notion in selective attention is a filtering process that ensures amplification of the target and/or attenuation of background information [START_REF] Broadbent | Perception and communication[END_REF][START_REF] Kahneman | Changing views of attention and automaticity[END_REF][START_REF] Shiffrin | A model of automatic attention attraction when mapping is partially consistent[END_REF]. In the present study, we used a letter-detection task (Chokron et al., 2000;[START_REF] Tabert | Visual target detection paradigm for the study of selective attention[END_REF] to test if right brain-damaged patients suffering from either left unilateral spatial neglect (LN) or left homonymous hemianopia (LH) may present a deficit of selective attention, in their right ipsilesional visual field as compared to normal controls.

Ipsilesional Attention Deficit 10

By previously using this task in healthy volunteers, we were able to demonstrate that when selective attention is required to identify a visual target surrounded by flankers, reaction times (RTs) are shorter in the right than in the left visual field [START_REF] Chokron | Hemispheric asymmetry for selective attention[END_REF]2003;[START_REF] Buchsbaum | Thalamocortical circuits: fMRI assessment of the pulvinar and medial dorsal nucleus in normal volunteers[END_REF], thus confirming a left hemisphere (LH) advantage for filtering irrelevant information and analyzing the local features of a visual scene [START_REF] Robertson | Neuropsychological contributions to theories of part/whole organization[END_REF][START_REF] Robertson | Effects of lesions of temporal-parietal junction on perceptual and attentional processing in human[END_REF]. Conversely, RTs were found to be shorter in the left visual field (LVF) than in the right visual field (RVF) when the target to be identified was presented alone and required less filtering activity (i.e. less selective attention). We thus demonstrated a left hemifields, lower performance when processing small stimuli surrounded by flankers than large stimuli presented alone. Unilateral Spatial Neglect was assessed using the BEN (Batterie d'évaluation de la Négligence; [START_REF] Azouvi | Sensitivity of clinical and behavioural tests of spatial neglect after right hemisphere stroke[END_REF]. Visual field defects were diagnosed using the BEN in all patients and confirmed with automatic perimetry in hemianopic patients (see Table 1 and Figure 1). All participants (controls and patients) had normal or corrected-to-normal vision (acuity), left-to-right reading habits, and used the Roman alphabet. Demographical and clinical data are detailed in Table 1.

Material and Methods

Participants

/Insert Table 1/ /Insert Figure 1/

Stimuli and Procedure

Ipsilesional Attention Deficit 12

Stimuli were either the letter O, the letter C, or the digit zero (0) appearing either alone as a large character (single large condition) or as a small character surrounded by eight other letters (the letter G or Q, flanked small condition; see Figure 2). The overall size of the stimuli was controlled so that the large letters were of the same dimensions as the pattern of small letters surrounded by flankers (19 mm wide × 22 mm high). Each trial began with a central fixation cross that was presented for 300 ms (in order to control the gaze direction to the center of the screen), and remained during the presentation of the stimulus displayed during 150 ms in either the left visual field (LVF) or the right visual field (RVF) at 2° from a fixation dot.

Participants performed a lateralized letter-detection task. The task consisted of pressing a button with the right hand only when detecting a target (large or small O) and to ignore the trials where a distractor was flashed (0 or C) (see [START_REF] Tabert | Visual target detection paradigm for the study of selective attention[END_REF] for complete procedure). The experiment contained 128 trials (16 LVF single large target, 16 RVF single large target, 16 LVF flanked small target, 16 RVF flanked small target, 16 LVF single large distractor, 16 RVF single large distractor, 16 LVF flanked small distractor, 16 RVF flanked small distractor).

Response accuracy and response times (in milliseconds) were recorded for each trial.

/Insert Figure 2/

Results

/Insert Table 2/

Correct responses (CR)

An ANOVA was performed on mCR (Table 2 andFigure 3) with Group (Normal controls, RBD, LN, and LH) and Visual field (LVF and RVF) as a between-subjects factors Ipsilesional Attention Deficit 13 and Stimulus type (single large and flanked small) as a within-subject factor. The ANOVA revealed a main effect of Group (F3,39 = 28.15, p < 0.0001), Visual hemifield (F1,39 = 50.33, p < 0.0001), and Stimulus type (F1,39 = 103.7, p < 0.0001), but the interaction Group × Visual field × Stimulus Type was not significant (F3,39 < 1). A priori specific hypotheses were tested using contrast analysis with modified Bonferroni-corrected alpha value (αadjusted) for nonorthogonal comparisons. We first hypothesized that LN and LH patients would present a deficit of selective attention in their ipsilesional field in comparison with NC. Indeed, when stimuli were displayed in the ipsilateral RVF, the mCR was significantly lower for LN (51.6 ± 21.9%) and LH (62.1 ± 28.5%) than NC (77.2 ± 20.3%; F1,39 = 12.61, p < 0.001, αadjusted = 0.033 for all 3 possible pairwise comparisons; residual effect: F1,39 = 1.73, p = 0.20). Then, to test a specific deficit for LH patients to process global information relative to local information in the ipsilateral RVF, we directly compared mCR between LH and NC on each stimulus type. For single large stimuli, the mCR was significantly lower for LH (70.3 ± 31.8%) than NC (98.7 ± 8.5%; F1,39 = 7.28, p < 0.01). For small flanked stimuli, there was no difference between LH (53.9 ± %) and NC (64.7 ± 16.8%; F1,39 = 1.37, p = 0.25). Concerning more specifically LN patients, we tested the hypothesis of a non-lateralized attentional deficit in LN patients by comparing mCR between LN and NC irrespective of the visual field. The mCR was significantly lower for LN (45.2 ± 21.2%) than NC (78.9 ± 18.3%; F1,39 = 44.21, p < 0.001). To test if the non-lateralized attentional deficit is only a consequence of the right hemisphere lesion, we directly compared mCR between LN and RBD. The mCR was significantly lower for LN than RBD (67.4 ± 24.8%; F1,39 = 13.49, p < 0.001). Finally, we tested if the attentional deficit is linked to the attentional load by comparing mCR between the two types of stimuli in both visual fields. The mCR was significantly lower for flanked small stimuli (33.1 ± 20.6%) than single large stimuli (57.2 ± 13.8%; F1,39 = 25.6, p < 0.001).

Ipsilesional Attention Deficit 14 /Insert Figure 3/

Reaction times (RT)

As presented in Table 2, mCR of LH patients is very low in the left visual hemifield, i.e. their blind contralesional visual field, causing the absence of mean correct reaction times (mRT) for 7 out of 8 patients. Thus, only mRT in the right visual hemifield (i.e. healthy ipsilesional visual field for LN, LH and RBD patients; Figure 4) were analyzed. An ANOVA was performed on mRT with Group (Normal controls, RBD, LN, and LH) as a between-subjects factors and Stimulus type (single large and flanked small) as a within-subject factor. The ANOVA showed a main effect of Stimulus type (F1,39 = 13.25, p < 0.001), with small stimuli surrounded by flankers eliciting longer RT than large stimuli presented alone. We found neither a main effect of Group (F3,39 = 1.15, p = 0.34), nor a significant Group × Stimulus Type interaction (F3,39 = 1.06, p = 0.38). A priori specific hypotheses were here tested when concerning the right visual hemifield only, using contrast analysis with modified Bonferronicorrected alpha value (αadjusted) for non-orthogonal comparisons. The mRT did not significantly differ between LN (532 ± 123 ms), LH (493 ± 129 ms) and NC (470 ± 90 ms; F1,39 = 12.61, p < 0.001, αadjusted = 0.033 for 3 possible pairwise comparisons). Then, there was no significant difference between LH and NC, for neither single large stimuli (476 ± 135 ms and 429 ± 82 ms, respectively; F1,39 = 1.12, p = 0.30) nor flanked small stimuli (509 ± 129 ms and 513 ± 80 ms, respectively; F1,39 > 1). Finally, there was no significant difference between LN (532 ± 123 ms) and RBD (527 ± 101 ms; F1,39 < 1).

/Insert Figure 4/

Discussion

The present study investigated a possible selective attention deficit in the right, ipsilesional visual field of right brain-damaged patients suffering either from left neglect or left hemianopia.

In fact, our findings demonstrate a significant difference in performance between control participants and LH and LN patients. Indeed, when stimuli were displayed in the ipsilateral right visual field, LN and LH patients presented lower performance than healthy controls (NC). More specifically, LH patients presented significantly lower performance in detecting a large visual stimulus, but not a flanked small stimulus, in their ipsilesional visual field compared to NC. LN patients, for their part, presented lower performance than NC, but also than RBD controls, in detecting all type of stimulus in both visual hemifields. The present findings bring evidence for the presence of a non-lateralized attentional deficit in LN patients that cannot be attributed solely to the presence of right brain damage, as well as a subtle attentional deficit in the ipsilesional visual field of LH patients and are discussed below regarding models of neglect and homonymous hemianopia.

Ipsilesional attentional bias in left neglect patients

The present paper confirms previous findings emphasizing the presence of an ipsilesional spatial bias in RBD patients suffering from left neglect that, according to some studies may be correlated to the lateralized contralesional deficit of these patients [START_REF] Rusconi | Is the intact side really intact? Perseverative responses in patients with unilateral neglect: a productive manifestation[END_REF][START_REF] Battelli | Unilateral right parietal damage leads to bilateral deficit for high-level motion[END_REF]Bartolomeo & Chokron, 1999;Bartolomeo et al., 1999;[START_REF] Robertson | Do we need the "lateral" in unilateral neglect? Spatially nonselective attention deficits in unilateral neglect and their implications for rehabilitation[END_REF]. As pointed out by [START_REF] He | Breakdown of functional connectivity in frontoparietal networks underlies behavioural deficits in spatial neglect[END_REF] previous studies on healthy subjects indicate that the dorsal network mediates control of spatial attention with a contralateral bias [START_REF] Corbetta | Voluntary orienting is dissociated from target detection in human posterior parietal cortex[END_REF][START_REF] Corbetta | Control of goal-directed and stimulus-driven attention in the brain. [Review][END_REF][START_REF] Macaluso | Directing attention to locations and to sensory modalities: multiple levels of selective processing revealed with PET[END_REF][START_REF] Sereno | Mapping of contralateral space in retinotopic coordinates by a parietal cortical area in humans[END_REF][START_REF] Silver | Topographic maps of visual spatial attention in human parietal cortex[END_REF], while the ventral system is involved in nonlateralized attentional functions, including spatial and temporal capacity [START_REF] Husain | Non-spatially lateralized mechanisms in hemispatial neglect[END_REF][START_REF] Peers | Attentional functions of parietal and frontal cortex[END_REF][START_REF] Shapiro | Control of visuotemporal attention by inferior parietal and superior temporal cortex[END_REF] Ipsilesional Attention Deficit 16 vigilance [START_REF] Pardo | Localization of a human system for sustained attention by positron emission tomography[END_REF], saliency detection [START_REF] Serences | Preparatory activity in visual cortex indexes distractor suppression during covert spatial orienting[END_REF], and reorienting of attention [START_REF] Corbetta | Voluntary orienting is dissociated from target detection in human posterior parietal cortex[END_REF][START_REF] Macaluso | Directing attention to locations and to sensory modalities: multiple levels of selective processing revealed with PET[END_REF][START_REF] Carter | Differential white matter involvement associated with distinct visuospatial deficits after right hemisphere stroke[END_REF]. Along these lines and as highlighted by [START_REF] He | Breakdown of functional connectivity in frontoparietal networks underlies behavioural deficits in spatial neglect[END_REF], neglect patients may show both spatially lateralized and nonlateralized deficits, as seen here, because of the interaction between structural and functional damage to the ventral and dorsal frontoparietal attention networks. Recent studies dealing with the neuroanatomy of neglect signs in RBD patients revealed that specific neural correlates could be put forward for the different components including the right inferior parietal lobule for the perceptive/visuo-spatial component, the right dorsolateral prefrontal cortex for the exploratory/visuo-motor component, deep temporal lobe regions for the allocentric/objectcentred component whereas subcortical damage to paraventricular white matter tracts was associated with severe neglect encompassing several tests (Verdon et al., 2010). However, in this model, the presence of an ipsilesional deficit was not specifically looked for and correlated to specific neuroanatomical damage. Nevertheless, in a recent investigation of structural whitematter mediating left neglect components in RBD patients, [START_REF] Vaessen | Structural white-matter connections mediating distinct behavioral components of spatial neglect in right braindamaged patients[END_REF] suggested that posterior parts of the superior longitudinal fasciculus (SLF), as well as nearby callosal fibers connecting ipsilateral and contralateral parietal areas, were associated with perceptual spatial deficits, whereas more anterior parts of SLF and inferior fronto-occipital fasciculus (IFOF) were predominantly associated with object-centered deficits in left neglect patients. Along those lines, a damage to the nearby callosal fibers connecting ipsilateral and contralateral parietal areas could easily explain the ipsilesional deficit that can be found, as in the present experiment, in left neglect patients. Further studies are needed to investigate the specific neuroanatomical correlates of this ipsilesional deficit.

From a functional viewpoint, regarding our predictions expressed in the Introduction, the presence of an ipsilesional deficit for both small and large targets in left neglect patients is compatible with a general non-lateralized attentional deficit. In addition, the fact that this deficit Ipsilesional Attention Deficit 17 is more salient (in terms of correct responses) in the condition with a high attentional load (for small rather than large stimuli) than in global visual detection could indicate that the type of attentional processes required may also have an effect on this non-lateralized deficit confirming He and co-workers' (2007) model of an interaction between the dorsal and the ventral attentional systems. The present study confirms and extends Rapcsak and coworkers' (1989) findings in showing that increasing demands on visual selective attention adversely affects left neglect patients' performance in both hemifields. From a clinical point of view, the fact that the attentional load significantly modulates the ipsilesional deficit highlights the necessity of diagnosing neglect signs and attentional deficits using a battery of tests. In fact, it has been repeatedly found that tasks requiring selective attention are more suitable in revealing neglect signs than simple detection tasks (see for example [START_REF] Azouvi | Sensitivity of clinical and behavioural tests of spatial neglect after right hemisphere stroke[END_REF]. Importantly, the fact that LN patient performance is significantly lower than healthy controls and RBD controls underline that this non-lateralized deficit cannot be attributed solely to the presence of a right brain damage.

Ipsilesional attentional bias in left hemianopic patients

In line with previous studies [START_REF] Rizzo | Bilateral effects of unilateral visual cortex lesions in human[END_REF]Peyrin et al., 2006a;Bola et al., 2013b;Cavezian et al., 2015), we confirmed that a unilateral right visual cortex lesion produces ipsilesional visuo-attentional deficits at least for large stimuli. There are both anatomical and functional arguments to explain this finding.

Historically, from an anatomical point of view, it was established in the last century that the deficit caused by a unilateral occipital lobe lesion was restricted to the controlateral visual field and led to the assumption that there is a consistent relationship between visual field defects and loci of brain damage in the calcarine cortex, (i.e., Brodmann's area 17 or VI). However, according to [START_REF] Rizzo | Bilateral effects of unilateral visual cortex lesions in human[END_REF], even after a lesion of the primary visual cortex (V1), VI Ipsilesional Attention Deficit 18 dysfunction is unlikely to occur in isolation in human cases. Rather, extrastriate dysfunction, contralesional dysfunction, and/or parietal dysfunction resulting in attentional disorders should generally co-occur, as demonstrated here.

From a functional point of view, primate extrastriate areas receive extensive visual inputs from both ipsi-and contralateral hemispheres [START_REF] Rockland | Further evidence for two types of corticopulvinar neurons[END_REF]. They also contain neurons with receptive fields that overlap the vertical meridian [START_REF] Desimone | A role for the corpus callosum in visual area V4 of the macaque[END_REF] and neurons whose activity is modulated during attention tasks [START_REF] Moran | Selective attention gates visual processing in the extrastriate cortex[END_REF]Spitzer et al.1988;[START_REF] Logothetis | Neuronal correlates of subjective visual perception[END_REF][START_REF] Schiller | The role of the primate extrastriate area V4 in vision[END_REF]. Comparative anatomo-functional evidence suggests that similar neurons and connections exist in humans, and human visual cortex activity appears to be attention-dependent [START_REF] Corbetta | Selective attention modulates extrastriate visual regions in humans during visual feature discrimination and recognition[END_REF][START_REF] Sengpiel | Visual attention: spotlight on the primary visual cortex[END_REF][START_REF] Somers | Functional MRI reveals spatially specific attentional modulation in human primary visual cortex[END_REF]. Taken together, this anatomical and functional evidence explains that a unilateral human visual cortex lesion may reduce visual performance (accuracy and speed) in both hemifields. This explanation is in line with both the interhemispheric diaschisis effects put forward early last century, as well as attention-related deficits. Consequently, our results are in accordance with studies showing that the useful visual field of view in patients with homonymous hemianopia after a unilateral occipital lesion may be bilaterally constricted [START_REF] Ball | The useful field of view test: a new technique for evaluating agerelated declines in visual function[END_REF].

Although the specific mechanisms responsible for ipsilesional visual deficits in hemianopic patients remain to be clarified, several explanations have been proposed. First, [START_REF] Rizzo | Bilateral effects of unilateral visual cortex lesions in human[END_REF] interpreted these global effects of a unilateral occipital lesion in terms of a limited capacity attention model [START_REF] Broadbent | Perception and communication[END_REF]. According to this model, damage to a portion of the visual cortical pathways reduces information processing capacity and efficiency of the whole system. More recently, Bola et al. (2013b) proposed that weaker and delayed activation in the injured hemisphere might compromise inter-hemispheric interactions and alter synchronization of the non-lesioned hemisphere to induce subtle visual deficits in the IVF. The Ipsilesional Attention Deficit 19 present findings reinforce the premise that the side of the occipital lesion can influence the pattern of interhemispheric desynchronization.Indeed, given the evidence of hemispheric specialization for visual processing, we recently hypothesized that the side of the occipital lesion could indeed have specific effects on interhemispheric desynchronization (Cavezian et al., 2010;2015;[START_REF] Perez | An FMRI investigation of the cortical network underlying detection and categorization abilities in hemianopic patients[END_REF].

Finally, [START_REF] Dai | Resting-state functional MRI: Functional connectivity analysis of the visual cortex in primary open-angle glaucoma patients[END_REF] recently hypothesized and Bola et al. (2013b[START_REF] Bola | Brain functional connectivity network breakdown and restoration in blindness[END_REF] recently discussed the premise that the occipital lesion and its functional consequences (loss of the contralesional visual field) lead to widespread changes in the brain. In addition, [START_REF] Bola | Brain functional connectivity network breakdown and restoration in blindness[END_REF] proposed that vision loss in blind subjects after a peripheral lesion is caused not only by primary tissue damage but also by a breakdown of synchronization in brain networks. Thus, evidence has emerged that there is a complex and widespread reorganization of long-range brain networks following peripheral or cortical visual impairment. Indeed, as recently pointed out by [START_REF] Lanyon | Visual search and line bisection in hemianopia: computational modelling of cortical compensatory mechanisms and comparison with hemineglect[END_REF], deficits in homonymous hemianopia after unilateral damage to the primary visual cortex might also vary across time, with more attentional deficits at the acute phase than after a few months.

In addition, in the present study, right brain-damaged patients with left hemianopia show a specific deficit in processing large stimuli and no deficit for local processing in their right ipsilesional visual field. This finding confirms previous results showing right hemisphere dominance for global processing [START_REF] Chokron | Hemispheric asymmetry for selective attention[END_REF] and raises the question of a hemispheric specialization for visuo-spatial processing at the occipital level as we recently proposed (Cavezian et al., 2010;2015;[START_REF] Perez | An FMRI investigation of the cortical network underlying detection and categorization abilities in hemianopic patients[END_REF]. As a matter of fact, this asymmetry between the left and right hemisphere has mostly been interpreted in terms of a superiority of the right hemisphere for the detection of simple visual stimuli. However, as underlined by [START_REF] Marzi | Is interhemispheric transfer of visuomotor information asymmetric? Evidence from a meta-analysis[END_REF], this could also be interpreted as related to an asymmetry of interhemispheric transmission of visuomotor information, with transfer from the right hemisphere (side of Ipsilesional Attention Deficit 20 stimulus entry) to the left (side of response generation) faster than in the reverse direction.

Interestingly, the role of the corpus callosum in patients with unilateral lesions has been emphasized these past years. Indeed, in addition to the recent data showing that blindsight relies on an intact patway between the LGN and MT (see for review and discussion, [START_REF] Tamietto | Visual Plasticity: Blindsight Bridges Anatomy and Function in the Visual System[END_REF], Celeghin and colleagues (2017) recently demonstrated in one patient with early primary visual cortex damage that blindsight and in particular the fact that HH patients can act on targets they do not consciously perceive could depend partly on the compensatory activity of the intact hemisphere, which can be dynamically recruited through the corpus callosum.

These

Right hemisphere dominance for visuo-spatial processing in both visual fields

The hypothesis that the right occipital lobe dominates in visuo-spatial processing in the entire visual field parallels the well-described superiority of the right parietal lobe in spatial organization over the entire extra-personal space [START_REF] Heilman | Right hemisphere dominance for attention: the mechanism underlying hemispheric asymmetries of inattention (neglect)[END_REF] as well as the recurrent finding that left neglect after right cortical damage is more severe and more frequent than right neglect after left lesion (for review, see [START_REF] Bartolomeo | Orienting of attention in left unilateral neglect[END_REF].

Ipsilesional Attention Deficit 21

According to the present findings, right hemisphere dominance for attention would account for bilateral attentional deficits not only following parietal lesions as discussed above, but also following occipital lesions as found in the present study.

Interestingly, we recently demonstrated that in hemianopic patients, the deficit in the central and in the ipsilesional visual field is more marked in right brain-damaged patients than in left brain-damaged patients, suggesting that the dominance of the right hemisphere for visuospatial processing influences the severity of the deficit in both hemifields (Cavezian et al., 2010;2015). In addition, we were able to show that the lesion side might also play a role in cortical reorganization after an occipital lesion [START_REF] Perez | An FMRI investigation of the cortical network underlying detection and categorization abilities in hemianopic patients[END_REF]. Indeed, during a visual categorization task performed in the central visual field, whereas left brain damaged patients with right hemianopia showed activation predominantly in their right hemisphere (namely, in their occipital lobe and posterior temporal areas), right brain damaged patients with left hemianopia showed a more bilateral activation (in their occipital lobes).

Taken together, the present findings as well as previous results further corroborate the superiority of the right hemisphere in visual processing recently discussed in normal controls using EEG [START_REF] Le | A toggle switch of visual awareness[END_REF]. Given right hemisphere superiority for visuo-spatial, and especially for global visual processing, a right occipital lesion would thus induce a loss of visual perception in the contralesional visual field (hemianopia) and an ipsilesional visuo-attentional deficit more marked for large visual stimuli processing as reported here.

Conclusions

The present findings emphasize the need to thoroughly test for visuo-attentional capacities in the assumed 'healthy' ipsilesional visual field of patients suffering from unilateral spatial neglect or homonymous hemianopia following unilateral parietal or occipital damage.

Contralesional visual field training in rehabilitation is nearly always recommended for these

Ipsilesional Attention Deficit 22 patients. However, the present study clearly demonstrates that right brain-damaged patients with either left neglect or right hemianopia may present an ipsilesional visuo-attentional deficit as well. In addition, and as discussed above, the nature of the ipsilesional deficit seems to be dependent upon the pathological condition (left hemianopia vs left neglect) and could thus be dependent upon the specific location of cerebral damage. As a matter of fact, recently, blindsight has been hypothesized to depend partly upon the interaction between the damaged and the non-damaged hemisphere [START_REF] Celeghin | Speeded manual responses to unseen visual stimuli in hemianopic patients: what kind of blindsight?[END_REF][START_REF] Celeghin | Intact hemisphere and corpus callosum compensate for visuomotor functions after early visual cortex damage[END_REF][START_REF] Silvanto | Abnormal functional connectivity between ipsilesional V5/MT+ and contralesional striate cortex (V1) in blindsight[END_REF], the present findings suggest that this could also be the case for ipsilesional deficits in patients with unilateral parietal or occipital lesions.

Consequently, further studies should focus on the nature and severity of ipsilesional attentional deficits, both in homonymous hemianopia and in unilateral spatial neglect in relation with the side and site of brain damage, to establish if this bilateral deficit is mainly due to right hemisphere dominance for visuo-attentional processing or if this could be due to inter and intrahemispheric cortico-subcortical connectivity. This is of importance given the role of attention both in increasing sensitivity and awareness in hemianopic patients (Vernet et al., in press). Ipsilesional Attention Deficit 36

  hemisphere (LH) specialization for selective attention and a right hemisphere (RH) specialization for global visual detection. According to these results, a number of predictions can be made regarding the performance of left neglect and left hemianopic patients while performing the present task: (1) If left neglect patients and left hemianopic patients present an attentional deficit in their ipsilesional field, we should observe lower performance in their right IVF as compared to controls' performance; (2) If the right occipital lobe is specifically involved in the global processing of visual information in both hemifields, as we previously hypothesized, we should observe a specific deficit for big stimuli (global processing) in the right IVF of left hemianopic patients as compared to controls' performance; (3) If there is a more general non-lateralized deficit of arousal in left neglect patients, as suggested for example by Robertson (2001), performance in both visual fields (RT and accuracy) should be worse for all types of stimuli (with high or low attentional demand) compared to controls; (4) If this nonlateralized arousal deficit is specifically linked to the neglect syndrome, and not a consequence of the right hemisphere lesion, performance should be worse for all types of stimuli in both visual fields compared to right brain damaged controls; (5) If the non-lateralized attentional deficit of LN patients is linked to the attentional load, we should observe, in both visual Ipsilesional Attention Deficit 11

  Seventeen healthy, dextral, male adults (Normal controls); age range 52 to 77 years; M = 60.2, SD = 7.94), eight right brain-damaged male patients with no sign of left hemianopia or left unilateral spatial neglect (RBD patients; age range 53 to 79 years; M = 63.7; SD = 12.87), ten right brain-damaged male patients diagnosed with left unilateral spatial neglect (LN patients; age range 46 to 69 years; M = 58.8; SD = 6.61), and eight right brain-damaged male patients with a right occipital lesion and diagnosed with left homonymous hemianopia (LH patients; age range 48 to 72 years; M = 63, SD = 8.24) participated in the study.

Figure 1 :

 1 Figure 1: Visual field examination (Humpreys 24-2) for hemianopic patients. In each box the

Figure 2 :

 2 Figure 2: Examples of stimuli displays. (a) The target can be a small letter o surrounded by

Figure 3 :

 3 Figure 3: Percentage of correct responses as a function of the visual field (left visual field:

Figure 4 :

 4 Figure 4: Mean correction reaction times (in ms) in the right visual hemifield as a function of

Figure1Rev2

  Figure1Rev2Click here to download high resolution image

  review the original submission of the paper, but only this revised version. In retrospect, I agree with most of the previous comments, especially on the necessity to add data on the performance in the left visual field. As far as I can see this and other concerns have been addressed carefully and cogently in this revised version.

									Analyses are (now) sound, and the topic
	clearly	fits	well	with	the	special	issue	honoring		Larry	Weiskrantz.
	I did not The	paper		thus	looks	in	good	shape	for	publication.
	I	only	have	a	relatively	minor,	though	relevant,	comment	to	offer.

Table 2 :

 2 Mean percentage of correct responses (mCR) and standard deviation (SD) and mean correct reaction time in ms (mRT) and SD in the left and right visual hemifields for the two stimulus types (flanked small and single large stimuli) and all groups (Normal controls, right brain-damaged/RBD patients, left neglect patients, left hemianopic patients).

			Normal	Left Neglect	Left Hemianopic	RBD
			controls	patients	patients	patients
		mCR	69.9	26.9	1.6	51.6
	Flanked	(SD)	(14.9)	(17.7)	(2.9)	(19.7)
	small	mRT	522	615	516*	571
	Left visual	(SD)	(104)	(163)	(42)*	(124)
	field	mCR	94.5	50.6	14.1	85.1
	Single large	(SD) mRT	(8.2) 419	(16.3) 564	(8.7) 453**	(11.6) 502
		(SD)	(75)	(36)	(54)**	(56)
		mCR	64.7	39.4	53.9	50.0
	Flanked	(SD)	(16.8)	(23.6)	(24.1)	(25.4)
	small	mRT	512	545	509	562
	Right visual	(SD)	(80)	(117)	(129)	(120)
	field	mCR	89.7	63.8	70.3	82.8
	Single large	(SD) mRT	(8.5) 429	(11.3) 518	(31.8) 476	(14.8) 493
		(SD)	(82)	(133)	(135)	(68)
	*mRT and SD calculated on 2 LH patients
	**mRT and SD calculated on 7 LH patients

Acknowledgements

We are grateful to the E. and B. De Rothschild Foundations (NewYork and Geneva).

Ipsilesional Attention Deficit 32

Verdon V, Schwartz S, Lovblad KO, Hauert CA, Vuilleumier P. (2010). Neuroanatomy of hemispatial neglect and its functional components: a study using voxel-based lesionsymptom mapping. Brain. (Pt 3):880-94.

Vernet M, Japee S, Lokey S, Ahmed S, Zachariou V, Ungerleider LG. (in press). Endogenous


Hydrogen isotope separation plays an important role in modern industrial applications, particularly in the nuclear industry where it will have an even greater importance with the advent of nuclear fusion technology. Historically, it was accomplished by cryogenic distillation or by Girdler method but their separation efficiency is rather low. [START_REF]Separation of Hydrogen Isotopes[END_REF] Recently, an alternative approach based on the adsorption in nanoporous solids has been proposed. This technique relies on the "quantum sieving" effect which takes place at cryogenic temperatures (< 100 K) when the size of the molecules is close to the pore diameter. [START_REF] Cai | [END_REF]3 Under these conditions, the effective molecular radius of H 2 is larger than those of its heavier isotopes, resulting in their preferential adsorption. [4][5][6] A number of coadsorption studies on zeolites [7][8][9][10] and metal organic frameworks (MOFs) [11][12][13][14] reported D 2 /H 2 selectivity values higher than one, which indicates a preferential adsorption of D 2 . These values are high at low loading and decline as the adsorbed amount increases. This effect implies that such adsorbents are poorly suitable for industrial separations which are usually rea Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), UMR 6303 CNRS/Université de Bourgogne Franche-Comté, F-21078 Dijon, France. E-mail: jean-pierre.bellat@u-bourgogne.fr b CEA, DAM, Valduc, F-21120 Is-sur-Tille, France. † Electronic Supplementary Information (ESI) available: details of the experimental methods including sample characterization, simulation details and additional simulation results. See DOI: 00.0000/00000000. alized at high loading. As suggested by molecular simulations, the increase of D 2 /H 2 selectivity with loading might be achieved under strong confinement of the adsorbed phase in small pore zeolites 15 or carbon nanotubes 16 . Recently, such effect has been observed experimentally in ultramicroporous MOFs at 20 K, below the boiling points of H 2 and D 2 , and only for low loadings (1-2 mmol g -1 ). 17,18 In the present communication, we report an increase of the D 2 /H 2 selectivity with pressure in pure silica chabazite at 47 K for high loadings (> 10 mmol g -1 ). As far as we know, this phenomenon has never been reported in the literature. Moreover, the mechanism governing this effect is elucidated by grand canonical Monte Carlo (GCMC) simulations. Based on a detailed analysis of the simulation data, we advance an explanation of the increase of selectivity which results from the rearrangement of the adsorbed phase associated with its strong confinement.

The structure and properties of the pure silica chabazite as well as the details of the experimental techniques used in this work are described in ESI. † In the GCMC simulations, we used our own force field developed for pure silica zeolites. As in previous works devoted to zeolites, [19][20][21][22] the quantum effects emerging at cryogenic temperatures were taken into account by the 4 th order Feynman-Hibbs effective interaction potential. [START_REF] Feynman | Quantum Mechanics and Path Integrals[END_REF][START_REF] Sesé | [END_REF] The zeolite framework was kept rigid during the simulations. See ESI † for additional details about the simulation methods.

Figure 1 reports H 2 and D 2 single gas adsorption isotherms measured and simulated at 47 K and 77 K in the 1-100 000 Pa pressure range. At 77 K, our simulations reproduce perfectly the shape and the adsorbed amounts. At 47 K, a striking feature is the presence of a step in the adsorption isotherms. In the experimental curves, the step starts at ∼1000 Pa for D 2 and at ∼10 000 Pa for H 2 . The simulations reproduce correctly this behavior but with the positions of the steps shifted to ∼2000 Pa for D 2 and ∼30 000 Pa for H 2 . Interestingly, the step occurs at the same load- ing for both species, at a value of 15-18 molecules per unit cell (6.9-8.3 mmol g -1 ). The presence of a step in the adsorption isotherms can be explained either by a flexibility of the adsorbent or by a rearrangement of the adsorbed phase. Given that we used a rigid zeolite structure in our simulations, the rearrangement of the adsorbed phase appears to be the most plausible hypothesis, as it will be shown in the following.

The simulation results presented in figure 1 were obtained with the unit cell parameters of chabazite determined at room temperature. However, this zeolite is known to have a large negative thermal expansion coefficient. 25 The only available values of this coefficient have been determined in the 293-873 K temperature range. Nonetheless, we carried out additional simulations with an expanded chabazite unit cell. The increase of the cell parameters has only a small influence on the maximum adsorption capacities. In contrast, the position of the steps in the simulated isotherms become closer to the experimental ones (see ESI, † figure S4).

To investigate the mechanism giving rise to the step in the isotherms, a density profile analysis of the adsorbed molecules inside the chabazite pores was done. The results are plotted in figure 2 as a function of the distance from the center of the octagonal windows (see the schematic representation of the chabazite structure in figure 3). It can be seen that before the step (dashed lines) only two peaks are visible, corresponding to molecules adsorbed inside the cages at a 2 Å distance from the centers of the octagonal windows. Only a very small fraction of the molecules is located at the window centers. After the step (solid lines), these sites become heavily populated as evidenced by the appearance of a high central peak. Moreover, the two other peaks, already observed before the step, are displaced at a 3-3.5 Å distance from the octagonal window centers. Thus, this rearrangement is related to the appearance of molecules at the window centers, which repel the surrounding molecules. In consequence, a denser adsorbed phase is formed as evidenced by the analysis of the snapshots and the pair radial distribution functions (see ESI, † figures S5 and S6).

To understand how the adsorbed phase rearrangement influences the D 2 /H 2 selectivity, we carried out GCMC simulations and coadsorption experiments of a 3:1 H 2 + D 2 mixture at 47 K 2 Density profiles of H 2 and D 2 molecules in the single gas adsorption case in pure silica chabazite at a temperature of 47 K, both before the step (P = 316 Pa, dashed lines) and after the step (P = 100 000 Pa, solid lines). The density profiles are computed on small cylinders distributed along an axis going from the center of a cage (r = -4.65 Å) to the center of a neighboring cage (r = 4.65 Å) and passing through the octagonal window separating them (r = 0 Å). The diameter of these cylinders is chosen to be 3.72 Å, corresponding to the size of the windows. The density ρ * is normalized by a reference value, arbitrarily chosen as the average density of D 2 molecules adsorbed at 47 K and 100 000 Pa.

Hexagonal prism

Octagonal window Cage Fig. 3 Schematic representation of the chabazite structure, composed of two sub-units: hexagonal prisms and cages. Only the latter are accessible to adsorbed molecules, which can diffuse through the octagonal windows. For the sake of clarity, the inaccessible pores and windows are rendered in opaque blue. Note that a unit cell of chabazite is composed of 3 cages and 3 hexagonal prisms and its chemical composition is (SiO 2 ) 36 for the pure silica variant. 4 Experimental (solid lines) and simulated (dashed lines) adsorption selectivity of D 2 towards H 2 in pure silica chabazite at 47 K. This value is calculated as the ratio of the molar fractions of D 2 in the adsorbed and gas phases, respectively, divided by the same ratio for H 2 .

(see ESI † for details). The D 2 /H 2 selectivity values are plotted in figure 4 as a function of the total adsorbed quantities per unit cell. The simulated data exhibit an excellent agreement with the experimental ones. For a loading below 18 molecules per unit cell (8.3 mmol g -1 ), the selectivity slowly increases from a value of 1.5 at zero loading to 1.9. Above this threshold value, corresponding to the start of the step in the adsorption isotherms (see figure 1), the selectivity increases promptly to a maximum of 4.0 at complete saturation of the microporous volume. Namely, for a loading of 27 molecules per unit cell (12.5 mmol g -1 ).

To investigate this effect, as previously done for single gases, density profiles are calculated and given in figure 5 before and after the step. The rearrangement observed when the pressure increases is quite similar to that obtained in the single component adsorption case discussed above. The effect on the D 2 /H 2 selectivity is directly visible on these density profiles. Specifically, before the step, a 2:1 density ratio between H 2 and D 2 can be calculated from the intensities of the peaks compared to a 3:1 ratio in the gas phase. After the step, the same adsorption sites inside the cages become even more selective, with an almost 1:1 density ratio. The most remarkable feature concerns the new sites located at the window centers, where the D 2 density is about three times greater than the H 2 one.

Based on our density profile analyses, we can attribute this selectivity increase to a strong confinement effect in chabazite pores with filling. Indeed, after the step in the adsorption isotherm, the adsorbed phase becomes denser due to the repulsion effect of the molecules located at the window centers. This strong confinement favors the adsorption of D 2 molecules which have a smaller effective size than H 2 due to quantum effects. 4 Our study evidences a novel effect consisting in the increase of the D 2 /H 2 selectivity at high loading in pure silica chabazite at 47 K. Based on GCMC simulations, we show that this phenomenon is produced by the rearrangement of the adsorbed phase that increases its confinement. Thus, we can conclude that in quantum sieving the window size is not the only important parameter. At high loading, the fine balance between the pore geometry and the intermolecular interactions defines the guest molecules packing. In particular, for hydrogen isotopes separation this confinement effect may induce a significant increase of the selectivity in favor of heavier species. This opens new perspectives for the design of more selective nanoporous materials.

  J o u r n a l Na me Enhanced Quantum Sieving of Hydrogen Isotopes via Molecular Rearrangement of the Adsorbed Phase in Chabazite † Bastien Radola, a Igor Bezverkhyy, a Jean-Marc Simon, a José Marcos Salazar, a Mathieu Macaud, b and Jean-Pierre Bellat * a Coadsorption experiments reveal an unexpected increase of the D 2 /H 2 selectivity with loading in pure silica chabazite at 47 K. This effect is correlated with the appearance of a step in the adsorption isotherms of H 2 and D 2 . Grand canonical Monte Carlo simulations show that this phenomenon is related to a molecular rearrangement of the adsorbed phase induced by its strong confinement. In the case of a H 2 and D 2 mixture, this rearrangement favors the adsorption of D 2 having a smaller size due to quantum effects.

  Fig.2Density profiles of H 2 and D 2 molecules in the single gas adsorption case in pure silica chabazite at a temperature of 47 K, both before the step (P = 316 Pa, dashed lines) and after the step (P = 100 000 Pa, solid lines). The density profiles are computed on small cylinders distributed along an axis going from the center of a cage (r = -4.65 Å) to the center of a neighboring cage (r = 4.65 Å) and passing through the octagonal window separating them (r = 0 Å). The diameter of these cylinders is chosen to be 3.72 Å, corresponding to the size of the windows. The density ρ * is normalized by a reference value, arbitrarily chosen as the average density of D 2 molecules adsorbed at 47 K and 100 000 Pa.

  Fig.4 Experimental (solid lines) and simulated (dashed lines) adsorption selectivity of D 2 towards H 2 in pure silica chabazite at 47 K. This value is calculated as the ratio of the molar fractions of D 2 in the adsorbed and gas phases, respectively, divided by the same ratio for H 2 .

Fig. 5

 5 Fig.5 Density profiles of adsorbed molecules for a 3:1 ratio H 2 + D 2 mixture in pure silica chabazite at a temperature of 47 K, both before the step (P = 316 Pa, dashed lines) and after the step (P = 100 000 Pa, solid lines). The density profiles are computed in the same way as in the single gas adsorption case (see figure2).

  Experimental and simulated adsorption isotherms of single H 2 and D 2 in pure silica chabazite at 47 K and 77 K.

		30
		25	Exp. H 2 47 K Exp. D 2 47 K
				Sim. H 2 47 K
	N ads (molec./u.c.)	10 15 20	Sim. D 2 47 K Exp. H 2 77 K Exp. D 2 77 K Sim. H 2 77 K Sim. D 2 77 K
		5
		0	1	10	100	1000	10000	100000
					P (Pa)
	Fig. 1

J o u r n a l N a me , [ y e a r ] , [ v o l . ] ,

Conflicts of interest

There are no conflicts to declare.