Didier Letourneur

Kieran Joyce

Cédric Chauvierre

Yves Bayon

Abhay Pandit

Enabling Biomaterials Translation in Academia: Redefining Value Proposition with Updated Regulations

Keywords: Biomaterials, Tissue Engineering, Translation, Medical Device Regulation, Innovation

Academic institutions are becoming more focused on translating new technologies for clinical applications. A transition from "bench to bedside" is often described to take basic research concepts and methods to develop a therapeutic or diagnostic solution with proven evidence of efficacy at the clinical level while also fulfilling regulatory requirements. The regulatory environment is evolving in Europe with transition and grace periods for the full enforcement of the Medical Device Regulation 2017/745 (MDR), replacing the Medical Device Directive 93/42/EEC (MDD). These new guidelines increase demands for scientific, technical and clinical data with reduced capacity in regulatory bodies creating uncertainty in future product certification. Academic translational activities will be uniquely effected by this new legislation.

The barriers and threats to successful translation in academia can be overcome by strong clinical partnerships, close-industrial collaborations, and entrepreneurial programs, enabling continued product development to overcome regulatory hurdles, reassuring their foothold of medical device development.

Introduction

The landscape for academic translation is evolving to align with recent and upcoming changes in regulatory policies. Historically, the efficiency of University technology transfer is generally inferior, characterized by protracted timescales, and low adaptation of Invention disclosure forms (IDFs) towards patents and licenses. Less than half of IDFs will be transformed into patents while only 15% of original disclosures will be licensed for development and commercialization. [1] This difficulty in transforming innovative ideas from academic research into industry-produced marketable products can be attributed to the high-risk of product success and the uncertainty of the return on investment, such as the cost of patents. [2,3] Industry-based ventures of medical devices accounted for 82% of all devices obtaining regulatory approval in clinical trials. Collaborative engagement with industry has been shown to incredibly beneficial, as the rate of regulatory approval rate doubles in academic-industrial collaborative ventures. [4] The main hurdle to overcome after regulatory approval is securing financial resources which can be overcome by defining the unmet clinical need and setting out a clear plan to ensure both clinical integration and subsequent reimbursement. [5] The transition into the new regulatory environment in Europe with the full enforcement of the Medical Device Regulation 2017/745 (MDR) will even further challenge the development of emerging technologies into the marketplace.

Where do academic institutions currently stand on the developing landscape of Medtech regulation?

Academic institutions are gaining a foothold in successful translational endeavors in recent years having a stake in at least a third of all developed devices (Fig 1). [4] Academic research has been the driving force behind the inception of emerging technologies and early development of potential products. [6] Academic centers are focused on implementing multidirectional and multidisciplinary translational research capabilities, with the priority of fulfilling key performance indicators and publication requirements from funding agencies while improving commercialization productivity and bridging translational gaps. [7] Innovation from academic laboratories can be fully realized to have a meaningful impact in the clinic and community through collaborative efforts of discovery and development from both academic and industrial and clinical input. [8] Clinicians and industrials share common views for medical device development. These clinical/industrial-oriented projects require research steps to provide innovative solutions or preclinical validations for clinical needs-these factors alone or in combination, drive industrial production towards clinical validation of an end-product. Many companies have graduated from relying on internal R&D to external collaboration, supported by governmentled initiatives to promote open-innovation projects. [9] Academia-industry joint activities can be characterized as formal (consulting, contract and collaborative research) and informal (academic discourse, guidance and advocacy, and networking with academic and clinical researchers). [10] For instance, proposed and patented the idea of a new open and suturable aortic ring using previously accredited material components, to reduce the dilated diameter of the aortic root while maintaining expandability. [11] Together with an industrial partner and a research laboratory located within the same hospital, they developed prototypes, performed in vitro tests to evaluate their safety and mechanical effectiveness for a minimum life span of 15 years, and efficacy in sheep up to 6 months after implantation. [11] The clinicians then compared them to the current best clinical practice (mechanical valve replacement), in a prospective multicenter and international randomized prospective study (CAVIAAR Study: Aortic Valve Conservation in Aortic Insufficiency and Root Aneurysms). Positive clinical outcomes on 233 patients (89.9% survival at seven years) have now led to the 10-year follow-up with more than 5,000 patients (58 centers from 17 countries) undergoing this surgical approach using a medical device in humans (AVIATOR-AorticValve repair InternATiOnal Registry) which is nearing completion.

International and inter-sectoral partnerships are essential for successful clinical translation into a global market. [12] Initiatives such as The European Clinical Research Infrastructure Network (ECRIN), should facilitate multinational clinical research among scientific collaborations and consortia across Europe. ECRIN provides services to support clinical trials and ensure standard operation procedures are consistently implemented, creating reproducible high-quality data while overcoming resource constraints [13] Clinical evaluation pathways involving equivalency may still be used; however, with less flexibility, while equivalence rules will be presented in the next paragraph. Moreover, postmarket surveillance is a generalized requisite of constant update of clinical evaluation, based on 'active surveillance' of how the device performs in their real clinical life. Patient protection and transparency are strengthened with clinical data, increasingly available to the public, and to competitors, in the new EU database, Eudamed, which is planned to be implemented in 2022. [START_REF]European database on medical devices (EUDAMED) | Internal Market, Industry, Entrepreneurship and SMEs[END_REF] Eudamed will record essential information of medical devices, including certificatesand their status, conformity assessment procedures, a summary of safety and clinical performance, vigilance information (e.g. reports of a severe adverse event or device deficiency that occurs during a clinical investigation and post-market surveillance and their associated plans of corrective actions), clinical investigation information (i.e. sponsor, purpose, status, approval, summary).

What do equivalent medical devices mean under MDR? The Revision 4 update to MEDDEV 2.7/1 [START_REF]MEDDEV 2.7/1 revision 4, Clinical evaluation: a guide for manufacturers and notified bodies[END_REF] gave a detailed meaning of equivalence that is consistent with the expectations seen in the MDR. It includes three distinct dimensions: clinical, technical & biological. Briefly and non-exhaustively, equivalent devices should treat the same disease condition, with the same intended purpose and the same body site and, in the same target populations. They should show similar designs and technical features, and importantly, all their components -i.e. materials and/or substances -in contact with biological fluids or human tissues should be the same, and patient-contacting parts may require physicochemical characterization to establish the equivalency. The MDR meaning of equivalence is stricter than the US FDA meaning for 510(k)-regulated devices, relying on the same intended use and similar technological characteristics. [START_REF] Van Norman | [END_REF] What are the main expected impacts of MDR? CE mark dossier submissions should be delayed, particularly for new devices for which equivalency already CE marked devices may no longer represent a possible pathway for the pre-market clinical evaluation. They depend more and more on pre-market clinical data to be generated, not only to show safety but also [START_REF]European database on medical devices (EUDAMED) | Internal Market, Industry, Entrepreneurship and SMEs[END_REF] which may have a substantial impact, at least for the next coming years.

About expected evolution of clinical evidence sources? Clinical evidence sources should most certainly expand, notably to tackle MDR post-market surveillance requirements, as effectively and efficiently as possible. Randomized controlled clinical trials (RCT) and metaanalysis of RCT have undoubtedly a very high value, by allowing the evaluation of a new treatment with minimal biases versus carefully selected groups. [17] Generating continuous clinical evidence should provide equivalent additional value on medical devices regarding their safety, efficacy -including the long-term -efficacy and absence of non-desirable effects.

This can be achieved by national databases and registries but should be more rewarding if efforts are coordinated and synchronized. [START_REF] Hqip | Proposal for a Medical Devices Registry -HQIP[END_REF] This is supported by the International Medical Device Regulators Forum (IMDRF), an international voluntary group of medical device regulators. [START_REF] Hqip | Proposal for a Medical Devices Registry -HQIP[END_REF] Real-world data and real-world evidence are further substantiated by the FDA with the 21 st Century Cures Act passed in 2016, and issues of guidance to the use of real-world data and real-world evidence to support regulatory decision-making. [START_REF]Real-World Evidence | FDA[END_REF] But it is also important not to lose sight of the expectations of post-market surveillance and to be aware of the limits of the different approaches to generating clinical data, i.e. the value that they can actually produce. For example, registries for abdominal hernia surgeries have been developed following pan-national initiatives (e.g. Herniamed in German-speaking countries, Germany, Austria & Alemannic Switzerland) and clinical societies (e.g. EuraHS in Europe, AHSQC in the USA). Herniamed was successful at accumulating enough surgery cases with more than seven commercial meshes used for intraperitoneal on-lay mesh (IPOM) hernia repair to clearly show that one of them led to higher hernia recurrence rate, one year after surgery. [START_REF] Köckerling | [END_REF] Potentially, other tools can be used, nationwide clinical data sharing database initiatives (e.g. German Medical Informatics in Germany and a Health data hub in France) with enough depth of individual patient information to support retrospective and continuous clinical studies. [21] Recommendations by national and European agencies as well as by clinical societies are expected to guide post-market surveillance and the notion of what defines an acceptable, yet achievable, level of clinical evidence.

How Academia Should Move to be a Stronger Translation Initiator & Stakeholder -a SWOT analysis considering update MDR

A SWOT analysis identifies the internal strengths and weaknesses of university-based translation, as well as its external opportunities and threats (Fig. 2).

Strengths

Universities are in a unique position to partake in translational research with their intrinsic link to the clinic through institutional undergraduate and postgraduate programs integrating clinical students in bench and biomedical research. The pool of MD/PhD and broadly based PhD investigators capable of performing this translational research is gradually being increased with new integrated MD-PhD programs becoming accessible. [22,23] Furthermore, patient involvement and considerations into recommendations relevant to researchers' activities are valuable to gain experiential knowledge. [24] Close industry collaborations are valuable to mitigate risk and ensure a focused approach towards project selection and fast track translation. [2] There must be a clear discourse from the outset between an academic institution and a company from the beginning to agree on the timely release of data and a roadmap towards patenting. [25] This symbiotic relationship between academia and industry better aligns medical devices with market expectations and commercial success, when an affordable and reimbursable product is needed. Therefore, optimization of production costs and the early discussions with relevant authorities on reimbursement strategies play a crucial role in transforming these products into the standard of care therapeutics.

Specific niches in R&D processes have been identified in which these academicindustrial partnerships are most likely to see the best return on investment for all stakeholders. These research units are best equipped to deliver on small-scale product development in the early adoption phase of new technology. Academic institutions are becoming more involved in developing combination devices of an industry product with new delivery vehicles or through the expansion of existing, university generated platforms of materials, molecules and disease targets. Such an example is Cambridge-based Healx, which utilizes artificial intelligence to enhance drug discovery in rare diseases. [26] In the academicindustry partnerships, the focus shifted towards composite device(s) for renewal of patents to ward off competition from generic formulations. [START_REF] Ahn | Second Generation Patents in Pharmaceutical Innovation[END_REF] Most new medical product "innovations" introduced to the market are not innovations, but incremental changes to existing product classes, demonstrating improved efficacy and fewer off-target effects. The MDR includes articles addressing devices that contain a biologically active component on the market. These drug-device combinations are separated into two categories: 1) Devices incorporating a substance or drug that, if used stand-alone, would be considered a medicinal product and the action of the substance in the device is principal (Article 1.8) and 2) Devices that administer a medicinal product, in which the combination device forms a single integrated non-reusable product (Article 1.9). Any implantable substrate will be classified as a medical device or as an Advanced Therapy Medicinal Product (ATMP) according to its working principles and/or components and will be regulated accordingly.

Industries expand into new fields by collaborating with academic labs with prior expertise in such fields. [START_REF] Barnes | [END_REF] Lipocoat, a spin-out from the University of Twente, has patented a phospholipid-coating for implants for drug-delivery and to improve osteointegration, securing €3 million in funding to date. [29] Universities with a strong portfolio of university-industry linkages to reflect the scope of activities and the types of expertise better aligned with their institutional goals and funding criteria. A balanced portfolio of projects in risks and cost is crucial to bridge the gap to sustaining batch manufacturing for preclinical and first-in-human trials. To ensure success, these activities require exceptional support for protocol development and regulatory submissions. Regulatory bodies must also be involved early in these ventures, as they will specify the use of specific models for pharmacological and toxicological studies. [30]

Weaknesses

Translation in academia has traditionally been slow with few healthcare practices recommended by research institutes actually being implemented, and it frequently takes more than fifteen years for evidence-based research recommendations to be translated into standard practice in healthcare institutions, in an environment that has a high turnover in student and post-doctoral workers based on the nature and structure of funding calls and position durations. [1] The barriers to translation are interconnected, where the inadequate design of research programs means easy adoption into a healthcare setting is not facilitated.

Furthermore, poor or inadequate marketing to stakeholders may mean failure to recognize an evident value proposition for the new idea. The act of translation is one of the core problems in itself, as apparent from the disconnect of translating the evidence-based results from scientifically literate researcher to a common language understood by the clinicallyoriented practitioner and stakeholders in the form of tangible results and potential clinical outcomes. [31] Conversely, while scientists have difficulty expressing the importance of their concepts in real-world terms, clinicians also fail to translate clinical needs to researchers in a comprehensible way. [32] Increasing regulatory demands are resource-intensive. For example, methodical iteration and statistical validation of molecules, targets, pathways, doses, formulations/prototypes, and series of preclinical testing with certified quality-controlled methods are often difficult to find in classic academic laboratories. [33] The additional inspection, including increased onus on clinical evaluation, instructions for use, and postmarket surveillance will make some potential value propositions unsustainable. This clinical evaluation must be carried out conforming to the requirements stipulated in Chapter VI.

Altogether, these increased restrictions and stipulations will increase the cost of translating devices to market, highlighting the need for increased investment from the industrial or staterun enterprise.

Opportunities

Industry collaborations and formal entrepreneurial training activities equip academic entrepreneurs with the relevant knowledge and experience to understand regulatory challenges associated with clinical translation. [34] These skills allow them to augment their awareness of potential opportunities while further appreciating the resource configurations development pathways required to pursue newly recognized opportunities. Universities have been developing new educational programs and framework to support innovation with Bedside-to-Bench-and-Back programs, spurred by the mounting evidence that a disconnect between basic science and clinical researchers hinders entrepreneurial ventures. [35] In the US, project-oriented curricula have emerged within academic institutions to promote entrepreneurship; such is the case with SPARK-Stanford, where more than half of the incubated projects are licensed every year, to be implemented in the clinic or further commercialized. [36] An equivalent innovation program, Bioinnovate, has been installed in NUI Galway and seen similar success in its fellowship program. EMBO medical, specializing in single-shot reliable embolization devices, was Bioinnovate's first spin-out company in which was acquired ClearStream Technologies for almost €43.5 million in 2016. Similarly, EU programs, educational curricula and dedicated summer schools have been developed. The European Institute of Innovation & Technology (EIT) Health has been successful in facilitating collaborations between academics, clinicians and industry, resulting in 122 start-ups that have secured €27.9M in capital investment. [START_REF] Ribeiro | Heal. 2019 -12th Int. Conf. Heal. Informatics, Proceedings; Part 12th Int. Jt. Conf. Biomed. Eng. Syst. Technol. BIOSTEC[END_REF] In Ireland, for example, the Enterprise Ireland Commercialisation Fund Programme supports researchers in academic institutions that aim to convert the outputs of state-funded research into innovative licensed products, services and start-up companies. A researcher can apply for feasibility grants, commercialization funds and clinical innovation awards. Academic institutions have a unique opportunity to provide a hub for parties to create multi-disciplinary teams from medicine, science, engineering, business and law faculties with mutually aligned goals. [START_REF] Maher | [END_REF] Educating researchers with a commercialization mindset can have a significant impact on how researchers view and act on translational opportunities. [START_REF] Maher | [END_REF] Devices approved for minimal volume clinical indications with the MDD CE mark may be at risk of disappearing due to the quality and quantity of available clinical data to support post-market surveillance requirements. And more generally, the time of the first certification or certification renewal should also be affected by the slowly increasing number of MDR accredited notified bodies with fourteen to the date, just a few months before the end of the MDD to MDR transition period, in May 2021, [START_REF]European database on medical devices (EUDAMED) | Internal Market, Industry, Entrepreneurship and SMEs[END_REF] which may have a substantial impact, at least for the next coming years. Academic-led projects can address the need for increased, highquality clinical data by elucidating the mechanism of action, strengthening the safety and efficacy of a device through increased confirmatory preclinical investigations. [39] [40] Academic research can play a valuable role in influencing health policy by developing guidelines with network-driven national initiatives that include clinicians, scientists, industry experts, investors, regulatory experts and policymakers to guarantee clinical adoption, costeffectiveness and return on investment. The scope of translation can be broadened to include social impact and increased public engagement through film-making, classroom workshops, public events and media coverage. These outputs inform the community to enact change in societal values and policy to advocate health and well-being. A scientifically informed population will promote awareness and understanding for continued funding from national agencies. [START_REF]SFI discover | Engagement[END_REF] This communication between researchers and end-users creates a complex model of translational research, as an iterative, multidirectional and dynamic process, increasing the likelihood of technology adoption by the target group. [7] Community-driven research strategies focused on interdisciplinary collaborations, aim to more efficiently integrate proven health services interventions into clinical practice. [START_REF] Battaglia | [END_REF] Threats Concerns are already being raised regarding the time-to-market in Europe for new medical devices. While the EU moves to replace the MDD with the MDR, the US FDA have released new strategies aiming to "reduce the time and cost of generating clinical evidence, typically the most expensive and lengthy regulatory requirement for marketplace entry." This move comes at a time when few MDR accredited notified bodies have been approved for processing the expected increase in re-applications to conform to additional requirements. These factors combined could make EU market access difficult and costly, compelling start-ups to translate into other markets.

The new Articles of the MDR describe standards that must be conformed to, representing a significant increase in onus and responsibility on academics and all stakeholders. Additionally, a designated regulatory compliance officer must be appointed within an organization, with demonstrable prior experience and expertise in medical device regulation and compliance. While the classification system remains standard, definitions have narrowed and been altered for some products, which will cause some devices to be reclassified to higher classes (under Classification Rule 21 and Annex I). Furthermore, previously unclassified or exempt devices will now be classified and regulated within the scope of the new legislation. This will incur high cost on existing products licensed by universities, potentially leading to discontinuation if capital investment in such projects has not foreseen these increased demands for regulatory approval.

The EU MDR will impose the obligation to produce clinical data for the CE marking of biomaterial-based implants, as they are high risk devices. Compared to the MDD, The MDR puts significantly more focus on clinical evaluation and post-market surveillance. This new legislation eliminates the principle of equivalence for market approval, requiring more sophisticated trials and increased costs for clinical evaluation. To improve translation in academia, dedicated teams are necessary to screen the commercialization potential of projects with a health economic assessment to decide on further progression towards translation. [43] Across Europe, there is limited consensus clinical and economic analysis in health-technology assessment guidelines. [44] The evidence-based identification of unmet clinical needs and market research engages investors with an attractive value proposition to improve the efficiency of the translational system to move progress outside the academic sphere through start-ups formed of a multidisciplinary team. [45] Early input from stakeholders is crucial in guiding the development of biomaterials to market. To this end, industrial partners, funding bodies (private and/or public), clinicians and end-users should be consulted early, defining clear milestones with go/no-go decisions, to protect the integrity of the product for more successful translation.

Conclusion

Academic institutions remain a significant contributor to the creation and translation of clinicready and patient-focused medical devices while developing the next generation of industryrelevant, publicly engaged researchers to become an anchor for applicable industry research.

  While regulatory systems are evolving with uncertainty looming over the certification and market access, translational activities remain attractive ventures. Universities are wellpositioned to attract sufficient investment to meet increased regulatory demands through fruitful industrial partnerships and dedicated state-run funding schemes. The barriers and threats to successful translation in academia can be overcome by strong clinical partnerships, close-industrial collaborations, dedicated funding schemes and entrepreneurial programs, enabling continued product development to overcome regulatory hurdles, reassuring their foothold of medical device development.

Figure 1 .

 1 Figure 1. Insight into the current landscape for academic translation. Academia focuses on activities centered on clinical collaborations, industrial partnerships and translational programs. In 2016, universities were involved in the development of one-third of all devices approved by regulatory bodies. This market is expected to grow with a compound annual growth rate (CAGR) of 4.1% over the next five years. Examples of key translational activities are embodied by public research organizations, university-based spinout companies, collaborative networks and technology platforms. The unique value proposition of universities remains attractive despite growing challenges in device approval and path to market.

Figure 2 .

 2 Figure 2. SWOT analysis of University-based translational activities. The perceived weaknesses and threats to university-based translation are offset by the perceived strengths and opportunities in light of the developing landscape of regulatory legislation.

  Lansac et al. (Vascular Surgery, X. Bichat Hospital, INSERM U1148, Paris)

. EU Medical Device Regulation Impact on Industry and Innovation

  circulatory system are up-classified, i.e. to comply with stricter requirements, which would mean extended time to market access. Notified bodies will instruct any medical device filing for market approval, in a much more rigorous way, especially on clinical evidence. This would, most probably, prolong the time of the review process. A significant change of the MDR is a greater need for clinical investigations according to dedicated European rules and strengthened clinical data transparency.What is expected by the new MDR in terms of clinical investigation? Clinical data should be more detailed. They must, in principle, be sourced from clinical studies on the device, be supported by published literature or specific and/or strengthened by the relevant post-market experience. The clinical benefit must be demonstrated, either for the patient

	Recent years have seen increasing regulatory and safety requirements in the EU, fierce spine or central
	generic drug competition in the pharmaceutical industry, and the growing complexity of
	products in the pipeline. Stringent regulations are becoming too cumbersome to fulfill, while
	the policy is dictating what interventions are adopted. Manufacturing challenges and
	increasing R&D costs, meanwhile, are making drug and device development less attractive to
	multinational companies. This deterrence is reflected by a slowing in industry innovation and
	a reduction in R&D funding models. Shortly, we can expect additional challenges with an ever-
	changing landscape, but the focus will remain on innovation potential and differentiation
	value combined with demonstrable benefit.
	3Any medical devices, including biomaterials, intended to be used in the clinics should comply
	with current regulations for human use. The regulatory environment is evolving in Europe
	with transition and grace periods for the full enforcement of the Medical Device Regulation
	2017/745 (MDR), replacing the Medical Device Directive 93/42/EEC (MDD).
	Why is this happening? The change has been motivated to ensure a consistently high
	level of health and safety protection for European citizens and to adapt to technological and
	scientific progress. New medical devices will have to comply without exception to new
	Regulation from May 2021 (postponed due to COVID-19 crisis) and currently approved
	medical devices under the MDD will have to be approved in conformity with the MDR, by Apr
	2024 at the latest, to be placed on the market after this date. The MDR is highly descriptive,
	with more details and new requirements as illustrated by the number of pages, which jumps
	from 95 for the former Directives to 175 for the new regulation.
	What is not changing? The MDR relies on the same necessary regulatory process, by
	including these crucial stages of medical device lifecycle: i) product design and manufacturing
	controls, ii) safety and performance evidence, iii) conformity assessment to in force directives,
	regulations and harmonized standards involving qualified notified bodies, iv) CE marking and
	v) vigilance and post-market follow-up.
	What is new? The MDR is, in fact, a modernized and strengthened system with
	significant impacts on the regulation of high-risk devices, notified bodies and clinical evidence
	generation. Briefly, high-risk devices such as joint replacements, materials in contact with

Although industrial partnerships are vital to driving technological advances towards the market, nongovernmental bodies such as ECRIN fulfil an important role to ensure clinical research and innovation are scientifically substantiated, transparent, and meet demanding regulatory stipulations.

and/or for clinical practice. Sole demonstration that the device "works" is not enough. Clinical investigations under MDR are mandatory for implants and Class III devices, with limited exceptions. Legacy products found compliant with the MDD before May 2021 may not require additional clinical investigations if they already benefit from sufficient clinical evidence.

Acknowledgements

The authors would like to take this opportunity to thank Michael Gelinsky, Prof.

Dubruel for organizing the plenary session with Yves Bayon at the Annual Conference of the European Society for Biomaterials (ESB), 2019, in Dresden, from which this review has emanated. Works performed by DL and CC are supported by INSERM, University of Paris and University Sorbonne Paris Nord. DL has shares in the Siltiss Company for the development of Tissue Engineering products. Works performed by KJ are supported by CMNHS Scholarship, NUI Galway and the European Regional Development Fund and Science Foundation Ireland under Ireland's European Structural and Investment Fund, Grant Number 13/RC/2073.


Sylvie Chokron
email: sylvie.chokron@gmail.com

Lucas Dubourg

Clémentine 2 Garric

Fiora Martinelli

Céline Perez

Dissociations between perception and awareness in hemianopia

Keywords: Homonymous Hemianopia, blindsight, anosognosia, hallucinations, awareness, occipital

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Homonymous hemianopia: definition, etiology and lesion location

Clinically, the most common visual field defect to follow a retrochiasmatic lesion is homonymous hemianopia (HH) [START_REF] Zihl | Rehabilitation of Visual Disorders After Brain Injury[END_REF]. In most cases, the hemianopic defect is congruent: the losses to the contralesional field of each eye are symmetric to the point that they can be superimposed [START_REF] Zihl | Rehabilitation of Visual Disorders After Brain Injury[END_REF] (see Figure 1). 70% of strokes that involve the posterior cerebral arteries lead to HH [START_REF] Pambakian | Can visual function be restored in patients with homonymous hemianopia[END_REF]. On the other hand, HH occurs in 30% of patients that have suffered a stroke [START_REF] Zhang | Homonymous hemianopias: Clinical-anatomic correlations in 904 cases[END_REF].

Regarding lesion side, our group recently demonstrated that the defects in hemianopic patients, as well as the cortical reorganization that follow a V1 lesion, can depend on the hemisphere in which the lesion occurs (Cavezian et al., 2010;[START_REF] Perez | An fMRI Investigation of the Cortical Network Underlying Detection and Categorization Abilities in Hemianopic Patients[END_REF]. These results suggest the existence of hemispheric specialization at the occipital level, which could influence the adaptive and reorganizational phenomena that follow visual-cortex lesions and visual field defects (for a discussion, see [START_REF] Perez | An fMRI Investigation of the Cortical Network Underlying Detection and Categorization Abilities in Hemianopic Patients[END_REF]Cavezian et al., 2015).

Although homonymous hemianopia is generally considered only as a visual field defect, below we present and discuss why this deficit is an interesting model to study the dissociation between perception and awareness.

Anosognosia

Lesions in the primary visual cortex (V1) cause a loss of conscious access to most visual information in the contralesional visual field [START_REF] Holmes | Disturbances of vision by cerebral lesions[END_REF][START_REF] Weiskrantz | Visual capacity in the hemianopic field following a restricted occipital ablation[END_REF]. However, hemianopic patients might be unaware of their visual field defect and may suffer from anosognosia. In 1885, Von Monakow published the first description of unawareness of disorders due to brain lesions. Subsequently, [START_REF] Babinski | Anosognosie[END_REF] coined the term anosognosia to describe this phenomenon ranging from uncritical underestimation to explicit, intractable denial of the clinical signs including cortical blindness, spatial neglect, cortical deafness, hemiplegia, word deafness, dyslexia, dysphasia (see for review and discussion, [START_REF] Gainotti | History of Anosognosia[END_REF]. In a seminal paper on this topic, [START_REF] Bisiach | Unawareness of disease following lesions of the right hemisphere: anosognosia for hemiplegia and anosognosia for hemianopia[END_REF] investigated awareness of motor and visual-field defects in 97 right brain-damaged subjects. Both kinds of anosognosia were found to be double-dissociated and anosognosia for hemianopia fails to show any association to unilateral neglect. In addition, four of the 10 patients with severe anosognosia for hemianopia had minimal (if at all) anosognosia for hemiplegia. These findings confirm the previous crucial observation of [START_REF] Anton | Ueber die Selbstwahrnehmung der Herderkrankungen des Gehirns durch den Kranken bei Rindenblindheit und Rindentaubheit[END_REF] that his patient Mercz., although quite unaware of her blindness, was painfully conscious of her mild verbal disorders. In addition, in Bisiach et al' study (1986), important unawareness of hemianopia was found to be much more frequent than unawareness of motor impairment. These authors proposed that the lesions involving the visual pathways could be very closed to the brain area damage responsible for disordered monitoring of the resulting dysfunction. Indeed, as [START_REF] Breitmeyer | Contributions of magno-and parvocellular channels to conscious and non-conscious vision[END_REF] stated, patients will visual field defects, may thus fail to acknowledge their visual deficits and appear as being cognitively blind to their neurological blindness. [START_REF] Critchley | The problem of awareness or non-awareness of hemianopic field defects[END_REF] identified various degrees of awareness of the visual field defect: (1) total lack of awareness of the deficit, (2) unawareness of the defect itself, but a recognition of the consequences of the defect (e.g. frequent bumping into objects or persons), ( 3) Attribution of the deficit to external causes (e;g; lack of illumination), (4) Aware that 'there is something wrong' with vision, although the deficit itself cannot be defined or described, (5) Awareness of a lateralized visual defect, although the patient think that it is an eye problem instead of a visual field defect, (6) full awareness of the hemianopia defect. As a matter of fact, in most of the cases, the patient does not experience a 'black spot' in place of his/her blind visual field. Indeed, the hemianopia can be considered as a reduction of the visual field, with new peripheral borders, leading to conscious perception in only half of the previous visual field. Along those lines, being conscious of the absence of visual stimulation in the contralesional visual field might be particularly difficult thus leading to anosognosia of the visual field loss. In this way, [START_REF] Levine | Unawareness of visual and sensorimotor defects: a hypothesis[END_REF] proposed that a post-chiasmatic lesion does not necessarily provide any specific information about the direct experience that uniquely specifies the defect. For this reason, according to [START_REF] Zihl | Rehabilitation of Visual Disorders[END_REF], unawareness of the visual field defect can be commonly found in patients with normal intellectual functions.

Indeed, this author insists on the fact that due to the absence of an immediate sensation, hemianopic patients need to infer the presence of the visual field defect from failures resulting from it (e.g. car accidents, falls, difficulties in reading etc…). In addition, according to [START_REF] Levine | Unawareness of visual and sensorimotor defects: a hypothesis[END_REF] discovery of visual loss requires 'the ability to change the mental set or outlook based on evidence from the external world' and is mainly dependent upon mental flexibility [START_REF] Zihl | Rehabilitation of Visual Disorders[END_REF]. Regarding the neuro-anatomical correlates of anosognosia for hemianopia, clinical and experimental reports (see for example [START_REF] Bisiach | Unawareness of disease following lesions of the right hemisphere: anosognosia for hemiplegia and anosognosia for hemianopia[END_REF] demonstrate that various types of lesions involving different anatomic regions can lead to anosognosia in hemianopia and that conversely, similar lesions are not always associated with anosognosia. In 1997, Celesia, Brigell and Vaphiades showed that twenty of 32 patients with hemianopia (62%) had anosognosia of their visual deficit. Anosognosia for hemianopia was observed in 16 of 26 right-brain damaged patients (62%), and was also observed in four of six left-brain damaged patients (67%). As previously found in Bisiach and colleagues study (1986), anosognosia for hemianopia was clearly dissociated from anosognosia for neglect and, for 14 patients did appear in the absence of cognitive impairment. Interestingly and as we will further discuss, patients with positive spontaneous visual phenomena (PSVP), either phosphenes, photopsia, visual hallucinations, or palinopsia, were usually aware of their deficit. Indeed, only three of 12 patients with PSVP had visual anosognosia. Regarding the neuroanatomical correlates of anosognosia for hemianopia, [START_REF] Celesia | Hemianopic anosognosia[END_REF] could not identify any cortical areas specific for awareness of the visual deficit. Lesions limited to V1, V2, and portions of V3

or their connections from the lateral geniculate nucleus were sufficient to produce anosognosia for the visual field defect. These findings infirm the previous study of [START_REF] Koehler | Aware or non-aware[END_REF] who proposed (on the basis of CT correlations) that patients aware of their hemianopia had purely occipital lesions, whereas patients unaware of their hemianopia had more anterior lesions such as parietal lesions or lesions interrupting the associative pathways from the primary visual cortex. Interestingly, in search for a hemispheric specialization for unawareness of the visual deficit, [START_REF] Celesia | Hemianopic anosognosia[END_REF] found that sixteen of 20 patients with anosognosia for hemianopia had lesions of the right hemisphere, as did four of seven patients with left brain-damage. According to these findings, anosognosia for hemianopia could be preferentially linked to right hemisphere lesions such as what has been proposed for left unilateral spatial neglect [START_REF] Heilman | Right hemisphere dominance for attention: The mechanism underlying hemispheric asymmetries of inattention (neglect)[END_REF]. As emphasized by [START_REF] Celesia | Hemianopic anosognosia[END_REF] and has we will discuss at the end of the paper, anosognosia for hemianopia could be linked to the other behavioral phenomena we present below. Indeed, in addition to this dissociation between the presence of a perceptual deficit and its awareness, blindsight, that is the ability to process stimuli in the blind visual field in the absence of conscious detection, depicts another dissociation between perception and awareness.

/Insert Table 1/ 3. Blindsight

Definition

Since pioneer work of Weizkrantz et al. (1974), we know that from a behavioral perspective, hemianopic patients can exhibit implicit residual capacities in the contralesional, so-called "blind" visual field, despite exhibiting a severe visual-field defect. Such capacities are usually referred to as blindsight, a term proposed by [START_REF] Weiskrantz | Visual capacity in the hemianopic field following a restricted occipital ablation[END_REF]. In a seminal study, [START_REF] Pöppel | Residual Visual Function after Brain Wounds involving the Central Visual Pathways in Man[END_REF] found that four patients could accurately steer their gaze toward a flashing light presented in their blind field yet did not report having perceived the stimulation.

Subsequently, several visual residual functions were tested in the patient D.B. through forcedchoice methods [START_REF] Sanders | Blindsight": Vision in a field defect[END_REF]. D.B. was asked to distinguish the orientation of stripes (horizontal vs. vertical), to identify letters (X vs. O), to reach, grasp, or sch his gaze towards a stimulus in his contralesional visual field [START_REF] Sanders | Blindsight": Vision in a field defect[END_REF]. Interestingly, in addition to performing significantly above chance in all the tasks, the patient never reported any conscious perception of the stimuli in his blind field. These results led to the first apparition of the term blindsight. Later, another blindsight patient named G.Y.

reported awareness of certain stimuli despite not attesting to any concrete visual perception of them [START_REF] Weiskrantz | Parameters affecting conscious versus unconscious visual discrimination with damage to the visual cortex (V1)[END_REF]. Consequently, blindsight was classified into two types: type I, the ability to discriminate specific attributes of a stimulus in the contralesional visual field without any awareness of it; and type II, exhibiting objective performance and subjective performance in the blind visual field above chance level, without any conscious detection of the stimuli [START_REF] Brogaard | Type 2 blindsight and the nature of visual experience[END_REF][START_REF] Weiskrantz | Pupillary Responses With and Without Awareness in Blindsight[END_REF].

Typically, type II blindsight corresponds to patients that exhibit significant objective performance scores in their blind visual field and report having felt something in the absence of conscious perception (for a review, see [START_REF] Brogaard | Type 2 blindsight and the nature of visual experience[END_REF]. As discussed below, experimental design is crucial for enabling researchers to ascertain and classify blindsight among patients.

Diagnosing blindsight implies not only an accurate measure of objective performance, but also a well-controlled and interpretable measure of subjective experience. On one hand, the stimulipresentation parameters (e.g. duration, contrast, size or location) and the response mode (e.g. verbal or motor; for a review, see [START_REF] Fayel | Characteristics of contralesional and ipsilesional saccades in hemianopic patients[END_REF] of a given experiment activate dissimilar objective abilities that may differ among subjects. On the other hand, although blindsight is defined by an absence of subjective experience, the literature reflects debates on the methodology used to assess patients' awareness [START_REF] Overgaard | Seeing without Seeing? Degraded Conscious Vision in a Blindsight Patient[END_REF]. For example, use of a binary scale (i.e. Aware vs. Unaware) may compel a subject to report being "unaware" of a stimulus despite having experienced a minor degree of awareness [START_REF] Overgaard | Seeing without Seeing? Degraded Conscious Vision in a Blindsight Patient[END_REF][START_REF] Overgaard | Visual experience and blindsight: a methodological review[END_REF]. Distinct responses on G.R.'s level of awareness in the blind visual field were found according to whether the patient was tested using a binary scale (Seen vs. Not Seen) or the Perceptual Awareness Scale (PAS) [START_REF] Ramsøy | Introspection and subliminal perception[END_REF], which comprises four levels: Clear Experience, Almost Clear Experience, Weak Glimpse and Not Seen. Indeed, when asked to process a stimulus in his contralesional visual field and subsequently report a dichotomous answer (Seen vs. Not Seen), G.R. exhibited a typical type-I-blindsight profile (i.e. implicit processing without awareness of the stimuli).

However, when assessed by the PAS, he significantly reported some degree of awareness in the presence of stimuli in his contralesional visual field, thus exhibiting a type-II profile. Despite this proven drawback, binary questionnaires are still widely used to study blindsight; indeed, very few researchers use graduated measurements of perception [START_REF] Overgaard | Seeing without Seeing? Degraded Conscious Vision in a Blindsight Patient[END_REF][START_REF] Mazzi | Blind-Sight vs. Degraded-Sight: Different Measures Tell a Different Story[END_REF]. However, understanding the nature of the patients' perceptual experience in their blind field remains an important issue as discussed below.

Perceptual experience in the blind visual field

Three distinct hypotheses have been proposed in order to account for blindsight. On one hand, some studies have emphasized that blindsight is based on unconscious perceptual abilities [START_REF] Sanders | Blindsight": Vision in a field defect[END_REF][START_REF] Leh | Unconscious vision: new insights into the neuronal correlate of blindsight using diffusion tractography[END_REF]. On the other hand, some authors have proposed that blindsight relies on residual remaining 'normal' vision [START_REF] Cowey | The blindsight saga[END_REF][START_REF] Hadid | From Cortical Blindness to Conscious Visual Perception: Theories on Neuronal Networks and Visual Training Strategies[END_REF]. Along those lines, blindsight is seen as reduced but normal residual vision. Finally, blindsight has also been interpreted as degraded, abnormal vision, that is a different form of vision than 'normal' visual perception as if looking in deforming glasses. This latter hypothesis arose from studies on type II blindsight and has been described as a "conscious experience, though of a very different nature to that of normal vision" [START_REF] Mazzi | Blind-Sight vs. Degraded-Sight: Different Measures Tell a Different Story[END_REF][START_REF] Weiskrantz | Is blindsight just degraded normal vision[END_REF][START_REF] Kentridge | What is it like to have type-2 blindsight? Drawing inferences from residual function in type-1 blindsight[END_REF].

These three hypotheses are still in debate and it is difficult to disentangle them since most of the research in this area are case studies showing one or the other type of blindsight.

Indeed, group studies using both objective visual detection and discrimination tasks and subjective perceptual scales could permit to evaluate what type of perceptual experience is the most frequent in hemianopic patients. In addition, group studies are also needed to study the occurrence of blindsight. Given the fact that blindsight stimulation has been proved to induce visual restoration (see [START_REF] Chokron | From blindsight to sight: cognitive rehabilitation of visual field defects[END_REF]Perez andChokron, 2014 for review), it would be important for clinicians to know what kind of perceptual experience is the most observed in hemianopic patients in order to design the more appropriate therapy. However, only a few studies have been conducted on groups of patients, and most of them have provided only indirect information on the occurrence of blindsight. In a group of 8 patients, [START_REF] Perenin | Residual vision in cortically blind hemiphields[END_REF] found blindsight in six out of eight patients but they did not use any perceptual subjective scale. Studying the anatomical bases of blindsight in seventeen hemianopic patients, [START_REF] Ajina | Human blindsight is mediated by an intact geniculo-extrastriate pathway[END_REF] distinguished between twelve of whom they classified as "blindsight positive" and five as "blindsight negative", based on two alternative forced-choice detection tasks related to the contralesional visual field. Using the Redundant Signal Effect (RSE) task involving indirect flash presentation to assess visual information processing in the blind and in the healthy visual field, only one out of 20 patients (5%) exhibited faster responses after simultaneous presentation of visual stimuli in the two visual fields, compared to single visual stimulation in the preserved field, expected for blindsight [START_REF] Marzi | Spatial summation across the vertical meridian in hemianopics: a test of blindsight[END_REF]. Thus, in this study, the incidence of blindsight was only 5%. In another study, [START_REF] Sahraie | Pupil response as a predictor of blindsight in hemianopia[END_REF], blindsight incidence was evaluated among nineteen patients by measuring their pupil responses to visual stimuli presented in the hemianopic visual field, which reflects residual visual reflexes.

These authors found a blindsight incidence of 70% [START_REF] Sahraie | Pupil response as a predictor of blindsight in hemianopia[END_REF], however, in this study it was an indirect measure of blindsight and not a direct measure of unconscious visual capacities in the blind visual field.

Recently we sought to investigate objective and subjective perceptual experience in a group of 8 complete post-stroke hemianopic patients [START_REF] Garric | Dissociation between objective and subjective perceptual experiences in a population of hemianopic patients: A new form of blindsight?[END_REF]. To do so, patients firstly performed a letter detection and identification tasks (is it a X or a O?) to evaluate objective perceptual abilities in the two visual fields. Here, the objective detection task was performed on a classical binary scale: "Something was presented" vs. "Nothing was presented".

Secondly patients were submitted to the Sensation Awareness Scale (SAS) in order to investigate the nature of the perceptual experience in their blind visual field, which has only been examined in single-case studies so far. In this way, during the detection and identification tasks, after each trial, the patient was asked to choose the most appropriate assertion: [1] I did not see anything; [2] I don't think that I saw anything, but I am not sure; [3] I felt something;

[4] I saw something; and [5] I clearly saw something and can identify it. The assertion 'I felt something' was added in order to let a chance to the patient to express that he had a sensation that could be different from a visual sensation. As a matter of fact, in clinical practice, patients often 'feel' the presence of something although being unable to report a visual sensation per se.

Subjective performance was calculated based on the SAS and compared to the objective performance, which was evaluated through the forced-choice detection and identification tasks.

In this way, we were able to reclassify our homonymous hemianopic patients according to the dissociation between objective and subjective performance and by different concepts of blindsight described in the literature. As a matter of fact, using both experimental tasks investigating detection and categorization tasks in the blind visual field as well as the SAS questioning the nature of the perceptual experience lead to four distinct profiles that could theoretically be found in hemianopic (and perhaps other) patients:

1.

Absence of blindsight: objective performance and subjective performance both being at chance level.

2.

Type I blindsight: objective performance above chance level, combined with a lack of statistically significant subjective sensitivity.

3.

Type II blindsight: objective performance and subjective performance both being above chance level.

4.

Blindsense: objective performance at chance level combined with a statistically significant subjective performance (previously unreported phenomenon).

Interestingly, our findings showed that only one of the eight complete-HH patients met the criteria for blindsight. More importantly, our SAS enabled us to identify a previously unreported dissociation, which we characterized as blindsense, in four of the eight complete-HH patients. Specifically, these four patients exhibited better-than-chance sensitivity to the presence of a stimulus on the subjective scale, despite being unable to identify the stimulus during the forced-choice task. Moreover, three out of the four blindsense patients presented a significant subjective sensitivity using the gradual SAS scale while being at chance level on the binary detection task. These findings underline the need to investigate not only objective perceptual abilities in the blind visual field of hemianopic patients but also their degree of awareness and suggest that blindsight is not as frequent as previously thought in complete poststroke hemianopic patients and in any case is far from being the most common dissociation between perception and awareness. Contrary to the case of blindsight, which has been extensively studied in hemianopic patients, vision quality in the central visual field and in the ipsilesional visual field of these patients has scarcely been assessed, and moreover, has traditionally been assumed to be fully preserved.

However, as we discuss below, hemianopic patients may present a subtle deficit in their ipsilesional (thought to be healthy) visual field they are not aware of.

Sightblindness

Hess [START_REF] Hess | SPATIAL AND TEMPORAL CONTRAST SENSITIVITY IN HEMIANOPIA[END_REF] were among the first authors to demonstrate that spatial and temporal sensitivities were lower in the ipsilesional visual field of hemianopic patients than in control subjects. In the same vein, [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 investigated a few years ago the performance in her right ipsilesional visual field [START_REF] Peyrin | Neural correlates of spatial frequency processing: A neuropsychological approach[END_REF]. We 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. Results clearly confirmed that damage to the right primary visual cortex (V1) induces a decrease in performance in the right ipsilesional visual field. By the way, the patient was found even before surgery to perform with lesser accuracy and higher reaction times in the right ipsilesional visual field 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 ipsilesional visual field 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 leading thus to a massive visual field defect in the contralesional visual field and to a weaker visual deficit in the ipsilesional visual field.

Whereas [START_REF] Schadow | Impairments of Gestalt perception in the intact hemifield of hemianopic patients are reflected in gamma-band EEG activity[END_REF] found deficits in the early and late visual processing of Gestalt patterns in the ipsilesional visual field, [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 background in the ipsilesional visual field. In addition, Bola, Gall and Sabel (2013a) confirmed these findings and reported processing-speed deficits in a simple detection task in the ipsilesional visual field.

The authors termed this phenomenon sightblindness, as the reverse situation of blindsight (Bola, Gall, & Sabel, 2013b): the former referring to visuo-attentional deficits in the ipsilesional visual field, whereas the latter refers to residual (although implicit as discussed above) visual abilities in the controlateral visual field (CVF) that are highlighted in forced-choice tasks (e.g., [START_REF] Weiskrantz | Visual capacity in the hemianopic field following a restricted occipital ablation[END_REF][START_REF] Leopold | Primary Visual Cortex: Awareness and Blindsight[END_REF]. Interestingly, hemianopic patients are not supposed to be aware neither of residual capacities in their contralesional visual field in the case of blindsight nor of their subtle visual deficit in the ipsilesional visual field in the case of sightblindness.

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;[START_REF] Sanchez-Lopez | Visually evoked responses from the blind field of hemianopic patients[END_REF] 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 [START_REF] Mikellidou | Plasticity of the human visual brain after an early cortical lesion[END_REF]. 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 | Is there an ipsilesional deficit in hemianopia? The question of 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 | Is there an ipsilesional deficit in hemianopia? The question of 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 brain-damaged 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. Together, these studies among right brain-damaged patients suffering from left homonymous hemianopia raise the question of the integrity of selective attention processing in the ipsilesional healthy right visual field. This is the reason why, recently we investigated the presence, the nature and the severity of a selective spatial attention deficit in the ipsilesional visual field of both left neglect and left hemianopic patients in order 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 [START_REF] Chokron | Ipsilesional deficit of selective attention in left homonymous hemianopia and left unilateral spatial neglect[END_REF]. To reach this aim, we used a letterdetection task [START_REF] Chokron | Hemispheric asymmetry for selective attention[END_REF][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. This study brought evidence for the presence of a non-lateralized attentional deficit in left neglect patients as well as a subtle attentional deficit in the ipsilesional visual field of left hemianopic patients and emphasize the need to thoroughly test for visuo-attentional capacities in the assumed 'healthy' ipsilesional visual field following unilateral parietal or occipital damage.

Of interest with the present discussion, neither left neglect patients nor left hemianopic patients were aware of this ipsilesional attentional deficit. Visual hallucinations are typically defined as visual perceptions that are completely removed from reality (i.e. perceptions without stimulus; [START_REF] Borruat | Hallucinations et illusions visuelles, des symptomes souvent méconnus du praticien[END_REF]. Interestingly and not often reported neither in the literature nor during clinical examination, hemianopic patients can also experience visual hallucinations in their blind contralesional visual field. However, in our view, this phenomenon should be studied conjointly with other dissociation between perception and awareness such as anosognosia, blindsight and sightblindness.

Hallucinations in hemianopic patients

Patients

The hallucinations experienced by hemianopic patients can be simple (e.g. points, lines, geometric shapes) or complex (e.g. objects, animals, people or animated scenes) and can involve the entire visual field or just part of it [START_REF] Panayiotopoulos | Elementary visual hallucinations, blindness, and headache in idiopathic occipital epilepsy: differentiation from migraine[END_REF]. Hemianopic patients are usually not aware that the visual perceptions in their blind visual field are in fact hallucinations. Indeed, being aware of it requires for the hemianopic patient to confront these visual perceptions to another sensory modality which is not systematic. Most of the time, hemianopic patients may experience visual perception in their blind visual field as if they had at least partly recovered from their visual field defect. When at some occasions the patient understands that what is perceived does not really exist, he/she can express negative feelings or fear of it and very often does not tell anybody about it. As a matter of fact, hemianopic patients are often afraid of being labeled "crazy" if they mention the hallucinations they experience on their own. Surprisingly, visual hallucinations in hemianopic patients have not been systematically researched perhaps, in part, because there a lack of specific and standardized questionnaire that could be easily used by practitioners. We have recently developed such a questionnaire for hemianopic patients and more generally, for patients with neurological visual impairment, named the Questionnaire for Evaluating Visual Hallucinations in Homonymous Hemianopia Patients (abbreviated as the "Q3H" questionnaire) (Perez et al., 2014). 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. Studying hallucinations in hemianopic patients reveal that they can vary in frequency and intensity, in time (instantaneous or enduring) and in complexity (simple or complex). However, the origin of these hallucinations remains poorly understood, although they are thought to depend on lesion location [START_REF] Alfaro | An Atypical Presentation of Visual Hallucinatory Experiences Following Prolonged Blindness*[END_REF]. In hemianopic patients, visual hallucinations could result from compensatory hyperactivation of neighboring tissue [START_REF] Braun | Brain modules of hallucination: an analysis of multiple patients with brain lesions[END_REF][START_REF] Rafique | Suppression of unformed visual hallucinations in homonymous hemianopia from occipital stroke using TMS[END_REF]. Thus, it has been reported that that the peri-lesional area of the visual cortex can generate visual hallucinations whose complexity depends on the lesion site (Kölmel, 1985): simple hallucinations would result from activation of the primary cortex, and complex hallucinations, from activation of the association cortex. Additionally, other studies have demonstrated that complex visual hallucinations can be triggered by stimulation of the temporo-occipital or the parieto-occipital lobe [START_REF] Rafique | Suppression of unformed visual hallucinations in homonymous hemianopia from occipital stroke using TMS[END_REF]. Over the past 5 years, our group and others have suggested that the side of the occipital lesion might be an important factor in the nature and severity of visual impairments in hemianopic patients [START_REF] Perez | An fMRI Investigation of the Cortical Network Underlying Detection and Categorization Abilities in Hemianopic Patients[END_REF]Cavezian et al., 2015).

Similarly, [START_REF] Walters | Lateralized Visual Hallucinations: An Analysis of Affective Valence[END_REF] investigated whether complex visual hallucinations caused by an occipital lesion might be linked to the lesion side and to patients' emotional valence. In their study, they systematically searched for hallucinations in left or right brain-damaged patients and recorded the side of the hallucination, as well as its emotional valence. They then assessed the associated perceptual deficits, including loss of vision within a visual field (left or right), loss of vision within a visual quadrant, allochiria, or extinction upon presentation of concurrent bilateral stimuli to the left and the right visual field.

Of the fifteen patients experiencing visual hallucinations within the left hemispace, ten had at least one visual field defect, all of which (10/10; 100%) were in the left visual field. In other words, among patients with a left visual field defect (right brain-damage), the hallucinations always occurred in the blind, contralesional visual field. In addition, all of the patients had associated negative affective valence to these events. With a total of ten patients experiencing visual hallucinations within the right hemispace, only four patients had demonstrated at least one visual field defect (tested by confrontation test only). All four of these (100%) were within the left visual field (right-side lesion), and three of them (75%) had an associated positive emotional valence. According to this study, it seems that the emotional valence of the hallucination depends on the side of its apparition rather than on the lesion side. However, all the patients (100%) with visual field defects in this study had left visual field defects. No right visual field defects were detected across confrontational tasks for any of the patients. Thus, the fact that only patients with right-side lesions reported visual hallucinations suggests an effect of the lesion side on the occurrence of hallucinatory phenomena. This study suggests that the side of the occipital lesion determines the occurrence of visual hallucinations whereas the visual field of apparition could influence the emotional valence, with more frequent hallucinations in the blind, contralesional visual field than in the ipsilesional visual field, as reported in the previously cited study by [START_REF] Walters | Lateralized Visual Hallucinations: An Analysis of Affective Valence[END_REF]. Regardless, further studies are necessary to elucidate the link between the lesion side, the visual field of apparition and the various parameters of visual hallucinations (nature, frequency, severity, similarity with mental imagery, emotional valence, etc.). Interestingly, preliminary results from our group current studies using the Q3H questionnaire suggest that the occurrence and type of visual hallucinations in hemianopic patients might strongly depend on the extent and on the location of the lesion.

Discussion and Conclusion

Damage or disconnection of all or some parts of the primary visual cortex (V1) results in a region of blindness (a scotoma) in the corresponding portion of the visual field [START_REF] Holmes | Disturbances of vision by cerebral lesions[END_REF].

In addition, in the present review, we have described four types of dissociations between perception and awareness that had never been put together to our knowledge despite the fact they represent behavioural manifestations, in addition to the visual field defect, of the damage or disconnection of V1 and the visual system. Indeed, as above-discussed, after a unilateral lesion of the occipital lobe, patients suffering from homonymous hemianopia: (1) are not always completely aware of their deficit, (2) present some residual, implicit capacities in their blind visual field such as blindsight, (3) may suffer from a subtle ipsilesional visual deficit in their ipsilesional (thought to be healthy) visual field although without being aware of it, (4) may experience visual hallucinations in their blind visual field without knowing that these perceptions are not real. These four phenomena which accompanies homonymous hemianopia remind us that contrary to pre-chiasmatic visual deficits, the lesion of V1, by disconnecting the eye from the cortical visual system induces a dissociation between visual perception and awareness that may take several forms. As pointed out by [START_REF] Mazzi | On the "blindness" of blindsight: What is the evidence for phenomenal awareness in the absence of primary visual cortex (V1)?[END_REF] blindsight has been influential in guiding neural models of phenomenal awareness, however, the other associated signs we described in the present review had yet received less interest although they may suggest a more complex role for V1 in conscious visual experience than what has been yet discussed (see e.g. [START_REF] Mazzi | On the "blindness" of blindsight: What is the evidence for phenomenal awareness in the absence of primary visual cortex (V1)?[END_REF]and Cowey, 2009[START_REF] Cowey | Stimulus cueing in blindsight[END_REF] for discussion).

Indeed, it could be the case that these phenomena are both part of a more general dysfunction and not independent one from each other. As a matter of fact, both blindsight and visual hallucinations in the blind visual field could major anosognosia by providing respectively implicit (real) and explicit (unreal) visual perceptions to the patient. In a contralesional visual field filled with implicit and illusory visual perception, it becomes more difficult for a patient to be aware of his/her visual field defect. Although in Celesia and colleagues' study (1997), most of the patients with visual hallucinations were aware of their deficit, apparently infirming our hypothesis, these authors have proposed an alternative explanation very close to ours.

According to these authors, anosognosia for hemianopia could result from a perceptual filling of the field loss by a phenomenon close to our lack of perception of the blind spot. Although it is difficult to imagine that the whole contralesional field defect can be filled out, a completion of the blind visual field has been reported in hemianopic patients, that is, in certain circumstances, patients describe that their scotoma is filled out by the surrounding scene [START_REF] Warrington | The completion of visual forms across hemianopic field defects[END_REF][START_REF] Sergent | An investigation into perceptual completion in blind areas of the visual field[END_REF]Mc Carthy, James-Galton and Plant, 2006). This phenomenon which states in between blindsight and visual hallucinations could in part explain anosognosia for hemianopia.

In addition, the presence of an ipsilesional although subtle deficit in the ipsilesional visual field such as sightblindness could decrease the difference in visual experience in both visual fields, thus increasing anosognosia for the contralesional visual field defect. Anyway, as Celesia et al.

(1997) claim, attempts to explain anosognosia in hemianopic patients with a single theory are destined to failure because of the complexities of "awareness." These authors proposed that unawareness in these patients may thus be due to different reasons such as: failure of discovery of the deficits, severe hemineglect, generalized cognitive impairment, "filling in" process, or to a combination of these factors. From the present review, we could reasonably add that blindsight, sightblindness and visual hallucinations can also interact and play a role in being aware or not of the visual field defect after a post-chiasmatic lesion.

On the other hand, visual hallucinations could in part be the product of the implicit visual perception (blindsight) in the contralesional visual field. Indeed, currently, since hallucinations had only be scarcely studied, it is still difficult to understand how implicit perceptions could participate to the construction of explicit visual hallucinations, but this certainly deserves some future research to thoroughly understand how the lesion of V1 alter both implicit and explicit visual sensations as well as the interaction between them. Recent neuro-anatomical studies investigated the role of pulvinar and superior colliculus in blindsight (see for example, [START_REF] Kinoshita | Dissecting the circuit for blindsight to reveal the critical role of pulvinar and superior colliculus[END_REF], however, further research is needed to understand the cortical and subcortical substrate of the other behavioural phenomena present in hemianopic patients such as anosognosia, sightblindsness and visual hallucinations. 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]2017;[START_REF] Silvanto | Abnormal functional connectivity between ipsilesional V5/MT+ and contralesional striate cortex (V1) in blindsight[END_REF], our recent findings suggest that this could also be the case for ipsilesional deficits in patients with unilateral parietal or occipital lesions [START_REF] Chokron | Ipsilesional deficit of selective attention in left homonymous hemianopia and left unilateral spatial neglect[END_REF]. In the same way, one cannot exclude the role of an interaction between the lesioned and the non-lesioned hemisphere in the production of visual hallucinations. Further studies dealing with the interaction between the visual field defect, anosognosia for it, blindsight, sightblindness and visual hallucinations should thus take into account the different neuroanatomical correlates of these phenomena, that is : a destruction or disconnection of V1 both from the eye and from higher cortical centers, the integrity of the superior colliculus and the pulvinar in order to experience blindsight, a change in interhemispheric connectivity leading to sightblindness as well as probably the integrity of part of the ventral pathway in order to experience visual hallucinations. Hemianopia and its behavioral consequences represent a complex deficit that may be associated to a damage of a distributed network around the lesion of V1.

From a more clinical perspective, hemianopic patients deserve a complete neuropsychological examination including a precise evaluation of the awareness of the deficit as well as the presence, nature and duration of hallucinations. Contralesional visual field training in rehabilitation is nearly always recommended for these patients, especially using blindsight stimulation [START_REF] Chokron | From blindsight to sight: cognitive rehabilitation of visual field defects[END_REF][START_REF] Das | Beyond blindsight: properties of visual relearning in cortically blind fbeauields[END_REF]Huxlin, 2014, Cavanaugh and[START_REF] Cavanaugh | Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness[END_REF],

. However, training visual discrimination and attention in the ipsilesional visual field seems to be necessary given the fact that hemianopic patients often tend to use their 'healthy' visual field to compensate for their visual field defect.

Figure 1 .

 1 Figure 1. Illustration of the visual field deficit in left HH (A) and right HH (B): Humphrey Automated visual perimetry from two hemianopic patients, in both eyes.

  , blindsight was also observed in patients lacking a functional primary visual cortex (Ajina, Pestilli, Rokem, Kennard, & Bridge, 2015; Mazzi et al., 2016) as well as in monkeys with complete ablation of V1 (Stoerig & Cowey, 1997). Indeed, Stoerig, (2006) has concluded that blindsight can occur without any functional portion of the primary visual cortex. Confirming this hypothesis, researchers have shown that blindsight could be mediated by subcortical pathways that bypass V1, such as the superior colliculus pathway and the dorsal lateral geniculate nucleus (dLGN) pathways. Moreover, several recent studies have underscored the roles of the ipsilateral hemisphere and the corpus callosum in processing of stimuli in the contralesional visual field of HH patients (Bridge, Thomas, Jbabdi, & Cowey, 2008; Celeghin et al., 2017; Leh, 2006).

  with visual deprivation may experience visual hallucinations apart from blindness, as it has been reported in the Charles Bonnet Syndrome (CBS) (see for review, Fernandez, Lichtstein and Vieweg, 1997). As a matter of fact, in 1769, Charles Bonnet described in his 89 year-old grandfather who suffered from a cataract-induced blindness visions of men, women, birds and buildings that changed in size, shape and place (De Morsier, 1967 ; Rosenbaum et al., 1987). Importantly, these hallucinations were reported although the elderly man did not present any sign of cognitive deficit. CBS was thus defined as visual hallucinations in elderly patients free of optic nerve impairment and with no concurrent psychiatric or cognitive disturbance (De Morsier, 1967 ; Bartlett, 1951). However, the definition of CBS was subsequently extended to describe "any state of visual hallucinations in the elderly irrespective of accompanying symptomatology" (Berrios and Brook, 1982). Nowadays, clinicians commonly associate CBS with eye and brain disease, probably considering that visual hallucinations after ocular lesions or after postchiasmatic lesions are both signs of CBS. However, as we present below, hallucinations in homonymous hemianopia may be another form of dissociation between perception and awareness due to the cortical lesion. Indeed, in addition to anosognosia, blindsight, and sightblindness, hemianopic patients can also experience visual hallucinations in their contralesional visual field or even in their entire visual field, they are not always aware of.

Acknowledgments

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

Acknowledgements

The research from our group that we report in this review was sponsored by the Edmond and Benjamin de Rothschild Foundations. We would like to thank Sébastien Allali, Marie-Laure Larcinèse, Fiora Martinelli, and Ariadna Albajara for their help in distributing the Q3H Questionnaire to hemianopic patients.