Nicolae Sanda

Leonardo Cerliani

Colas Niels Authié

Norman Sabbah
email: norman.sabbah@gmail.com

José-Alain Alain Sahel

Christophe Habas

Avinoam Bezalel Safran
email: avinoam.safran@unige.ch

Michel Thibaut De Schotten

Nicolaesanda

Colas N Authié

Saddek Mohand-Saïd

Amir Amedi

Visual brain plasticity induced by central and peripheral visual field loss

Keywords: Francis bacon, illusions, central metamorphopsia, dysmorphopsia, vision, art, neurological disorder cerebral disorders, color, consciousness, emotion, perception, synesthesia, vision arterial occlusion, ischaemic stroke, outcome, thrombolysis

ouvert les portes de la neuro-ophtalmologie, de m'avoir transmis ce savoir clinique, qu'on ne trouve pas dans les livres, mais que l'on reçoit seulement d'un maître tel que lui. Je le remercie également pour l'enthousiasme avec lequel il m'a incité à observer et explorer les facettes méconnues de la vision.

Je voudrais également remercier le Pr Michel THIEBAUT de SCHOTTEN pour son aide essentielle dans la réalisation de cette thèse de même que pour avoir partagé sa grande érudition et sa perspective unique sur le fonctionnement et la structure du cerveau.

J'aimerais remercier le Pr José-Alain SAHEL, tout d'abord pour avoir créé l'Institut de la Vision et réuni sous un seul toît tant d'esprits exceptionnels, et ensuite pour la confiance qu'il m'a accordée au cours de la réalisation de cette thèse.

Je remercie aussi le Dr Leonardo CERLIANI, qui m'a été d'une aide précieuse dans le cadre de l'un des travaux présentées dans cette thèse.

Je voudrais aussi remercier le Dr Christophe HABAS et le Service de neuroimagerie du Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, le Dr Saddek MOHAND-SAÏD et le Centre d'Investigation clinique (en particulier Dr Céline DE-VISME), qui ont été d'une aide précieuse dans la conduite des études en IRM et la difficile sélection des patients selon les critères stricts des exigences que nous avons énoncées. J'aimerais aussi remercier le Dr Colas AUTHIE, pour les innombrables fois où il nous a aidé et sans lequel les travaux présentés dans cette thèse n'auraient pas été possibles. Je voudrais également remercier le Dr Norman SABBAH, avec lequel nous avons eu de multiples et fructueuses collaborations, dont une fut essentielle pour l'une des études présentées dans cette thèse. Je remercie aussi le Pr Amir AMEDI et le Dr Sami ABBOUD

6

partie du jury de cette thèse.

Enfin, je remercie le Pr Elena SANDA et le Dr Nicolae SANDA, mes parents à qui je dois tout.

Morphological plastic changes induced by central and peripheral visual loss

We explored the effects of visual loss on cortical thickness (CoTks) and cortical entropy (CoEn, marker of synaptic complexity) in the cytoarchytectonic regions of the occipital lobe. Central visual loss associated thinning in dorsal stream regions, while peripheral visual loss in early visual cortex (EVC) and regions belonging both to dorsal and ventral stream. Theses effects were unpredicted by the canonical view "central vision -ventral stream", "peripheral vision -dorsal stream". Normal CoEn in theses areas suggests that synaptic complexity is preserved in the remaining networks. Only central visual field loss presented CoEn alterations, namely an increase in areas involved in object recognition, that likely reflects a synaptic complexity enhancement in response to the loss of the high spatial resolution of central vision. The gain in synaptic complexity could mask neuronal loss due to deafferentation and may account for the CoTks normality.

Plastic changes in the functional connectivity of central and peripheral EVC

We explored and compared to normally afferented EVC, the functional connectivity of afferented and deafferented parts of EVC and found that central and peripheral visual loss induce different patterns of reorganization. Residually afferented early visual cortex reinforce local connections presumably to enhance the processing of altered visual input, while deafferented EVC strengthen long-range connections presumably to assist high-order functions.

Combined structural and functional data indicate that areas with reduced CoTks superpose with several areas presenting reduced functional connectivity with the peripheral 8 CHAPTER 0. ABSTRACT EVC and that areas with increased CoEn superpose with several areas presenting increased functional connectivity with afferented peripheral EVC. These data point that alterations of the sensory input to the peripheral field are more prone to induce plastic changes.

Data in the current work provide an interesting perspective about the plasticity following central or peripheral visual field loss and show that it is more complex than the canonical model would have let to presume. These observations pave the way for further studies that could explain the exact functional role of the plastic changes and help revisiting the current, insufficient model of visual information processing.

Overview

[Résumé]

Les processus de plasticité cérébrale entrainés par la perte visuelle restent un domaine méconnu dans le champ des neurosciences. La vision centrale et périphérique, le meilleur compromis évolutionniste entre une bonne résolution spatiale et un volume d'espace échantillonné maximal, sont traitées par des régions différentes du cerveau. Par conséquent, étudier et comprendre l'impact de la perte visuelle centrale ou périphérique dans ces régions constitue une étape cruciale dans l'étude du cerveau visuel. Afin d'étudier ces processus, nous avons utilisé deux modèles de perte visuelle sélective de la vision centrale (la dystrophie maculaire de Stargardt) et périphérique (la rétinopathie pigmentaire), et nous avons évalué l'impact à terme de ces deux types de désafférentation sur la structure et la connectivité fonctionnelle du cerveau.

Plasticité structurelle induite par la perte sélective de la vision centrale ou périphérique

Nous avons étudié l'épaisseur corticale (EpCo) et de l'entropie corticale (EnCo, marquer de complexité synaptique) du lobe occipital, région pour laquelle nous disposons d'une cartographie complète des régions cytoarchitectoniques. Nous avons constaté que la perte de la vision centrale induit un amincissement des régions appartenant au flux dorsal, tandis que la perte de la vision périphérique occasionne un amincissement du cortex visuel primaire (CVP), ainsi que des régions du flux ventral et dorsal. Ces effets étaient inattendus si on se rapporte au modèle canonique qui associe la vision centrale au flux ventral et la vision périphérique au flux dorsal. La normalité de l'EnCo dans ces régions, suggère que la complexité synaptique est préservée dans les réseaux neuronaux résiduels. Nous avons identifié des modifications de l'EnCo seulement en cas de perte de la vison centrale, où l'augmentation de l'EnCo dans des régions impliquées dans la reconnaissance des objets pourrait traduire une réponse adaptative à la perte de la haute résolution spatiale de cette partie du champ visuel. Cette augmentation de la complexité synaptique pourrait compenser une éventuelle perte neuronale et être responsable de la normalité de l'EpCo dans ces régions. Dans cette étude, nous avons exploré et comparé la connectivité fonctionnelle des régions afférentées et desafférentées du CVP de sujets msouiffrant de dystrophie maculaire de Stargardt et retinitis pigmentosa, avec les régions afféréntées correspondantes du CVP de sujets avec une vision normale. Cette étude a révélé une réorganisation fonctionnelle distincte du CVP afférenté et désafférenté. Ainsi, le CVP qui reçoit les afférences visuelles résiduelles présente une connectivité fonctionnelle accrue avec des régions voisines, probablement afin de favoriser le traitement de l'information visuelle, tandis que le CVP désafférenté augmente sa connectivité fonctionnelle avec des régions plus éloignées, vraisemblablement pour contribuer aux fonctions supérieures et à des processus de type top-down.

Plasticité de la connectivité fonctionnelle des régions du cortex visuel

L'analyse comparative des données morphologiques et fonctionnelles suggère une correspondance des régions amincies du cortex visuel associatif avec des régions qui montrent une diminution de la connectivité fonctionnelle avec le CVP périphérique, et des régions présentant une augmentation de la complexité synaptique avec des régions qui montrent une connectivité fonctionnelle accrue avec le CVP périphérique. Ces données suggèrent que la désafferentation sensorielle du CVP périphérique est plus propice au développement d'une réorganisation cérébrale.

Ces travaux révèlent un aspect inattendu de la plasticité cérébrale induite une perte isolée de la vision centrale ou périphérique. La réorganisation s'avère plus complexe que le laisser présager le modèle canonique actuel, vraisemblablement trop simple. Ils ouvrent la voie à de nouvelles études permettant de clarifier la fonction spécifique des changements plastiques observés et contribuer à réactualiser le model canonique du traitement de l'information visuelle.

A brief history of vision

Vision is the long distance sense that allowed homo sapiens, a physically delicate ape, to explore the universe. It provided him with the means to survey directly and later through more and more complex devices of his own design -the space -further away up to distant stars and galaxies; and the time -further back -down to the oldest light imprinted on the sky when our Universe was only 380 000 years old. But how did the story of vision begin?

The beginning

Before searching for the beginning, one must first define vision as the answer is intimately related to definition. Does vision equals photoreception? If that would be the case, synthetizing photoreception (photosynthesis) would qualify as a form of vision, which is obviously not the case. As a sense, vision is indissolubly linked to information and therefore vision defines as a system that recognizes and extracts information from light.

The first witness of light among the living things on Earths is yet borrowed in the mist of time. Little we know about the first eon of our planetthe hadean (4600 -3750 million years ago), but we believe that it was the chemical laboratory that allowed the emergence of prebiotic compounds (amino acids, reactive molecules, and finally the ribonucleic acid) and maybe even life [START_REF] Schwab | Evolutions's Witness[END_REF]. The next eonthe archean (3750 -2500 million year ago) -was likely the one when photoreception appeared for the first time. It was an age of unicellular life forms -archea and bacteria [START_REF] Schwab | Evolutions's Witness[END_REF]. Some of these organisms evolved in photic marine environment and developed the first light receptors -chlorophylls (chlorine-derived pigment), rhodopsins (vitamin A-derived opsins) and photolyases (riboflavin derived enzymes, [START_REF] Willstutter | Zur Kenntniss der Zusainmensetzung des Chlorophylls[END_REF][START_REF] Lucas-Lledó | Evolution of mutation rates: Phylogenomic analysis of the photolyase/cryptochrome family[END_REF][START_REF] Schwab | Evolutions's Witness[END_REF]. In these organisms, chlorophylls act as photosynthetic machines converting carbon dioxide in organic compounds, rhodopsins, light-driven proton pumps produce energy and photolyases, light-activated enzymes, repair DNA damaged by the exposure to ultraviolet light. These functions cannot be qualified as vision, but bacterial and archeeal rhodopsins and photolyases are ancestors of rhodopsin and chromophores, used for vision by metazoans (multicellular eukaryote organisms). However, before metazoan radiation, the protists, unicellular eukaryotes, which likely emerged in proterozoic (2500 -543 million years ago), achieved a certain degree of visual information integration.

The evolution

The evolution 1.2.1 Photoreceptors

The emergence of photoreceptor cells in metazoans

With the rise of metazoans, which radiated in the neoproterozoic (1000 -543 million years ago), the true story of vision began. It is in this eon and those that followed that eye and nervous system developed and further perfected to optimize the capture and integration of visual information.

Metazoans developed an impressing array of eye designs, but certain pieces are common to all of them (see Figure 5). Each eye includes a photoreceptor cell structure, a lens and is connected to a neural network. To increase its capacity to gather light and to sample spatial characteristics, eye had two possible ways to develop: invagination (e.g. a pit) or evagination (e.g. a bulge). Invagination leads to a camera-style eye like our own eyes (also common to all vertebrates and certain invertebrates like cephalopods), while evagination constitutes the basic design of compound eye (common in invertebrates) and founds its most exquisite exponents in arthropods (insects, crustaceans; Schwab 2012; see Figure 5).

Lenses, made of various compounds (i.e. minerals, carbohydrates, proteins), are present in both designs and their role is to focus the image on the photoreceptor layer.

Another common structure for all eyes is the retina, the layer containing the photoreceptors. Beside photoreceptors, it also includes pigmentary cells and other neural cells. The pigmentary cells limit the direction of the incoming light and allow the spatial organization of information. They may also have metabolic or protection roles in regard to photoreceptors [START_REF] Schwab | Evolutions's Witness[END_REF]. The various neural cells in the retina allow a certain degree of local information processing. Converging axons of theses neural cells form the optic nerve that transfer the visual information to higher processing centers (i.e. the brain).

Metazoans developed two major classes of photoreceptive cells -ciliary and rhabdomeric. Ciliary cells have a single long projection with many folds and stacked appearance called cilium, while rhabdomeric cells have multiple short projections called microvilli. Both photoreceptor types developed from an epidermal ciliated cell ancestor containing photopigment molecules embedded in the membrane and evolved to increase the membrane surface and to stock a maximal quantity of photopigment (Arendt and Wittbrodt 2001). Rhabdomeric and ciliary photoreceptors diverged from a common ancestor, likely before the split between protostomes (most of the invertebrates) and deuterostomes (tunicates and vertebrates). The differences between these photoreceptors are not limited to morphology but extend to opsins and their phototransduction pathway (see Figure 2) (Arendt 2003).

Figure 2 -The evolution of rhabdomeric and ciliary photoreceptor sister cells. I.

A phylogenetic tree of metazoans. II. Rhabdomeric and ciliary photoreceptor cells with schematics of rhabdomeric (A) and ciliary (B) photoreceptors and their main phototransductions cascades. C and D -paralogy of the effector genes of rhabdomeric and ciliary photoreceptors. C -tree calculated on opsin protein sequences. D -tree calculated on G-DNAsequences. cGMP -cyclic guanosylmonophosphate; DAG -diacylglycerol; GTP -Guanosytriphosphate; IP3 -inositol-1, 3, 5 triphosphate; PDE -phosphodiestherase; PIP2 -phosphatidylinositol-4,5-biphosphate; PLC -phospholipase C. The tree brackets enclose orthologous genes that can be traced back to the same precursor gene in Urbilateria. On the phylogenetictree colors code with green Deuterostomia, with yellow Lophotrochozoa and with red Ecdysozoa. The red star marks the human genes (modified from Balavoine andAdoutte 2003, andArendt 2003) Opsins are membrane proteins that combined to photopigments (retinal-derived) form all known light sensors in Neuralia (Cnidaria, Ctenophora and Bilateria;Feuda et al. 2012). The role of opsins and their photopigment is to absorb light in the visible specter and to trigger signal transduction through G-protein activation. Noteworthy, the chromphore retinal has maximum absorption in the ultraviolet spectrum but the opsins shift the absorption peak in the visible region [START_REF] Terakita | Protein family review The opsins[END_REF]. There are seven opsin subfamilies, of which not all are visual. The rabdomeric cells, the photreceptors of most invertebrates, have a rhabdomeric opsins (r-opsin), while cilliary cells the photoreceptors of vertebrates (and tunicates), cilliary opsins (c-opsin). Phototransduction for c-opsins employ transducin-cGMP cascade and its activation results in hyperpolarization whereas r-opsines employ Gq-α-phospholipase C cascade and its activation results in depolarization. Most interestingly, if vertebrates' photoreceptors are cilliary and evolved from a ciliate precursor, retinal neurons like the amacrine cells, horizontal cells and ganglion cells evolved from a rhabdomeric photoreceptor (see Figure 3, Arendt 2003;[START_REF] Graham | Melanopsin ganglion cells use a membrane-associated rhabdomeric phototransduction cascade[END_REF][START_REF] Nilsson | Eye Evolution: The Blurry Beginning[END_REF]. Moreover, various retinal ganglion cells express melatonin, a vertebrate ortholog of invertebrate r-opsins and are involved in pupillary light response and circadian rhythm [START_REF] Hattar | Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity[END_REF]. Data from molecular comparative cell biology points that photoreceptors (rods and cones) evolved from a common ciliary photoreceptor precursor while horizontal, amacrine and ganglion cells evolved from a common rhabdomeric photoreceptor precursor. The origin of bipolar cells is uncertain, but it might also be derived from a ciliary precursor (modified from Arendt 2003; Lamb 2013).

Metazoans developed two different types of photereptor cells derived from a presumed ciliated ancestorrhabdomeric and cilliary. Cilliary photoreceptors became the visual photoreceptors in vertebrate lineage and possibly bipolar cells, while rhabdomeric photoreceptors evolved in amacrine, horizontal and ganglion cells. Some of the cells derived from rhabdomeric photorecptors (i.e. melatonin containing ganglion cells) preserve intrinsic photosensitivity and their main role is probably non-visual. These aspects are essential in optogenetics and related attempts to restore vision in degenerative disorders affecting the photoreceptors.

Overview

Evolution of photoreceptors in vertebrates

Vertebrate photoreceptors (ciliate cells) are the cones and the rods. Cones were the first to appear in vertebrate ancestors, probably > 540 million years ago [START_REF] Davies | Molecular ecology and adaptation of visual photopigments in craniates[END_REF] and duplex retina containing both cones and rods likely developed for the first time in jawless vertebrates (agnatostoma, [START_REF] Yokoyama | Adaptive Evolution of Photoreceptors and Visual Pigments in Vertebrates[END_REF][START_REF] Yokoyama | Molecular Genetic Basis of Adaptive Selection : Examples from Color Vison in Vertebrates[END_REF][START_REF] Lamb | Evolution of phototransduction, vertebrate photoreceptors and retina[END_REF]. Cones developed for vision in photopic conditions while rods evolved to ensure vision in low luminance (mesopic and scotopic conditions). The capacity to provide a rapid response, light sensitivity over a very broad range of intensities, which also prevents saturation in steady light, and the ability to recover almost instantaneously a substantial degree of responsiveness following the vanishing of an intense light stimulus, represent the critical traits of cones [START_REF] Lamb | Evolution of phototransduction, vertebrate photoreceptors and retina[END_REF]. The main feature distinguishing rods from a cones is rods ability to respond reliably to the absorption of individual photons, with a good signal-to-noise ratio and under dark-adapted conditions [START_REF] Hecht | Energy, quant, and vision[END_REF][START_REF] Baylor | Responses of retinal rods to single photons[END_REF][START_REF] Lamb | Evolution of phototransduction, vertebrate photoreceptors and retina[END_REF].

Cone opsins evolved from genetic duplication of the ancestral cone opsin. The first duplication created a pair of retinal cone opsins -SWS (short wavelength sensitive) and LWS (long wavelength sensitive, [START_REF] Okano | Primary structures of chicken cone visual pigments: vertebrate rhodopsins have evolved out of cone visual pigments[END_REF]. Through further duplication of SWS gene, new opsins with pick sensitivities to different wavelengths appeared in jawed fish -SWS1, SWS2 (SWS-1 like), RH1 (rhode 1) and RG2 (Rh-1 like, middle wavelength sensitive; for details see Figure 4; [START_REF] Pisani | Molecular evidence for dim-light vision in the last common ancestor of the vertebrates[END_REF][START_REF] Lamb | Evolution of phototransduction, vertebrate photoreceptors and retina[END_REF][START_REF] Kim | Recruitment of Rod Photoreceptors from Short-Wavelength-Sensitive Cones during the Evolution of Nocturnal Vision in Mammals[END_REF]. It is believed that rods evolved from a RH-1 cone through gradual changes. Almost their entire outer segment became sealed over, allowing for extensive longitudinal spread and shut-off reactions sufficiently slow that the response to a single photoisomeration exceeds the intracellular noise [START_REF] Lamb | Evolution of phototransduction, vertebrate photoreceptors and retina[END_REF]. Therefore, the rods became steadily slower but more sensitive and fit for scotopic vision [START_REF] Lamb | Evolution of phototransduction, vertebrate photoreceptors and retina[END_REF]. Noteworthy, cones remain major photoreceptor population in most vertebrates, excepting mammals and some nocturnal, non-mammal species [START_REF] Davies | Molecular ecology and adaptation of visual photopigments in craniates[END_REF].

Later in vertebrate evolution, the five initial opsines were preserved, multiplied (i.e. zebrafish), lost (i.e. mammals), or reinvented (i.e. primates) (see Figure 4; [START_REF] Davies | Molecular ecology and adaptation of visual photopigments in craniates[END_REF]. Mammals, whom extant representatives are divided into three branchesmonotremes (Protheria), marsupials (Metatheria) and placentals (Eutheria) -radiated from the therapside lineage of synapsids (reptile-like amniotes) between 267 and 310 million years ago with the first fossils records dating from 255 million years ago [START_REF] Lucas | Adelobasileus from the Upper Triassic of West Texas : The oldest mammal[END_REF][START_REF] Kemp | The origin and early radiation of the therapsid mammal-like reptiles: A palaeobiological hypothesis[END_REF]. Rods dominate mammals' retinae, nocturnal species exhibiting Partie I, Chapter 1 -A brief history of vision only 3 % cones and diurnal species 5-30 % [START_REF] Peichl | Diversity of mammalian photoreceptor properties: Adaptations to habitat and lifestyle?[END_REF], with some rare exceptions where cones are preponderant (> 50 %, [START_REF] Müller | Topography of cones and rods in the tree shrew retina[END_REF][START_REF] Kryger | The topography of rod and cone photoreceptors in the retina of the ground squirrel[END_REF]. Marsupials and placentals lost SWS2 and medium wavelength RH2 and preserved only SWS1, LWS and RH1 (rod opsin) opsins genes. This loss is explained by the "twilight (mesopic) bottleneck hypothesis" that states that adaptation to mesopic and scotopic lifestyle determined the loss of the redundant SWS2 and RH2 opsines [START_REF] Davies | Molecular ecology and adaptation of visual photopigments in craniates[END_REF]. Consequently, the majority of mammals are dichromatic in bright light and might exhibit conditioned trichromacy in dim-light (mesopic condition) when both cones and rods are activated [START_REF] Davies | Molecular ecology and adaptation of visual photopigments in craniates[END_REF]. Primates however, constitute a particular case that "recovered" tricromatic vision in bright light through duplication of the X-linked LWS gene, the copies of the gene coding pigments with pick spectral sensitivity around 560 nm (L) and 535 nm (M), respectively. This "reinvention" also puts closer L and M cones in terms of downstream circuitry [START_REF] Lee | Connections of diffuse bipolar cells in primate retina are biased against S-cones[END_REF].

In mammalian retina, S cones are considered the default fate of postmitotic generic photoreceptor precursors (i.e. without other influence will become a S cones, [START_REF] Swaroop | Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina[END_REF][START_REF] Hunt | S cones: Evolution, retinal distribution, development, and spectral sensitivity[END_REF]. Exposure to various factors (i.e. TRβ2 or NRL/NR2E3) will induce differentiation into L and M cones or into rods [START_REF] Lamb | Large layer VI neurons of monkey striate cortex (Meynert cells) project to the superior colliculus[END_REF][START_REF] Swaroop | Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina[END_REF]. Moreover, the intense recruitment of S cones into the rod pathway during the embryological development may explain the rod-dominant retinas of the overwhelming majority of mammals [START_REF] Kim | Recruitment of Rod Photoreceptors from Short-Wavelength-Sensitive Cones during the Evolution of Nocturnal Vision in Mammals[END_REF]. Persistence of rod-dominant retinas in most of the extant mammal species is attributed to their complex interactions with cones, which is not limited to the rod-cone coupling that mediates mesopic vision (i.e. rod-cone gap junctions, DeVries and Baylor 1995; [START_REF] Soucy | A novel signaling pathway from rod photoreceptors to ganglion cells in mammalian retina[END_REF][START_REF] Pang | Rod, M-cone and M/S-cone inputs to hyperpolarizing bipolar cells in the mouse retina[END_REF]Asteriti et al. 2014) but also concerns the circadian photoentrainement [START_REF] Altimus | Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities[END_REF], horizontal cell mediated surround inhibition of cone signal [START_REF] Szikra | Rods in daylight act as relay cells for cone-driven horizontal cell-mediated surround inhibition[END_REF]) and the trophic support of cones (Aït-Ali et al. 2015).

Partie I, Chapter 1 -A brief history of vision

Early after their radiation, vertebrates developed cones photoreceptors and at least five types of opsines. The default mode differentiation of photoreceptor precursors in embryological development is the S cone; different factors induce their differentiation in L cone, M cone and rods. Mammals have preserved only SWS and LWS cone opsins and therefore are dichromatic. Primates "reinvented" photopic trichromacy by evolving a medium wavelenght sensitivity opsin (MWS) through LWS gene duplication. Rods appeared later than cones in vertebrate lineage, as adaptation to scototopic and mesopic conditions and they rarely constitute the dominant photoreceptor class in vertebrate retina. At least in mammals, where they are the dominant, rods also assure other complex visual and non-visual functions. Overview 1.2. The evolution

Eyes

Emergence of the metazoan eyes and retinas -inverted and everted retinas Metazoan retina evolved in two different models of photoreceptor disposition -towards the light or everted (the composed eye of insects, camera style eye of the cephalopodes) or away from the incident light or inverted (all vertebrates). If the everted type seems the most ergonomical because there is no cell interposed between the light and photoreceptor, the inverted retina has its own unique advantages. In camera-style eye, it allows a maximal density of photoreceptors (photoreceptors and pigmentary cells are not in the same layer) and provides the necessary space for the retinal neurons, which assures a local, low-order visual information processing [START_REF] Kröger | Space-saving advantage of an inverted retina[END_REF]. The contact between photoreceptors outer segments with pigmentary epithelium permits the later to assist the regeneration of isomerised visual pigment and to regulate the light flux to the photoreceptors [START_REF] Lamb | Large layer VI neurons of monkey striate cortex (Meynert cells) project to the superior colliculus[END_REF]).

The "capital sin" of inverted retina -the interposition of intermediary cells between incident light and photoreceptors resulting in light scattering -is reduced through local modification of the retinal architecture over a limited area, called fovea in the most developed vertebrate eyes. This structure exhibits a pit-like configuration and an increased number of photoreceptors that are exposed directly to the incoming light due to the lateral displacement of inner retina cells (see Figure 4 -D, F). Moreover, the deep fovea of certain species (fishes, reptile birds) -called convexiclivate fovea -behaves as a third refractive element and provides a telescope-like magnification of the image [START_REF] Kröger | Space-saving advantage of an inverted retina[END_REF][START_REF] Schwab | Evolutions's Witness[END_REF]). Significant telescope-like magnification is likely to be absent in humans but the concave form of the fovea behaves like a mirror and focalizes light into the vitreous; the presence of this reflected spot of light is used as a sign of retinal integrity [START_REF] Safran | Macular reflexes in optic atrophy[END_REF].

For light scattering in the rest of the retina, Franze et al. proposed that Müller cells (radial retinal glial cells that span the entire retinal thickness) might act as optic fibers, transporting light with minimal distortion and loss through the entire retina down to photoreceptors [START_REF] Franze | Muller cells are living optical fibers in the vertebrate retina[END_REF]. Macroscopic view -note the smaller and more densely packed omatidia ("little eyes") placed frontally and offering a better spatial acuity. 2 Microscopic view -the corneal lens has been lost. Note the cristaline cone (CC) that focuses the light, the iris pigment (IPC) that prevent light from spilling across adjacent cells, the rhabdomeric photoreceptor cells (RC) and the rhabdom (Rh), formed by the microvilli of several adjacent receptor cells and acting like a fiber optic cable. B. Bony fish eye. 1. Macroscopic view -note the spheric lens, the falciform process providing nutrition to the inner retina, the choroidal gland providing nutrition to the outer retina and the scleral ossicles that evolved to strengthen the eye wall. 2. Microscopic view -note the thin retina and the choroid gland. C. Reptilian eye. 1. Macroscopic view -note the different shape of the lens and the conus (red arrow) a structure derived from the hyaloid artery that is responsible for the nutrition of the inner retina. 2. Microscopic view -note the cartilaginous coup (yellow arrow), the thicker retina and the optic nerve (ON). D. Avian eye. 1. Macroscopic view -note the flattened shape and the pectin a vascular structure similar to the reptilian conus and responsible for eye's thermoregulation and the nutrition of the inner retina. 2. Microscopic view -note the thick steep fovea that allow for a supplementary "telescopic" magnification of the image. E. Monotreme eye. 1. Macroscopic view -note the presence of a cartilaginous cup in the sclera (like in the reptilian eye) and the thick choroid. The eye is spherical; the current flattened image is a preparation artifact. 2 Microscopic view -note the thick choroid; Ph -photoreceptors, Gang -ganglion cells. Interestingly, cones in monotremes are bothsimple and double with some double cones presenting, as in reptiles, eye droplets that contribute in discrimination and spatial tuning (not shown). F. Human eye. 1. Macro schematics of the human eye. 2. Microscopic view of the fovea -the depression and the lateral displacement of the neural cells allows a direct exposure of photoreceptors and the avoidance of light scattering. G. Human eye fundus and macular reflexes. 1. The exterior annular reflex demarcates the ridge of the pit; the central reflex -a reflected telescope-like image of the incident light, due to the concave shape of the fovea. 2. Loss of ganglion cells axons in optic nerve atrophy flattens the ridge of the macula inducing the disappearance of the central reflex and the distortion of the annular reflex. (modified from [START_REF] Safran | Macular reflexes in optic atrophy[END_REF][START_REF] Schwab | Evolutions's Witness[END_REF] 1.2. The evolution Optokinetic system responds to wide field motion across retina by generating movements that reduce the drift of the image and corrects residual slips non-corrected by vestibubuloocular reflex, while pursuit system is particularly sensitive to small moving images in the foveal region and permits the tracking of these images even when they cross a featured background (Miles, F.A, Lisberger 1981).

The evolution

Vision requires image refreshing and image stabilization both which are assured by the action of the extraocular muscles. Vestibuleocular reflex represents the main visual stabilization system, operates both in light and dark conditions and is assisted by the "accessory" optokinetic and pursuit systems that require light and the integrity of the entire visual field for adequate function (Miles, F.A, Lisberger 1981).

Overview

Partie I, Chapter 1 -A brief history of vision

Brains

As seen before, an unexpected kind of intracellular "eye", the ocelloid, appears in protists. Considering its complex structure, it is conceivable that light information it gathers requires complex processing. However, the structure of the "intracellular brain" that performs these operations remains obscure [START_REF] Schwab | Evolutions's Witness[END_REF].

In metazoans, the presence of eyes necessitates at least a basic neural circuit, connecting them with the effector -the muscular cells (i.e. cnidarians), Schwab 2012). More complex metazoans have dedicated neural networks that process the visual information. Neural networks, through parallel hierarchical processing, decompose visual information into various attributes (i.e. position, wavelength and time) and transmit it to the subsequent stations that recompose it into new ones and so on until it is suited to regulate responses and to embed percepts (i.e. luminance, contrast, colour, contours, shape, texture, depth, movement ;[START_REF] Wässle | Parallel processing in the mammalian retina[END_REF][START_REF] Bloomfield | The diverse functional roles and regulation of neuronal gap junctions in the retina[END_REF][START_REF] Nassi | Parallel processing strategies of the primate visual system[END_REF]; see Figure 6).

The emergence of central nervous system

If simple metazoans, like certain cnidarians, have a nervous system represented by a neural net, it is yet unclear if the bilaterian ancestor (clade that results in the vertebrate and invertebrate lineages) possessed a diffused nervous system or a centralized network, namely a central nervous system [START_REF] Holland | Evolution of bilaterian central nervous systems: a single origin?[END_REF]. Central nervous system is roughly defined as a structure where neurons are concentrated and interpolated in a more complex way that elsewhere in the body [START_REF] Holland | Evolution of bilaterian central nervous systems: a single origin?[END_REF]. It may be subdivided into separate parts (ganglia) and connects with the periphery through nerves. Physiologically, central nervous system integrates sensory information originating in the periphery and initiates body-wide responses through direct stimulation of the effector structures (i.e. musculature) or through neurosecretion into the body fluid [START_REF] Nilsson | Eye Evolution: The Blurry Beginning[END_REF]. Most evidence advocates that bilaterian ancestor already had a central nervous system that later evolved into the dorsal central nervous system of chordates and the ventral central nervous system of protostomes (see Figure 7A, B, [START_REF] Holland | Evolution of bilaterian central nervous systems: a single origin?[END_REF]. Centralization of central nervous system allowed not only a local concentration of neurons, but also their functional and spatial segregation and interrelation, marking thus the beginnings of the "operational centralization" [START_REF] Nilsson | Eye Evolution: The Blurry Beginning[END_REF]. Evolution of central nervous system also paralleled the one of sensory structures, including the development of photoreceptors and eyes (Arendt and Wittbrodt, 2001;[START_REF] Nilsson | Eye Evolution: The Blurry Beginning[END_REF]. Thus, the visual processing starts in the periphery, in the eye and the neuronal networks of the retina, and continues in specific regions of the central nervous system. , cb -cerebellum, ch, cerebral hemispheres, m -medula oblongata, ob -olfactory bulb, ot -optic tectum, p -pituitary gland (modified from Hollandet al. 2013 and[START_REF] Northcutt | Understanding Vertebrate Brain Evolution[END_REF].

The evolution

One of the most important "inventions" of bilaterians was the central nervous system, namely a condensed network of neurons that allowed the operational centralization of information.

Overview

The emergence and evolution of vertebrate brain

In vertebrates, the anterior part of the central nervous system evolves into a brain and finally, in Homo sapiens, into "The Brain". Brain evolves as a modular structure, that initially presents three cranio-caudal divisions (e.g. forebrain, midbrain and hindbrain) that through further segmentation and compartmentalisation, increases in size, complexity and processing power [START_REF] Puelles | Forebrain gene expression domains and the evolving prosomeric model[END_REF]Schlosser and Wagner, 2004). All vertebrates have the same number of brain divisions with the exception of agnathans (e.g. jawless fishes) that lack cerebellum (see Figure 7 C, Northcutt, 2002). This high conservation of the major brain divisions across vertebrates suggest it appeared early in their evolution.

The evolution of main divisions of vertebrate brain was however unequal with certain structures changing little, like medulla or cerebellum, others changing more, like optic tectum, and some changing dramatically, like the forebrain, particularly the cerebral hemispheres [START_REF] Northcutt | Understanding Vertebrate Brain Evolution[END_REF]. Increase in the number of neural centers induced an increase in brain size, more evolved vertebrates exhibiting bigger brains. Noteworthy, despite different macroarchitectures, the main types of cortical cells and neuronal circuits are likely present in all amniotes [START_REF] Karten | Neocortical evolution: Neuronal circuits arise independently of lamination[END_REF]. The six layers neocortex for example, which is the newest part of the forebrain in mammals and the most developed part of the brain in primates (Kaas, 2013a), is homologous to specific cortical areas in non avian Partie I, Chapter 1 -A brief history of vision reptiles and to the dorsal ventricular ridge nuclei in birds [START_REF] Dugas-Ford | Cell-type homologies and the origins of the neocortex[END_REF].

Visual brain in birds and mammals exhibit both divergent and shared neural characters that likely reflect the requirements of their ecological niche [START_REF] Butler | Evolution of the brain in vertebrates[END_REF]. Visual processing in birds relays chiefly on collothalamic pathway that presumably allows a more rapid, reflex processing of information, likely more fitted for flight [START_REF] Butler | Evolution of the brain in vertebrates[END_REF][START_REF] Schwab | Evolutions's Witness[END_REF]. Birds are nevertheless able to categorize a wide array of stimuli, to generalize the categories to novel stimuli, to perform complex tasks depending on working memory, episodic memory, transitive interference and multistability of ambiguous visual perceptions rising questions about the neural basis of these high-level mental abilities [START_REF] Butler | Evolution of the brain in vertebrates[END_REF].

Vertebrate brains evolved in multiples designs to suit the requirements of specific ecological niches. Nevertheless, all vertebrate brains evolved on the modular brain structure present in early vertebrates and using similar neuronal cells types and circuits.

Overview

Mammal brain

Early mammals radiated from mammal-like synapsids over 200 million years ago and they likely had 15-20 anatomically and functionally distinct cortical areas, including V1, V2, visual area(s) in temporal cortex and a visual area medial to V1area prostriata [START_REF] Kaas | The Organization and Evolution of Dorsal Stream Multisensory Motor Pathways in Primates[END_REF]. Interestingly, early mammals seem to have possessed no distinct motor or premotor cortex, the cortical motor function being mediated by the somatosensory cortex (Kaas, 2013a).

Early placental mammals radiated about 125 million years ago, and likely continued to have small brains, with relatively little neocortex and the addition of motor cortex (Kaas, 2013a). Placental radiation includes 4 superorders -Xenartra (i.e. armadillos, slots), Afrotheria (i.e. tenrecs, elephants), Laurasiatheria (shrews, bats, cats, bovines, whales) and Euarchontoglires (i.e. rodents, rabbits, tree shrews, primates) -that evolved brains of different sizes and adapted to different ecological niches [START_REF] Murphy | Mammalian phylogenomics comes of age[END_REF]Kaas, 2013a). Certain representatives of theses superorders, like whales, 1.2. The evolution elephants and primates considerably developed the stem brain design of early mammals (Kaas, 2013a).

The evolution of primate brain

Archaic primates radiated about 82 million years ago from Euarchonta superorder (includes also scadentia -i.e. tree shrews and dermoptera -i.e. flying lemurs) and formed strepsirrhin and haplorhine branches about 65 million years ago. Haplorhine further divided into tarsiers and anthropoid primates (simiformes) that emerged about 35 million years ago. From catarrhin branch (old world monkeys) of the anthropoid primates, 6 million years ago, radiated genus Homo of which the only extant species is Homo sapiens [START_REF] Murphy | Mammalian phylogenomics comes of age[END_REF][START_REF] Steiper | Evidence for a convergent slowdown in primate molecular rates and its implications for the timing of early primate evolution[END_REF].

Extinct, stem primates had grasping hands and feet, convergent orbits and a large brain relative to body size with an expanded temporal lobe suggesting an evolved visual function (Kaas, 2013a). Extant primates have greatly expanded representations of central vision in V1 and other visual areas [START_REF] Rosa | Visual field representation in striate and prestriate cortices of a prosimian primate (Galago garnetti)[END_REF]. Moreover, primate V1 has structural differences compared to other mammals, namely sublayers of the layer 4. In primates, the inner half of layer 4 receives input from the parvocellular layers of the lateral geniculate nucleus and is important in high spatial resolution processing, while the outer part receives input from the magnocellular layers of the lateral geniculate nucleus and is important in kinetic information processing (Casagrande and Kaas, 1994). Moreover, the superficial layers of V1 are organized in dot-like distributed functional modules, called blobs important in colour vision (Casagrande and Kaas, 1994). This line of evidence suggest theses features evolved in the primate ancestors [START_REF] Kaas | The evolution of neocortex in primates[END_REF].

In anthropoid primates, V2 exhibits a unique design of repeated subdivisions of three types of band-like modules, each having neurons with specific properties that receive input from specific regions of V1 and provides input to other cortical areas (Casagrande and Kaas, 1994;[START_REF] Kaas | The evolution of neocortex in primates[END_REF]. As theses characteristics are already present in a simpler form in prosimian primates (i.e. Galago a strepsirrhine primate), and absent in rodents and tree shrews (non-primate Euarchontoglires), it is likely that V2 bands evolved with the early primates and become more complex and individualized in higher primates [START_REF] Kaas | The evolution of neocortex in primates[END_REF].

V3 and dorsal motor middle temporal area (MT) are other areas that are present only in primates (although very primitive in lower primates) and no other members of Euarchontoglire clade [START_REF] Lyon | Connectional Evidence for Dorsal and Ventral V3, and Other Extrastriate Areas in the Prosimian Primate, Galago garnetti[END_REF][START_REF] Lyon | Connectional Evidence for Dorsal and Ventral V3, and Other Extrastriate Areas in the Prosimian Primate, Galago garnetti[END_REF][START_REF] Kaas | Archotan affinities as reflected in the visual system[END_REF][START_REF] Kaas | The evolution of neocortex in primates[END_REF]. Noteworthy, in the light of the current available data, V3 area that was described in cats and other carnivores seem to have evolved independently [START_REF] Kaas | The evolution of neocortex in primates[END_REF].

Partie I, Chapter 1 -A brief history of vision

Together with V1, V2, V3 and MT, some additional areas with no described homologues in other mammals are part of the primate visual brain : dorsolateral visual area (V4), dorsomedial visual area (V3A), temporal areas related to MT such as the medial superior temporal area (MST), the fundus of superior temporal area (FST) and the middle temporal crescent (MTc; [START_REF] Kaas | The evolution of neocortex in primates[END_REF]. To theses regions should be added the limbic area prostriata, common to all mammals [START_REF] Kaas | The evolution of neocortex in primates[END_REF]. Moreover, in all primates, an extensive part of the posterior parietal cortex is involved in visual information processing, allowing to elaborate, initiate and guide the movements of eyes, forelimbs and other parts of the body [START_REF] Kaas | The Organization and Evolution of Dorsal Stream Multisensory Motor Pathways in Primates[END_REF]Stepniewska, 2011, Kaas, 2013b). Areas involved in grasping, reaching, defence of the face and eye movements were described in lower primates but not in non-primate Euarchontoglires like tree shrews and rodents, suggesting that theses movement-specific parietal domains emerged with the early primates. Within primates order, the parietal cortex differs in organization and complexity, with more functional domains existing in humans, than in prosimians and monkeys [START_REF] Orban | Mapping the parietal cortex of human and non-human primates[END_REF]Kaas, 2013b). It also seems that the developmental advantage of Homo sapiens over other Homo species was the extensive development of the parietal cortex, especially of the precuneus that allowed for complex computations related to body-tool and body-tool-environment interactions [START_REF] Bruner | Extending mind, visuospatial integration, and the evolution of the parietal lobes in the human genus[END_REF].

• Compared to other mammals, primates expanded the neocortex and within neocortex, the visual areas. In primates, the visual brain has more numerous and complex areas including V3, MT and temporal visual areas. They also have a more developed parietal cortex, likely related to to a more complex visuo-motor control.

• Compared to other primates, humans have more specialized visual areas and a more developed parietal lobe. Moreover, the expansion of the posterior parietal cortex possibly represented the evolutionary advantage of Homo sapiens over the other Homo species.

Overview

Chapter 2

Visual processing

Retinal processing

General organization and photoreceptor distribution

Retina is the first level where processing of the visual information occurs. It contains five classes of neuronal cells -photoreceptors (cones and rods), bipolar, horizontal, amacrine and ganglionar cells. Retinal cells are organized into three layers of neuron cell bodies called nuclear layers separated by two layers of synaptic connections, called plexiform layers (y Cajal 1893). Due to the anatomically limited capacity of information transfer through the optic nerve, the retinal output has to be properly compressed. Therefore, numerous computations are performed in the retina, between photoreceptors and ganglion cells [START_REF] Bloomfield | The diverse functional roles and regulation of neuronal gap junctions in the retina[END_REF]. The processing starts at the level of photoreceptors, which encode light as a function of wavelength, position (2D), intensity and time [START_REF] Bloomfield | The diverse functional roles and regulation of neuronal gap junctions in the retina[END_REF]. Further on, photoreceptors connect with bipolar and horizontal cells; bipolar cells transfer the signal to amacrine and ganglion cells; ganglion cells axons form the optic nerve that transfer visual information to the brain [START_REF] Wässle | Parallel processing in the mammalian retina[END_REF].

Photoreceptor type and distribution vary across retina in a pattern designed to optimize the sampling for parallel processing. Consequently, in vertebrates with good vision, retina presents an area with increased photoreceptor density allowing for maximal spatial sampling; eccentrically to this region, photoreceptor density decreases [START_REF] Osterberg | Topography of the layer of rods and cones in the human retina[END_REF]. Cones populate this area in most species [START_REF] Schwab | Evolutions's Witness[END_REF]. Besides other properties mentioned above, cones exhibit peak sensitivities at various wavelengths and the comparison of their output opens a processing channel resulting in chromatic percepts that further enhance discrimination [START_REF] Wässle | Parallel processing in the mammalian retina[END_REF][START_REF] Schwab | Evolutions's Witness[END_REF].

In mammals and therefore in humans, retina is dominated by rods with the exception of fovea, where cones are dominant. Actually, in the very center of the fovea, in an area of 350 µm (1.25°), rods are totally absent. Cones maximal density is in the central 500 µm of the fovea, in an area called foveola (98,200 -324,100 cones/mm2, the highest values being close to those measured in birds of prey, [START_REF] Reymond | Spatial visual acuity of the falcon, Falco berigora: A behavioural, optical and anatomical investigation[END_REF][START_REF] Curcio | Human photoreceptor topography[END_REF]). Cone density is 40-45% higher in the nasal than temporal retina. It falls rapidly outside foveola, Partie I, Chapter 2 -Visual processing faster along the vertical than horizontal meridian, reaching half of the maximal density at an eccentricity of 120 µm inferior and 150 µm temporal. Rods density increase rapidly outside the rod-free zone, reaching its highest value (157,900 -188,600 rods/mm2) in a broad, horizontal elliptic ring at the same eccentricity as the optic disk and extending more into nasal retina. Rod density is higher in the superior retina, especially in its nasal part and is reduced by 15-25% in the region where the ring intersects the horizontal meridian, both nasally and temporally [START_REF] Curcio | Human photoreceptor topography[END_REF]). Beyond the ring, rod also present a progressive decrease in density, but much slower than cones to a minimum of 49,000 rods/mm2 at 20 mm from the center of the fovea (see Figure 8, Curcio et al. 1990).

Partie I, Chapter 2 -Visual processing Detail -central slope of rod ring and the foveal rod-free zone. C. Rods : cones ratio in the retina [START_REF] Curcio | Human photoreceptor topography[END_REF]. D. The classical diagram of Osterberg with cone and rods distribution over the horizontal meridian (1 -fovea centralis, 2-optic disk, 3 -ora serrata) (modified from [START_REF] Dacey | Parallel Pathways for Spectral Coding in Primate Retina[END_REF][START_REF] Curcio | Human photoreceptor topography[END_REF][START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF].

Cones and rods have different local densities across retina. In humans, in the center of the fovea, cone have maximal density, whereas rods are absent. Outside fovea, cone density falls rapidly. Rods have maximal density on a horizontal ellipse at about the eccentricity of the optic disc.

Overview

Cones neural circuitry.

Cone circuitry is the backbone of the retinal processing toolkit [START_REF] Masland | The Neuronal Organization of the Retina[END_REF]. Phylogenetically newer rods end-up "pigging back" the existing pathways. Both cones and rods transmit the light-evoked signals to bipolar and horizontal cells. In mammals, three types of horizontal cells provide lateral interactions in the outer plexiform layer. Horizontal cells are depolarized by the light, sum light responses from a broad area and subtract them from the local signal (their receptive fields are larger than their dendritic fields due to gap-junctions coupling). It is believed that through this mechanism, they diminish the response to areas with uniform brightness and enhance the response to edges of visual stimuli [START_REF] Wässle | Parallel processing in the mammalian retina[END_REF]).

More than nine types of cone bipolar cells and one type of rod bipolar cell grouped in two functional classes -ON and OFF -transmit the light-evoked signals to amacrine and ganglion cells. Blue cone bipolar cell and rod bipolar cell are of ON type. In the inner plexiform layer, ON bipolar neurons connect with ON ganglion cells and OFF bipolar neurons with OFF ganglion cells through excitatory synapses. Consequently, ON ganglion cells are triggered by stimuli brighter than background while OFF ganglion cells by stimuli darker than background [START_REF] Wässle | Parallel processing in the mammalian retina[END_REF].

Like in cones, bipolar and ganglionic cells density is higher in central retina and lower in peripheral retina. Moreover, the dendritic field of bipolar and ganglionic cells decreases towards the center of the retina with the anatomic limit reached when each cone is connected to a single bipolar and ganglionic cell [START_REF] Wässle | Functional architecture of the mammalian retina[END_REF]. This design establishes a direct link between cone and brain thus optimizing the spatial resolution (visual acuity). It also allowed the "reinvention of trichromacy" in old world monkeys and humans [START_REF] Wässle | Parallel processing in the mammalian retina[END_REF]. It is believed that this one-to-one connection in the central retina was required before the subsequent mutation of LWS gene that resulted in the L-cone and M-cones pigments [START_REF] Mollon | Eine evolutionäre Interpretation des menschlichen Farbensehens[END_REF][START_REF] Nathans | The Evolution and Physiology of Human Review Color Vision: Insights from Molecular Genetic Studies of Visual Pigments[END_REF]) and suggests that trichromatic channels "piggy-backs" on the high acuity system. The impossibility of transgenic mouse expressing human L and M opsins to perform trichromatic colour discrimination [START_REF] Jacobs | Human cone pigment expressed in transgenic mice yields altered vision[END_REF]Wässle 1999;[START_REF] Smallwood | Genetically engineered mice with an additional class of cone photoreceptors: implications for the evolution of color vision[END_REF][START_REF] Wässle | Parallel processing in the mammalian retina[END_REF]) and the steep decline in red and green perception outside the foveal projection area in humans support this view [START_REF] Franze | Muller cells are living optical fibers in the vertebrate retina[END_REF][START_REF] Hansen | Color perception in the intermediate periphery of the visual field[END_REF].

The outputs of the various types of bipolar cells are sampled by specific sets of amacrine and ganglion cells. The main structural characteristic defining a bipolar cell is the level of the inner plexiform layer where its axon terminates. It dictates the type of ganglion and amacrine cells it will connect with and the specific information channel to the brain it belongs to. Most of the retina connectivity is done within the layers, with only some interlayer connectivity assured by amacrine cells. The partially selective inputs transmitted by bipolar cells are refined by feedbacks from amacrine cells. Therefore, the bipolar cells output to ganglion cells results from the intrinsic response of bipolar cells and the tuning of amacrine cells [START_REF] Euler | Light-evoked responses of bipolar cells in a mammalian retina[END_REF][START_REF] Masland | The Neuronal Organization of the Retina[END_REF][START_REF] Saszik | A Mammalian Retinal Bipolar Cell Uses Both Graded Changes in Membrane Voltage and All-or-Nothing Na+ Spikes to Encode Light[END_REF].

Amacrine cells are a numerous and yet poorly understood class of retinal interneurons (29 types in rabbit retina, MacNeil et al. 1999;[START_REF] Masland | The Neuronal Organization of the Retina[END_REF]. Most of them are axonless and the lack of obvious polarity makes difficult to recognize their sites of input and output. Moreover, amacrine cells have complex output synapses that make even more difficult their study: feedback synapses to the bipolar cells that drive them, synapses with other amacrine cells and with various types of ganglion cells [START_REF] Lin | Distribution of glycine receptor subunits on primate retinal ganglion cells: a quantitative analysis[END_REF][START_REF] Jusuf | Localization of glycine receptor alpha subunits on bipolar and amacrine cells in primate retina[END_REF][START_REF] Hadzibeganovic | Cross-linguistic neuroimaging and dyslexia: a critical view[END_REF][START_REF] Eggers | Multiple pathways of inhibition shape bipolar cell responses in the retina[END_REF]. Overall, it is considered that they create contextual effects for the responses of ganglion cells like center-surround antagonism and stimulus over background motion detection [START_REF] Gollisch | Eye Smarter than Scientists Believed: Neural Computations in Circuits of the Retina[END_REF], perform some variety of vertical integration between various layers of the inner plexiform layer (called crossover inhibition; [START_REF] Demb | Intrinsic properties and functional circuitry of the AII amacrine cell[END_REF][START_REF] Buldyrev | Synaptic pathways that shape the excitatory drive in an OFF retinal ganglion cell[END_REF], participate in task-specific functions like motion direction discrimination (starburst amacrine cells; [START_REF] Fried | Mechanisms and circuitry underlying directional selectivity in the retina[END_REF][START_REF] Lee | The Synaptic Mechanism of Direction Selectivity in Distal Processes of Starburst Amacrine Cells[END_REF], mediate of blue-OFF signals [START_REF] Sher | A non-canonical pathway for mammalian blue-green color vision[END_REF][START_REF] Chen | A color-coding amacrine cell may provide a blue-Off signal in a mammalian retina[END_REF]) and optimize of the information conveyed by the rod bipolar cells [START_REF] Grimes | Retinal Parallel Processors: More than 100 Independent Microcircuits Operate within a Single Interneuron[END_REF].

The total number of ganglion cell functional types in mammals is unknown but it is estimated that there might be around 20 [START_REF] Masland | The Neuronal Organization of the Retina[END_REF]. The classical textbook view Partie I, Chapter 2 -Visual processing recalls only three types (midget, parasol and bi-stratified) representing about 90% of the primate retina and linked to parallel pathways that remain anatomically segregated through lateral geniculate nucleus and primary visual cortex (see Figure 9) attributed to each stream (i.e. P-high acuity, red-green oponency, M -achromatic, low acuity, Kblue-green opponency).

The "three paths" model is however contested by numerous anatomical, physiological and psychophysical findings, which show that these pathways do not fulfill the required characteristics, namely homogeneity, independence (structural and perceptual) and compatibility between the stream's properties and its presumed function [START_REF] Kaplan | The P, M and K Streams of the Primate Visual System: What Do They Do for Vision? In Senses a compr[END_REF][START_REF] Kaplan | The M , P and K pathways of the Primate Visual System revisited[END_REF]. The current knowledge is unfortunately insufficient and unable to produce a better, comprehensive model of visual channels. It is likely that the numerous types of ganglion cells encode visual information in more parallel channels than previously believed. It is now clear that ganglion cells response and receptive field are dynamic and modulated by various contextual influences such as object motion segmentation, direction selectivity, anticipatory responses to moving stimuli and saccadic suppression [START_REF] Olveczky | Segregation of object and background motion in the retina[END_REF]Roska and Werblin 2003;[START_REF] Hosoya | Dynamic predictive coding by the retina[END_REF][START_REF] Münch | Approach sensitivity in the retina processed by a multifunctional neural circuit[END_REF][START_REF] Masland | The Neuronal Organization of the Retina[END_REF]. Parallel visual processing starts in the retina and cone circuitry represents its foundation. Visual information is decomposed and structured in various information channels by the retinal neurons and conveyed to central structures by the axons of ganglion cells. Noteworthy, the reinvented trichromatic vision in primates "piggybacks" the high acuity system of the central vision. The "three paths" model (parvocellular, magnocellular, koniocellular) is obsolete, as likely more numerous output channels exist. Unfortunately, the insufficient current knowledge cannot provide a better, comprehensive model.

Overview

Rod neural circuitry

Rod photoreceptors are a later phylogenetic acquisition and in terms of information transmission, they "piggy-back" cone circuitry. As developed in previous chapters, rods are responsible for the scotopic vision, but their role is much complex including the relay of cone-driven, horizontal cell-mediated surround inhibition (photopic conditions, [START_REF] Szikra | Rods in daylight act as relay cells for cone-driven horizontal cell-mediated surround inhibition[END_REF]. Rod signal is transmitted through at least three different pathways, each tuned for a primarily non-overlapping range of intensities, the ganglion cells receiving either convergent or segregated inputs [START_REF] Volgyi | Convergence and Segregation of the Multiple Rod Pathways in Mammalian Retina[END_REF]. The "classical" rod transmission pathway is preeminent in scotopic conditions and likely conveys slow, low-threshold rod signals [START_REF] Volgyi | Convergence and Segregation of the Multiple Rod Pathways in Mammalian Retina[END_REF]. It relays the rod signal to the unique type of rod bipolar cell that conveys it radially into the inner plexiform layer to AII amacrine cells that form sign-inverting synapses with ON cone bipolar cells and sign-conserving synapses with OFF cone bipolar cells (See Figure 10). Two secondary pathways are active at higher light intensities, when the primary pathway is saturated and they covey the signal through gap-junctions located between photoreceptor axonal terminals [START_REF] Volgyi | Convergence and Segregation of the Multiple Rod Pathways in Mammalian Retina[END_REF][START_REF] Bloomfield | The diverse functional roles and regulation of neuronal gap junctions in the retina[END_REF]). The first one conveys fast, high-threshold rod signals through rod-cone coupling and is active in mesopic conditions; the signal is transmitted to cones and further to cone bipolar cells and then to ganglion cells (see Figure 10, Volgyi 2004). Interestingly, the rod-cone coupling is modulated by the circadian retinal clock through dopamine release during the day, which inhibits the conductance of rod-cone gap-junctions [START_REF] Ribelayga | The Circadian Clock in the Retina Controls Rod-Cone Coupling[END_REF]. The second path (see Figure 10), less well understood, conveys relatively low-threshold signals through rod-rod coupling; the signal is transmitted to an OFF bipolar cell, which further relay it to a subset OFF ganglion cell. It was proposed that this pathway helps identifying dark objects moving through the visual field and that it evolved to improve predators detection during the dusk and dawn [START_REF] Tsukamoto | Microcircuits for night vision in mouse retina[END_REF][START_REF] Volgyi | Convergence and Segregation of the Multiple Rod Pathways in Mammalian Retina[END_REF]).

Figure 10 -Rod circuitry.

A. The primary rod pathway comprises synapses between AII amacrine cells and between AII amacrine cells and cone bipolar cells. Rods transmit signals to rod bipolar cell that convey them to AII cells that relay through electrical synapses to cone bipolar cells (sign conserving with ON cone bipolar cells and signinverting synapses with OFF cone bipolar cells) that further transmit it to ganglion cells. B. The secondary rod pathway involving electric synapses between rods and.cones Rods convey the signal directly to cones that further relay it through their downstream circuitry. C. The tertiary rod pathway that involves only electric synapses between rods. Rods make direct chemical synapses with an OFF subtype of bipolar cell that relays the signal to specific OFF ganglion cells. No ON counterpart was identified for this pathway. Solid arrows represent excitatory and dotted arrows inhibitory chemical synapses. C -cone; R -rod; CB -cone bipolar; RB -rod bipolar; GC -ganglion cell (from [START_REF] Bloomfield | The diverse functional roles and regulation of neuronal gap junctions in the retina[END_REF].

Rods have three currently known transmission pathways. All of them employ cones' neural circuitry. They demonstrate that rods intervene not only in scotopic conditions, but also have a visual role in mesopic conditions (dim-light).

Overview

Partie I, Chapter 2 -Visual processing

Cerebral visual processing

General view on the central nervous system organization

Different groups of vertebrates exhibit a common general plan of central sensory and motor pathways. In the case of sensory system, incoming information is initially conveyed to intermediary stations in brainstem (body and trigeminal somatosensory and visceral senses, lateral line/ vestibulocohlear, gustatory senses), to the olfactory bulb (olfaction) or to various layers in the retina (vision). Further on, in amniotes, most of information follows two paths -it can be relayed through the midbrain roof structures and from there to dorsal thalamic nuclei (the collothalamic pathway, in reference to colliculi) or can reach directly the dorsal thalamus (the lemnothalamic pathway, meaning "ribbon-like"); from dorsal thalamus, information is conveyed to various parts of telecephalic pallium (cortex). Dorsal thalamus has two fundamental divisions across all jawed vertebrates: an embryologically more rostral part that receives direct sensory input (lemnothalamus) and a more caudal part that receives information relayed through midbrain roof nuclei (collothalamus; [START_REF] Butler | The dual elaboration hypothesis of the evolution of the dorsal thalamus[END_REF][START_REF] Butler | Evolution of the brain in vertebrates[END_REF]. In what concerns vision, in mammals, geniculostriate pathways are lemnothalamic and relay directly into the lateral geniculate nuclei in dorsal thalamus, while retinotectothalamocortical pathways are collothalamic and relay in the superior colliculi before reaching the lateral posterior/pulvinar nuclei in dorsal thalamus. From their thalamic relay, lemnothalamic visual pathway projects into the lemnopallium, namely into the primary visual cortex and collothalamic visual pathway into association visual cortices (parietal and temporal) but also the basolateral division of the pallial amygdala, especially its lateral nucleus [START_REF] Butler | Evolution of the brain in vertebrates[END_REF]. The exact role of collothalamic pathways is poorly understood but it is believed that it participates in visual attention mechanisms and blindsight, a form of vision that persists after the destruction of the primary visual cortex (V1), the destination region of lemnothalamic pathway [START_REF] Zeki | The Riddoch syndrome: Insights into the neurobiology of conscious vision[END_REF][START_REF] Tamietto | Visual Plasticity: Blindsight Bridges Anatomy and Function in the Visual System[END_REF]see Figure 11).

Besides lemnothalamic and collothalamic pathways, other less well understood visual projections have been described. Direct retino-pulvino-cortical pathways ending in middle temporal area (MT) area exist in primates, at least in early life, and are responsible for remarkably good residual vision they exhibited after postnatal removal of the primary visual cortex [START_REF] Kaas | Blindsight: Post-natal potential of a transient pulvinar pathway[END_REF][START_REF] Warner | Preservation of vision by the pulvinar following early-life primary visual cortex lesions[END_REF]. Interestingly, MT structure is closer to a primary sensory area than to associative cortex [START_REF] Bourne | Hierarchical development of the primate visual cortex, as revealed by neurofilament immunoreactivity: Early maturation of the middle temporal area (MT)[END_REF]. The role of this regressive, direct pulvino-MT connection is unknown. Warner et al speculated that it might be required for the dorsal expansion of the visual cortex in primates [START_REF] Warner | Preservation of vision by the pulvinar following early-life primary visual cortex lesions[END_REF] while Kaas argued that it might prevent the significant wiring of the visual cortex by the collothalamic pathway as seen in close relatives of primates (i.e. three shrews, Kaas 2015).

Accessory optic system, represented by the dorsal, lateral and medial nuclei positioned in the periphery of rostral mesencephalon on a side branch of the optic tract of the optic tract, complements the vestibular system in detecting self motion. It registers the speed and direction of of the environment's global movements and relay them to cerebellum via the inferior olive. This information is also employed in the long-term adaptation of vestibulo-ocular reflex [START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF].

Motor pathways are also unidirectional relay systems, which are regulated and gated by recurrent circuits controlling the initiation and the guidance of movements [START_REF] Butler | Evolution of the brain in vertebrates[END_REF]. Visuomotor system deserves a particular interest due to its complexity and similarity across the major taxa. In addition to the lemnothalamic and collothalamic pathways, retina also projects to multiple pretectal and accessory optic nuclei, involved in oculomotor control and pupillary light reflex. Moreover, in mammals, the tectum and reticular formation have important roles in eye movement regulation both as response to visual stimuli or vestibular input [START_REF] Butler | Evolution of the brain in vertebrates[END_REF]. Cortical visual input follows two main afferent channels: lemnothalamic and collothalamic. Lemnothalamic pathway relays directly in the dorsal thalamus from where it projects to cerebral cortex. Collothalamic pathway, preeminent in many vertebrates has a first relay in the superior colliculus from where visual information is conveyed to the dorsal thalamus and further to the cerebral cortex.

Overview

Lemnothalamic pathway

Lemnothalamic projections constitute the chief visual projections in primates [START_REF] Kaas | Blindsight: Post-natal potential of a transient pulvinar pathway[END_REF]. The current view described bellow is based on the "three paths model".

Retinothalamic projections

Axons of ganglion cells positioned in the temporal half of the retina project on the ipsilateral LGN, while axons of ganglion cells positioned in the nasal half of the nasal retina cross at the level of the optic chiasm and reach the contralateral LGN. Retinal ganglion cells terminate into a highly ordered manner into parvocellular (P), magnocellular (M) or koniocellular (K) layers of lateral geniculate nuclei (LGN) and from there, to different layers of the primary visual cortex (V1) (see Figure 12). Layers M1, P4 and P6 receive contralateral fibers, layers M2, P3 and P5 ipsilateral fibers, while K layers receive the same kind of fibers as the overlaying main layer (see Figure 12, Nieuwenhuys et al. 2008). Small bistratified blue/yellow opponent ganglion cells terminate in the layers K3 and K4 and the remaining K layers receive input from other retinal ganglion cells [START_REF] Hendry | The Koniocellular Pathway in Primate Vision[END_REF][START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF]. Moreover, ventral K layers receive extraretinal input from superior colliculus and its satellite, the parabigeminal nucleus (see Figure 12, Harting et al. 1973;[START_REF] Harting | Ascending pathways from the monkey superior colliculus: An autoradiographic analysis[END_REF][START_REF] Hendry | The Koniocellular Pathway in Primate Vision[END_REF].

Partie I, Chapter 2 -Visual processing

Thalamocortical projections

Fibers from the LGN project to the ipsilateral area V1, in the calcarin sulcus, on the medial aspect of the occipital lobe. They cross through the retrolenticular part of the internal capsule, arch around the lateral ventricle and pass posteriorly toward the occipital cortex. Fibers from the lateral aspect of LGN and bearing the projections from the superior visual field will take a longer route, sweeping around the inferior horn of the lateral ventricle ("the temporal knee" of the optic radiations) before reaching the inferior bank of the calcarine sulcus (see Figure 12, Nieuwenhuys et al. 2008).

Primary visual cortex (V1) exhibits retinotopic organization. The foveal region over represented, thus reflecting differences in information processing. Foveal projection is located in the posterior part of V1, whereas the peripheral retina projection in the anterior part of V1 [START_REF] Horton | The representation of the visual field in human striate cortex. A revision of the classic Holmes map[END_REF]. The nasal periphery of the retina, sampling the temporal, monocular part of the visual field project most anteriorly in the proximity of the splenius of corpus callosum [START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF]). Will we refer to the posterior part of V1, where foveal region project, as "central V1" and to the anterior part of V1, where peripheral retina projects, as "peripheral V1". The segregation between the projection of the left and right retina is persevered not only within LGN's layers but also in V1 where the afferences of the ipsilateral eye terminate in columns separated by other columns receiving afferences from the contralateral eye (see Figure 12, Nieuwenhuys et al. 2008).

V1 is formed by 6 functional layers. Magnocellular and parvocellular LGN neurons project into the 4th V1 layer, namely into sublayers 4C and 4C, 4A respectively; the koniocellular neurons project into layers 2/3. Koniocellular LGN neurons also project into MT area, bypassing V1. The three paths intermix into the blobs and interblobs of V1's layers 2/3 and are further transmitted via the thin and thick stripes of area V2 into the ventral and dorsal visual streams (see Figure 14, Nieuwenhuys et al. 2008). Likewise, V1 receives feedforward and feedback projections and send feedforward and feedback projections to various cortical and subcortical structures and suggesting a parallel multilevel processing of information [START_REF] Schmolesky | The Primary Visual Cortex by Matthew Schmolesky[END_REF]. Direct feedforward projections to V1 from pulvinar, LGN, claustrum, nucleus paracentralis, the raphe system, Meynert's basalis nucleus [START_REF] Ogren | Pathways between striate cortex and subcortical regions in Macaca mulatta and Saimiri sciureus: Evidence for a reciprocal pulvinar connection[END_REF][START_REF] Rezak | A comparison of the organization of the projections of the dorsal lateral geniculate nucleus, the inferior pulvinar and adjacent lateral pulvinar to primary visual cortex (area 17) in the macaque monkey[END_REF][START_REF] Graham | Some topographical connections of the striate cortex with subcortical structures in Macaca fascicularis[END_REF][START_REF] Blasdel | Termination of afferent axons in macaque striate cortex[END_REF][START_REF] Doty | Nongeniculate afferents to striate cortex in macaques[END_REF][START_REF] Perkel | Topography of the afferent connectivity of area 17 in the macaque monkey: a double-labelling study[END_REF][START_REF] Lachica | Direct W-like geniculate projections to the cytochrome oxidase (CO) blobs in primate visual cortex: Axon morphology[END_REF][START_REF] Hendry | A neurochemically distinct third channel in the macaque dorsal lateral geniculate nucleus[END_REF][START_REF] Adams | Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis[END_REF][START_REF] Schmolesky | The Primary Visual Cortex by Matthew Schmolesky[END_REF]), direct feedforward projections originating in V1 reaching V2, V3, V5, MT, medial superior temporal area (MST), frontal eye field (FEF) [START_REF] Lund | The origin of efferent pathways from the primary visual cortex, area 17, of the macaque monkey as shown by retrograde transport of horseradish peroxidase[END_REF][START_REF] Maunsell | The connections of the middle temporal visual area (MT) and their relationship to a cortical hierarchy in the macaque monkey[END_REF]Ungerleider and Desimone 1986;[START_REF] Livingstone | Connections between layer 4B of area 17 and the thick cytochrome oxidase stripes of area 18 in the squirrel monkey[END_REF][START_REF] Shipp | The Organization of Connections between Areas V5 and V1 in Macaque Monkey Visual Cortex[END_REF][START_REF] Boussaoud | Pathways for motion analysis: Cortical connections of the medial superior temporal and fundus of the superior temporal visual areas in the macaque[END_REF]Fitzpatrick et al. 1994;[START_REF] Schmolesky | The Primary Visual Cortex by Matthew Schmolesky[END_REF]), direct feedback projection to V1 from V2, V3, V4, V5, MT, MST, frontal eye field (FEF), lateral intraparietal cortex (LIP) [START_REF] Perkel | Topography of the afferent connectivity of area 17 in the macaque monkey: a double-labelling study[END_REF]Ungerleider and Desimone 1986;[START_REF] Shipp | The Organization of Connections between Areas V5 and V1 in Macaque Monkey Visual Cortex[END_REF]Zeki 1989, Rockland et al. 1994;Barone et al. 2000;[START_REF] Striem-Amit | Divergent backward projections from the anterior part of the inferotemporal cortex (area TE) in the macaque[END_REF][START_REF] Schmolesky | The Primary Visual Cortex by Matthew Schmolesky[END_REF]) and direct feedback projection from V1 to superior colliculi, LGN, pulvinar, pons [START_REF] Lund | The origin of efferent pathways from the primary visual cortex, area 17, of the macaque monkey as shown by retrograde transport of horseradish peroxidase[END_REF][START_REF] Graham | Some topographical connections of the striate cortex with subcortical structures in Macaca fascicularis[END_REF]Fries, W., Distel 1983;[START_REF] Fries | Pontine projection from striate and prestriate visual cortex in the macaque monkey: an anterograde study[END_REF][START_REF] Gutierrez | Area V1 in macaque monkeys projects to multiple histochemically defined subdivisions of the inferior pulvinar complex[END_REF][START_REF] Schmolesky | The Primary Visual Cortex by Matthew Schmolesky[END_REF] Lemnothalamic pathway represents the principal visual pathway responsible for conscious vision in primates. Its projections terminate in primary visual cortex with the exception of some koniocellular fibers that terminate in MT area. Lesion of the lemnothalamic pathway in adult primates results in cortical blindness and some degree of visual behavior can be regained through the reinforcement of the collothalamic pathways.

Overview

Partie I, Chapter 2 -Visual processing

Collothalamic pathway

Collothalamic projections represents the chief visual projections in in most vertebrates and are particularly developed in birds. They also important in most mammals except for primates [START_REF] Butler | Evolution of the brain in vertebrates[END_REF].

Superior colliculi play an important role in orienting behavior by directing the line of sight toward the targets of interest through coordinated movements of the eyes, head and body as well as in other visuo-attentional processes and blindsight [START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF][START_REF] Tamietto | Visual Plasticity: Blindsight Bridges Anatomy and Function in the Visual System[END_REF].

In primates, various type of retinal ganglion cells, accounting for up to 10% of the total retinal output, terminate in the superficial layers of the superior colliculi [START_REF] Leventhal | Retinal ganglion cell classes in the Old World monkey: morphology and central projections[END_REF]. Retinocollicular projections are bilateral, with a contralateral dominance: temporal fibers have both ipsilateral and contralateral projections, while the nasal fibers have only contralateral projections [START_REF] Cynader | Receptive-field organization of monkey superior colliculus[END_REF]. Therefore, while the binocular visual field has bilateral collicular representation, the monocular eye field has only contralateral representation (see Figure 13). Moreover, the superior colliculus receives input from the ipsilateral cerebral cortex mainly from the visual and visuomotor areas (V1, V2, area 19, MT, frontal and parietal visual areas, [START_REF] Leichnetz | The prefrontal corticotectal projection in the monkey; An anterograde and retrograde horseradish peroxidase study[END_REF]Fries, W., Distel 1983;[START_REF] Lynch | The differential projection of two cytoarchitectonic subregions of the inferior parietal lobule of macaque upon the deep layers of the superior colliculus[END_REF][START_REF] Abel | Distribution of neurons projecting to the superior colliculus correlates with thick cytochrome oxidase stripes in macaque visual area V2[END_REF][START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF]) and subcortical structures (pretectum, parabigeminal nucleus, nucleus of the optic tract, nucleus intercalatus and substantia nigra, [START_REF] Voogdt | Mammals[END_REF][START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF], see Figure 13).

The superior colliculus sends efferences to thalamic and other subcortical structures. The collothalamic fibres originating in the superficial layers, terminate in the ventral lateral geniculate nucleus, the inferior and lateral pulvinar and lateral geniculate nucleus, koniocellular layers. From thalamus, they further project in various cortical locations -V1, V2, MT, MT MST, parietal visual area and FEF [START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF].

Compared with most vertebrates and even mammals, in primates and thus in humans, collothalamic pathway is less well represented. It is also less well understood. Collothalamic pathway is responsible for the residual vision following lesions that block the lemnothalamic input (i.e. primary visual cortex lesions) and represents an invaluable resource for the sensory rehabilitation.

Overview

Associative visual cortex

Visual areas beyond V2, treat information issued from specific channels and are arranged into two streams: a dorsal stream directed toward the parietal lobe and a ventral stream directed to the temporal lobe. Ventral stream is identified with perceptual identification (the "what" pathway) while dorsal stream with action and visuo-motor control (the "where" pathway) (see Figure 14, Goodale and Milner 1992). Noteworthy, even though the two streams are separated processing channels, numerous interactions exist between them [START_REF] Wang | Relationship between ventral stream for object vision and dorsal stream for spatial vision: An fMRI+ERP study[END_REF]McKyton and Zohary 2007;[START_REF] Roe | Toward a Unified Theory of Visual Area V4[END_REF]. Like V1, associative visual cortex exhibit retinotopic organization, yet less definite, especially in higher-order visual areas (van [START_REF] Essen | The topographic organization of rhesus monkey prestriate cortex[END_REF]Sereno et al. 1995;Malach et al. 2002;Wandell et al. 2007;[START_REF] Wandell | Imaging retinotopic maps in the human brain[END_REF]. The main sensory input to these regions is from the primary visual cortex (lemnothalamic pathway) with a secondary sensory input from the collothalamic pathway [START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF].

Ventral stream

It is canonically considered that ventral stream processes information related to form and color and that it represents the continuation of the parvocellular pathway [START_REF] Troncoso | Vision's first steps: anatomy, phisiology and perception in the retine, lateral geniculate nucleus and early visual cortical areas[END_REF]. Within this stream, information processed in V1 and V2 is relayed to areas like like V4, V8, lateral occipital complex (LOC), fusiform gyrus (FG) and parahyppocamic gyrus (PH). V4 was considered the area for colour perception as suggested by animal studies, but in humans this view is contested and presumed that color information is processed in more anterior areas such as V8. (Bartolomeo et al. 2014). V4 is however central for the figure-ground segmentation. It integrates multiple stimulus properties like contour, shape, texture, motion, disparity through bottom-up salience-driven attentional mechanisms or top-down, proactive, spatial and feature selection [START_REF] Reynolds | Interacting roles of attention and visual salience in V4[END_REF][START_REF] Qiu | Figure-ground mechanisms provide structure for selective attention[END_REF][START_REF] Poort | The role of attention in figure-ground segregation in areas V1 and V4 of the visual cortex[END_REF][START_REF] Roe | Toward a Unified Theory of Visual Area V4[END_REF][START_REF] Schmid | Motion-sensitive responses in visual area V4 in the absence of primary visual cortex[END_REF]. LOC participates both in object identification and the spatial information related to objects [START_REF] Macneil | The shapes and numbers of amacrine cells: Matching of photofilled with Golgi-stained cells in the rabbit retina and comparison with other mammalian species[END_REF][START_REF] Larsson | Two retinotopic visual areas in human lateral occipital cortex[END_REF]McKyton and Zohary 2007;[START_REF] Malikovic | Cytoarchitecture of the human lateral occipital cortex: mapping of two extrastriate areas hOc4la and hOc4lp[END_REF]. FG contains several subdivisions involved in word, object, body and face recognition (Kanwisher 2001;[START_REF] Dehaene | The unique role of the visual word form area in reading[END_REF]Caspers et al. 2013a;Caspers et al. 2013b;[START_REF] De | The Dide-Botcazo syndrome: forgotten and misunderstood[END_REF]. A subdivision of PH, the "parahyppocampal place area" (PPA) participates in place scene and large objects identification (Kanwisher 2001). The "extra body area" (EBA), located in the lateral temporal cortex processes information related to the different body parts [START_REF] Taylor | Functional MRI analysis of body and body part representations in the extrastriate and fusiform body areas[END_REF][START_REF] Weiner | Not one extrastriate body area: Using anatomical landmarks, hMT+, and visual field maps to parcellate limb-selective activations in human lateral occipitotemporal cortex[END_REF].

Dorsal stream

Canonically, dorsal stream continues the magnocellular pathway at cortical level and process information related to motion, spatial representation and visuo-motor coordination. Within this stream, information originating in V1 and V2 is conveyed to MT/V5, V3d, V3A and further into parietal regions. MT is an area central for movement processing and receives sensory input from V1/V2, koniocellular layers of LGN and the collothalamic pathway [START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF]. Areas V3d and V3A are involved in various aspects of motion perception including the extraction of kinetic contours, chromatic motion perception and 3D form-from-motion (Vanduffel 2002;Zeki et al. 2003;[START_REF] Mckeefry | The contribution of human cortical area V3A to the perception of chromatic motion: A transcranial magnetic stimulation study[END_REF]. V6 area responds to unidirectional motion, has strong preference for coherent motion and participates in the detection of object and self-motion (Pitzalis et al. 2010;[START_REF] Pitzalis | The functional role of the medial motion area V6[END_REF]. Color code: red -dorsal stream; gray -ventral stream; black -V1; dark gray -V2. E. Diagram of the origin of dorsal and ventral streams. Both ventral and dorsal stream originate in V1 or V2. Magnocellular (black, M, m), parvocellular (red, P,p) and koniocellular (red contour, K, k ) pathways originate in the correspondent layers of the lateral geniculate body (LGB). Main direct and indirect projections of M pathway end up in V1 layers 4C and 4B. From 4B M pathway projects onto the thick stripes of V2 and onto middle temporal area (MT) of the dorsal stream. M, P and K pathways combine in the and interblobs of V1's layer 2/3. Thus, local projections (i) and remote projections of layer 2/3 via the thin and thick layers of V2 into dorsal and ventral stream carry mixed M, P and K signals. The intrinsic connections are shown for one ocular dominance column (odc). Meynert cells, involved in motion detection and located in small clusters in the V1's L5/L6 layers boundary, in the region containing the representation of the far periphery projects both to superior colliculus and MT area. K pathway also send direct projections to MT area. AIP-anterior parietal area; FFA -fusiform face area; inf.par.lob -inferior parietal lobule; LIP -lateral intraparietal area; LO -lateral occipital area; MST -medial superior temporal visual area; MIP -medial intraparietal area; PEip intraparietal part of area PE; STP -superior temporal polysensory area; sup.par.lob-superior parietal lobule; TE -inferior temporal area; V1-V6A, V8 -visual areas; VIP -visual intraparietal area (from [START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF].

Ventral and dorsal streams are canonical models based on the "three paths" model and therefore inherit its flows. Roughly, the ventral stream has identification attributes and the dorsal stream localization attributes.

Overview

Brain's non-perceptual light processing

We proposed at the beginning of the first chapter (Chapter 1.1) a definition of vision, namely that it represents a system that recognizes and extracts information from light. Information extraction should by no means be reduced to spatial frequency, position and wavelength that following processing result in visual percepts. In all bilaterians, the "perceptual" facet of vision is coupled with at least another facet that synchronizes physiological functions to the environmental light periods. It is a more "silent" type of vision, one that does not emerge explicitly into conscience.

In vertebrates, regulatory, synchronizing photoreception even disposes of its own "eye" -the pineal complex -with most developed exponents in certain reptilians where they present a cornea, lens and retina [START_REF] Ralph | The pineal gland and geographical distribution of animals[END_REF]. Interestingly, the most developed reptilian pineal complex is encountered in reptilians living at higher latitudes, while those with underdeveloped pineal complexes grouped mostly around the equator [START_REF] Ralph | The pineal gland and geographical distribution of animals[END_REF]. It is currently believed that one of the roles of this complex is thermoregulation [START_REF] Ralph | The pineal gland and geographical distribution of animals[END_REF][START_REF] Cipolla-Neto | Melatonin, energy metabolism, and obesity: a review[END_REF]; even in mammals and humans, which have a rudimentary pineal gland, melatonin (the main pineal hormone) activates the highly metabolic brown adipose tissue that converts energy into heat [START_REF] Tan | Significance and application of melatonin in the regulation of brown adipose tissue metabolism: Relation to human obesity[END_REF]). Noteworthy, the pineal complex is a part of the "photosensitive vertebrate brain" that also includes deep septal and hypothalamic photosensitive nuclei [START_REF] Vigh | Nonvisual photoreceptors of the deep brain, pineal organs and retina[END_REF]. If strong evidence supports the deep-brain photoreception in non-mammal vertebrates [START_REF] Peirson | The evolution of irradiance detection: melanopsin and the non-visual opsins[END_REF], in mammals evidence for true deep-brain photoreception remains largely circumstantial (Fernandes et al. 2013). This peculiarity in mammals was related to the presumed evolutionary "twilight (mesopic) bottle-neck" (see also Chapter 1.2.1, Davies et al. 2012), when deep-brains photoreceptors diminished or even lost light sensitivity, their physiological role being roughly taken over by retina presumably to maximize function in a poorly-lit environment [START_REF] Heesy | The nocturnal bottleneck and the evolution of mammalian vision[END_REF]Fernandes et al. 2013). In humans, photoperiodicity was suggested by sleep disturbances in night shift work, seasonal depression and jet-lag [START_REF] Vigh | Nonvisual photoreceptors of the deep brain, pineal organs and retina[END_REF]. Moreover, several studies on night-shift workers suggested an increased risk for cancer [START_REF] Schernhammer | Rotating night shifts and risk of breast cancer in women participating in the nurses' health study[END_REF]Schernhammer et al. 2003), vascular disorders [START_REF] Kawachi | Prospective study of shift work and risk of coronary heart disease in women[END_REF][START_REF] Chen | Obesity and high blood pressure of 12-Hour shift female clean-room workers[END_REF], obesity [START_REF] Chen | Obesity and high blood pressure of 12-Hour shift female clean-room workers[END_REF]) and decreased cognitive performance [START_REF] Maltese | Night shift decreases cognitive performance of ICU physicians[END_REF].

Non-perceptual, regulatory and synchronizing photosensitive brain is a part of the periventricular cerebrospinal fluid (CSF) contacting neuronal system [START_REF] Vigh | Nonvisual photoreceptors of the deep brain, pineal organs and retina[END_REF] that belongs to the circumventricular organs [START_REF] Béla | Evidence for a Frontoparietal Control System Revealed by Intrinsic Functional Connectivity[END_REF]. Interestingly, CSF-contacting neurons form the major population in echinoderm starfishes and the cephalocordate Branchiostoma lanceolatus [START_REF] Béla | Evidence for a Frontoparietal Control System Revealed by Intrinsic Functional Connectivity[END_REF] arguing for the ancient phylogenetic nature of this part of the visual brain.

Action and the evolution of visual processing

Brain continuously integrates information and unceasingly updates the ways it does it. Validated, constant patterns of information and the appropriate visuo-motor responses are imbedded in unconscious circuits. Therefore, most of the visual processing is unconscious and likely the main role of the "perceptual" vision (conscious) is to detect incongruences between the incoming signal and the expected pattern, to further orient processing (topdown control) and to orient action. However, important changes in the expected pattern may result in impaired performance as illustrated by difficult recognition of the grotesque version of da Vinci's Mona Lisa when presented in an unnatural, "upside-down" position (see Figure 15A).

In mammals, more particularly in primates and hominids action also shaped the evolution of visual brain. As illustrated by Zhuangzi's classical story of the skilled cook Ding, novel action requires sustained cognitive control, but once the optimal processing and response sequences are computed it became "mindless" (highly automatic) and precise [START_REF] Cheng | La main et l'esprit[END_REF]. The use and design of complex tools, a defining particularity of homo sapiens, relays on visual integration and visuo-motor coordination. In contrast to some primates and birds that can display tool-assisted foraging, homo sapiens became a tool-dependent forager [START_REF] Plummer | Flaked stones and old bones: Biological and cultural evolution at the dawn of technology[END_REF]). Tools-handling requires complex computations crucial for the appropriate body-tool and body-tool-environment interactions. Within the conceptual framework offered by theory of extended mind [START_REF] Clark | Re-Inventing Ourselves: The Plasticity of Embodiment, Sensing, and Mind, Transhumanist Read[END_REF], [START_REF] Bruner | Extending mind, visuospatial integration, and the evolution of the parietal lobes in the human genus[END_REF] proposed that tools-handling "embodied" tools and tool-action extending thus the peripersonal space, the world and the mind. It is believed that mastering tools determined cerebral adaptive morphological changes affecting especially the parietal lobe, namely longitudinal and lateral bulging of the parietal lobes [START_REF] Bruner | Extending mind, visuospatial integration, and the evolution of the parietal lobes in the human genus[END_REF]. Theses changes affected especially the precuneus, area with an important role in visuo-spatial integration (Bruner et al. 2016;[START_REF] Pereira-Pedro | Sulcal pattern, extension, and morphology of the precuneus in adult humans[END_REF].

Tool-design tool-handling and the development of language, with the later possibly emerging from the first (Hewes et al. 1973) further enlarged mind and the conscious domain. This expansion of mind affected also the range perceptual experience and most interesting, in the case of impairment in information processing, determined various types of altered perceptual experience (see Figure 15B, ffytche 2007).

Figure 15 -Aspects of visual perception. A. Abnormal perceptive accuracy when visual input is presented in a non-ecological way (i.e. upside-down). B. Neurophenomanological classification of human perceptual experience presented in a 3D spaces: x axis -perceptual locus (external perception or in the "mind's eye); y -vividness (color saturation, definition); z axis -agency (volitional control). To the left of the vertical, dotted plane are depicted visual experiences related to activity that predominates in specialized visual cortex, while to the right of the vertical plane are depicted visual experiences related to activity that predominates in parietal and frontal areas (from https://www.exploratorium.edu/exhibits/mona/mona.html and ffytche 2007) Chapter 3

Visual loss

Models of visual loss

The concept of visual loss subtends a large spectrum ranging from total blindness to the "exotic" loss of certain visual functions like prosopagnosia (incapacity to recognize faces), alexia (incapacity to read) or akinetopsia (incapacity to recognize certain types of movement). Disorders affecting lemnothalamic visual pathways up to V1 result in a specific configuration of visual field defects. Lesions to retina and optic nerve may result in the complete loss of the central or peripheral vision. Due to their different structure and function, the loss of central or peripheral vision determines different disabilities. Herein, we preferred to focus on two retinal disorders that specifically affect photoreceptors and therefore spare the inner retina -Stargardt macular dystrophy and pigmentary retinopathy. These disorders induce very structured visual field defects that allow the selection of clinically homogenous patients groups. Moreover, the selected forms of retinal dystrophies are restricted to retina and not associated with widespread cerebral neurodegenerative alterations, allowing for an unambiguous evaluation of the cerebral reorganization following central and peripheral visual loss.

Central visual field loss -Stargardt macular dystrophy

Stargardt macular dystrophy (SMD), initially described by Stargardt in 1909, is the most common juvenile-onset macular dystrophy with a a prevalence of 1/10000 (Stargardt 1909;[START_REF] Meunier | Maladie de Stargardt (Stargardt disease)[END_REF]; it induces slow, progressive, symmetrical visual loss. Eye fundus shows bilateral, beaten bronze-like pigmentary changes in the macula and pisciform shaped, yellow-white flecks at the level of the retinal pigment epithelium called "fundus flavimaculatus" (see Figure 16, Franceschetti 1963). The the mutation of the ABCA4 gene (on the chromosome 1p13-p21) is the cause of SMD. It codes for an "ATP binding cassette", a flippase that intermediates the clearance of all-trans-retinal after the photoexcitation of rhodopsin and prevents the accumulation of toxic by-products, namely bis-retinoid, N-retinylidene-N-retinylethanolamine (A2E) [START_REF] Meunier | Maladie de Stargardt (Stargardt disease)[END_REF]Sahel et al. 2015). Retinal pigment epithelium fagocitates A2E that induces its degeneration, and consequently the death of photoreceptors. Degeneration is focused on the macular region due to the high concentration of cones and rods in the foveal and parafoveal region Partie I, Chapter 3 -Visual loss

Plasticity induced by visual loss

Retinal plasticity following photoreceptor loss

Like in other central nervous system degenerations, deafferentation also activates remodelling in retina.Therefore, neuronal remodelling is a common feature in all photoreceptor degenerations. Retinal degenerations often result in photoreceptors loss regardless of the site of the initiating dysfunction or the genetic defect. The ensuing deafferentation of the neural retina supresses the intrinsic glutamatergic drive and eliminates the coordinated Ca 2+ -coupled signalling to neural retina [START_REF] Jones | Retinal remodeling triggered by photoreceptor degenerations[END_REF][START_REF] Jones | Retinal remodeling during retinal degeneration[END_REF].

In mammal models of rod-cone retinal degeneration, reorganisation can be divided into three phases (see Figure 18, Marc et al. 2003;[START_REF] Jones | Retinal remodeling during retinal degeneration[END_REF]. Phase I represents the initiating event that is responsible for rod insult, the loss of their outer segments and ultimately their death. During the initial stress and the loss of the outer segments, rods neurites sprout and enter the inner retina down to the ganglion layer. In phase II, cones start to degenerate by losing their outer segments, redistributing cone opsins into the inner segments and projecting transient extensions into the inner retina. Cones finally die due to multiple factors : metabolic, trophic and inflammatory. Following rods and cones death, deafferented bipolar and horizontal cells retract most of their dendrites. Dendrite truncation in rod bipolar cells induces changes in their macromolecular phenotype and transduction pathway, while horizontal cells develop anomalous axonal processes and dendritic stalks that enter the inner plexiform layer. Later, cones loss induces Müller cells to elaborate a dense fibrotic layer in the subretinal space, sealing the remnant outer retina from the choroid. If bipolar cell death starts in phase II, depletion of all neuronal classes is obvious in phase III. With time and the evolution of the retinal disorder (years), more and more neurones are lost and patches of ganglion cells can completely loose their afferent connection. This phase is also marked by the remodelling activity in the synaptic terminals of the surviving neuronal cells. Somme can elaborate new neurites that travel long distances beneath the glial seal and form with other types of processes microneuromas in the inner nuclear layer and cryptic connections through the retina. Moreover, some bipolar and amacrine cells are displaced into the former ganglion cell layer while other amacrine celles are everted to the distal glial seal through the inner nuclear layer [START_REF] Marc | Neural remodeling in retinal degeneration[END_REF][START_REF] Jones | Retinal remodeling during retinal degeneration[END_REF]. The new circuits engaged by bipolar, amacrine and ganglion cells are likely corruptive, manifesting as re-entrant, oscillatory, but visually fictive mechanisms [START_REF] Jones | Retinal remodeling triggered by photoreceptor degenerations[END_REF][START_REF] Marc | Neural remodeling in retinal degeneration[END_REF][START_REF] Marc | Neural remodeling in retinal degeneration[END_REF][START_REF] Jones | Retinal remodeling during retinal degeneration[END_REF]. Plastic changes in visual loss due to photoreceptor disorders begin at the very retinal level and include dramatic alterations in its neural circuitry.

Overview

Cerebral plasticity following visual loss

Canonically, cerebral plasticity canonically is viewed as an inherited dynamic capacity to undergo maturation, to organize and change functionally and structurally in response to experience and to adapt following injury [START_REF] Ismail | Cerebral plasticity: Windows of opportunity in the developing brain[END_REF]. Therefore, plasticity represents brain's response to change and it is balanced by homeostatic mechanisms that assure the stability of neural networks [START_REF] Dennis | Age, plasticity, and homeostasis in childhood brain disorders[END_REF]). However, not all plasticity is beneficial and could lead to some maladaptive outcomes depending on factors like the extent and localization of the neuropathological process, the age of onset and the integrity of homeostatic mechanisms [START_REF] Dennis | Age, plasticity, and homeostasis in childhood brain disorders[END_REF][START_REF] Tomaszczyk | Negative neuroplasticity in chronic traumatic brain injury and implications for neurorehabilitation[END_REF][START_REF] Ismail | Cerebral plasticity: Windows of opportunity in the developing brain[END_REF]. Conceivably, maladaptive changes, the "dark side" of plasticity, represent a non-intended side effect, similar to "the spandrels of Saint Marco" [START_REF] Gould | The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme[END_REF][START_REF] Nava | Adaptation and maladaptation insights from brain plasticity[END_REF][START_REF] Dennis | Age, plasticity, and homeostasis in childhood brain disorders[END_REF].

Plastic capacity differs between the developing and the adult brain. Multiple clinical observations supporting children's enhanced learning and memory capacity [START_REF] Klein | Age of language learning shapes brain structure: a cortical thickness study of bilingual and monolingual individuals[END_REF][START_REF] Li | Neuroplasticity as a function of second language learning: anatomical changes in the human brain[END_REF], easy acquisition of complex motor skills (Barrett et al. 2013) and the recovery after major brain injuries [START_REF] Kastrup | Cortical motor reorganization following early brain damage and hemispherectomy demonstrated by transcranial magnetic stimulation[END_REF] indicate that developing brain has a better intrinsic capacity for plasticity than adult brain [START_REF] Ismail | Cerebral plasticity: Windows of opportunity in the developing brain[END_REF]). However, this increased plastic capacity in young age may also associate more debilitating and lostlasting maladaptive plastic effects [START_REF] Dennis | Age, plasticity, and homeostasis in childhood brain disorders[END_REF]. Of particular interest for the young age plasticity are the critical periods -time points in development with high impact on neurogenesis, brain sculpting and learning [START_REF] Hubel | Receptive fields of cells in striate cortex of very young, visually inexperienced kittens[END_REF]. It is important to underline that there are multiple critical periods for different domains of the same sense [START_REF] Dennis | Age, plasticity, and homeostasis in childhood brain disorders[END_REF] In the case of human vision, the sensitive period for the development of global motion starts early after birth and ends around the first year of life, for visual acuity starts around 10 days after birth and ends around 10 years of age and for peripheral vision starts at birth and lasts until the early teenage years [START_REF] Lewis | Multiple sensitive periods in human visual development: Evidence from visually deprived children[END_REF]. Developmental sensitive periods are followed by periods of vulnerability when the sensory system is adult-like but yet flexible and sensitive to sensory deprivation [START_REF] Levi | Perceptual learning in adults with amblyopia: A reevaluation of critical periods in human vision[END_REF][START_REF] Lewis | Multiple sensitive periods in human visual development: Evidence from visually deprived children[END_REF].

During development and the following "flexible period" brain tunesup its networks and promote specialization. Plasticity, the intrinsic response capacity to change of the nervous system, is bridled by homeostatic mechanisms that ensure stability and is not restricted to early life but persists throughout the entire life span. Noteworthy, not plasticity alone, but the balance between plasticity and homeostatic mechanisms is responsible for positive or undesired outcomes of brain organization or reorganization. During the lifespan the functional duplex "plasticity-homeostatic mechanisms" exhibit different dynamics depending on the state of the neural networks and the degree of specialization.

Overview

Cerebral plasticity and MRI

Functional specialization and segregation in brain lays on an anatomical base that stretches from molecular level, up to complex neural systems. Cytoarchitectonic areas represent functionally relevant units in the cerebral cortex, their basic features being the specific regional and laminar distribution of diverse types of projection neurons and interneurons that characterize specific sensory, motor and associative brain regions. Fiber tracts connect different cytoarchitectonic areas and represent the foundation of the functional connectivity (Zilles and Amunts 2015). Available methods to asses in vivo, in humans, the morphology of gray matter are usually the voxel-based morphometry (VBM) and cortical thickness measurement (CoTks), while for the white matter -fiber tracts diffusion tensor imaging (DTI) or diffusion weighted images (DWI). These methods are currently used to explore neuroanatomical correlates both in normal brain and in neurological disorders. [START_REF] Hutton | A comparison between voxel-based cortical thickness and voxel-based morphometry in normal aging[END_REF].

The specific cellular mechanisms underlying the variations in cortical thickness as measured by MRI could be related to different factors like neuronal apoptosis, variations in cortical myelination, alterations in synaptic complexity or the summation of these events (Burge et al., 2016;Zilles and Amunts, 2015). Thus, to understand the meaning of the cortical thickness variations, the assessment of these factors through complementary approaches is required. Magnetization transfer ratio imaging (MTR) reflects the presence of large lipid macromolecules and therefore of the myelin. It provides a reliable method to identify and quantify changes in cerebral tissue myelin content due to demyelination or remyelination [START_REF] Schmierer | Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain[END_REF][START_REF] Giacomini | Measuring demyelination and remyelination in acute multiple sclerosis lesion voxels[END_REF]. The functional MRI entropy measured during resting-state (CoEn), a method derived from information theory, represents an indirect measure of the neural and synaptic complexity [START_REF] Tononi | Complexity and coherency: integrating information in the brain[END_REF]. In this approach increase in the cortical entropy relates to higher connective properties, while reduction in cortical entropy imply synaptic and dendritic degeneration [START_REF] Sokunbi | Inter-individual Differences in fMRI Entropy Measurements in Old Age[END_REF]Thiebaut de Schotten et al., 2016;Yao et al., 2013).

DTI combined with tractography represents an exquisite approach allowing to visualise white tracts in vivo. However, this approach has several limitations: DTI spatial resolution and the histologic properties of the cortical ribbon with its small, low myelinated fibres prevent the accurate identification of tract origin; fibres intermingle in large tracts (i.e. corpus callosum) misleads the identification of both their origin and destination; "kissing" or "crossing" fibres can led to errors in fibres tracking that are still incompletely solved by the available algorithms (Zilles and Amunts 2015).

Several MRI approaches allow the assessment of functional plastic changes following sensory loss. The most employed is the task-based f MRI that quantifies the BOLD signal (blood oxygenation level dependent) in the cerebral cortex following the execution of a specific task (e.g. colour or word identification). Another approach is the resting-state f MRI, a very low-demanding method, also based on the BOLD signal that quantifies spontaneous fluctuations of regional brain activity at rest (without performing any task) (Biswal et al. 1995). Resting-state fluctuations are well-organized into networks, identified during a variety of cognitive tasks (Biswal et al. 1995;Greicius et al. 2003;Hampson et al. 2004;[START_REF] Damoiseaux | Consistent resting-state networks across healthy subjects[END_REF]Fox et al. 2006;Dosenbach et al. 2007;Vincent et al. 2008;[START_REF] Smith | Correspondence of the brain's functional architecture during activation and rest[END_REF]Spreng et al. 2010;Buckner et al. 2013). Theses fluctuations are sufficiently specific be be used for the extraction of retininotopic or mototopic maps both in health and disease (Butt et al. 2013;[START_REF] Bock | Resting-State Retinotopic Organization in the Absence of Retinal Input and Visual Experience[END_REF]Butt et al. 2015;[START_REF] Striem-Amit | Functional connectivity of visual cortex in the blind follows retinotopic organization principles[END_REF]Zeharia et al. 2015).

MRI techniques, such as cortical morphometry, DTI, task-based f MRI, resting-state f MRI are available for in vivo evaluation of the plastic changes induced by visual loss.

Overview

Cerebral plasticity in early blindness

Numerous studies treat the cerebral reorganization following the early blindness and suggest that it induces complex plastic changes (Pascual-Leone et al. 2005). However, in the available literature "early blindness" is a fuzzy concept in what concerns the age of blindness. As developed in the previous chapter, the various sensitive periods have different dynamics and plastic potential. Therefore, a real congenitally blind subject may have significant differences in brain structure and functional connectivity, compared with a subject that loses vision when 6 months or 1-year-old. Therefore, the results of studies with inhomogeneous populations should be weighted with caution.

Subjects with early visual loss, compared to normally sighted, exhibit both enhancement of certain functions and deterioration of others (Bock and Fine 2014). They seem to have have superior aptitudes in certain non-visual tasks like tactile acuity [START_REF] Goldreich | Tactile acuity is enhanced in blindness[END_REF], pitch discrimination and sound localization [START_REF] Gougoux | Neuropsychology: Pitch discrimination in the early blind[END_REF][START_REF] Gougoux | A functional neuroimaging study of sound localization: Visual cortex activity predicts performance in early-blind individuals[END_REF] as well as higher-order tasks like speech discrimination [START_REF] Niemeyer | Do The Blind Hear Better-Investigations on Auditory[END_REF], verbal memory [START_REF] Amedi | Early "visual" cortex activation correlates with superior verbal memory performance in the blind[END_REF], tactile and auditory selective spatial attention [START_REF] Collignon | Improved selective and divided spatial attention in early blind subjects[END_REF]) and certain aspects concerning navigation (Fortin et al. 2008). Moreover, visual cortex in early bling presents enhanced functional connectivity with frontal areas involved in language (Liu et al. 2007;Butt et al. 2013) and attention (Burton et al. 2014;[START_REF] Wang | Altered restingstate network connectivity in congenital blind[END_REF]Striem-Amit et al. 2015;[START_REF] Qin | Functional Connectivity Density in Congenitally and Late Blind Subjects[END_REF]. Increased non-visual aptitudes associate the activation of the visual cortex and suggest a reorganization allowing the intermodal reallocation of the processing capacity (Merabet and Pascual-Leone 2010;[START_REF] Ricciardi | New light from the dark[END_REF]. These peculiarities, together with a similar visual brain organization in early blind and normally sighted [START_REF] Dormal | Functional selectivity in sensory-deprived cortices[END_REF][START_REF] Dormal | Plasticity of the dorsal "spatial" stream in visually deprived individuals[END_REF]Striem-Amit et al. 2012;Striem-Amit et al. 2015) point that brain is rather organized in a function-specific manner designed to treat a particular type of information (i.e. motion, object form, word form, body parts) regardless of the type of sensory input [START_REF] Pascual-Leone | Chapter 27 The metamodal organization of the brain[END_REF][START_REF] Amedi | Visuo-haptic objectrelated activation in the ventral visual pathway[END_REF][START_REF] Renier | Preserved functional specialization for spatial processing in the middle occipital gyrus of the early blind[END_REF][START_REF] Reich | A ventral visual stream reading center independent of visual experience[END_REF][START_REF] Striem-Amit | Visual cortex extrastriate body-selective area activation in congenitally blind people "Seeing" by using sounds[END_REF][START_REF] Abboud | A number-form area in the blind[END_REF].

Vision is essential for the build-up of certain representations like form or space and early visual loss impairs their development in other sensory modalities (i.e. tactile, auditory, Pascual-Leone et al. 2005). Morover, diminished functional connectivity between visual cortex and somatosensory [START_REF] Qin | The Development of Visual Areas Depends Differently on Visual Experience[END_REF]Burton et al. 2014), motor, auditory and multisensory areas in early blind (Liu et al. 2007;[START_REF] Yu | Altered functional connectivity of primary visual cortex in early blindness[END_REF]) supports this view (see Figure 19).

In terms of structural changes, atrophy of the visual pathways from the retina to early visual cortex [START_REF] Ptito | Alterations of the visual pathways in congenital blindness[END_REF][START_REF] Bridge | Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex[END_REF]Shu et al. 2009), reduced occipitotemporal connections, increased occipito-frontal connections [START_REF] Noppeney | Early visual deprivation induces structural plasticity in gray and white matter[END_REF][START_REF] Ptito | Alterations of the visual pathways in congenital blindness[END_REF]Shu et al. 2009) and increased cortical thickness of the early visual cortex Partie I, Chapter 3 -Visual loss [START_REF] Jiang | Thick Visual Cortex in the Early Blind[END_REF][START_REF] Park | Morphological alterations in the congenital blind based on the analysis of cortical thickness and surface area[END_REF][START_REF] Voss | Occipital cortical thickness predicts performance on pitch and musical tasks in blind individuals[END_REF][START_REF] Anurova | Relationship Between Cortical Thickness and Functional Activation in the Early Blind[END_REF]Bock and Fine 2014) represent the most consistent findings in early blindness (see Figure 19). If the atrophy of the visual pathways can easily be explained by the lack of sensory input, the altered connections of the occipital cortex are yet poorly understood. They may be related to the different function devoted to occipital cortex in early blindness (Bock and Fine 2014). The thicker occipital cortex of these subjects might reflect reduced pruning of the juvenile exuberant connections and their persistence in adult life as suggested by the fact that early visual input is a crucial factor in the selection of the relevant connections and the maturation of visual areas [START_REF] Innocenti | Exuberance in the development of cortical networks[END_REF]. Early visual loss induces complex plastic changes resulting in enhanced aptitudes in certain domains and altered abilities in other domains that require visual input for development and specialization. Plasticity in early blindness also suggests that brain is organized in a function-specific manner and that sensory deprived areas may treat information issued from other sensory modalities.

Overview

Cerebral plasticity in late blindness

After several days of sensory deprivation (blindfolding), normally sighted individuals exhibit activation of visual cortex during auditory and tactile tasks, activation that is absent in normal conditions [START_REF] Pascual-Leone | Chapter 27 The metamodal organization of the brain[END_REF][START_REF] Merabet | Rapid and Reversible Recruitment of Early Visual Cortex for Touch[END_REF]. Moreover, in normally sighted individuals trained in Braille character discrimination, the repetitive transcranial magnetic stimulation of the visual cortex impaired Braille lecture only in subjects trained while blindfolded. However, the effect disappeared after 24 hours of visual exposure [START_REF] Merabet | Rapid and Reversible Recruitment of Early Visual Cortex for Touch[END_REF]. This experiment demonstrated that sensory deprivation induced a rapid, dramatic and transitory change in brain activity likely representing the unmasking of preexistent multimodal connectivity [START_REF] Merabet | Rapid and Reversible Recruitment of Early Visual Cortex for Touch[END_REF]. This pattern of connectivity, inhibited by visual input, might represent the background for adaptive changes following visual loss in adulthood. Indeed, late blind activate occipital areas in auditory [START_REF] Kujala | Electrophysiological evidence for cross-modal plasticity in humans with early-and late-onset blindness[END_REF][START_REF] Voss | A positron emission tomography study during auditory localization by late-onset blind individuals[END_REF][START_REF] Voss | Differential occipital responses in early-and late-blind individuals during a sound-source discrimination task[END_REF][START_REF] Collignon | Impact of blindness onset on the functional organization and the connectivity of the occipital cortex[END_REF], tactile [START_REF] Cohen | Period of susceptibility for cross-modal plasticity in the blind[END_REF]Sadato et al. 2002;Burton et al. 2002;[START_REF] Sadato | Tactile discrimination activates the visual cortex of the recently blind naive to Braille: A functional magnetic resonance imaging study in humans[END_REF]) and linguistic tasks [START_REF] Amedi | Early "visual" cortex activation correlates with superior verbal memory performance in the blind[END_REF][START_REF] Burton | Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people[END_REF]Bedny et al. 2011b;Bedny et al. 2011a). This activity however is different from the one observed in early blind [START_REF] Cohen | Period of susceptibility for cross-modal plasticity in the blind[END_REF][START_REF] Burton | Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people[END_REF][START_REF] Goyal | Tactile perception recruits functionally related visual areas in the late-blind[END_REF][START_REF] Voss | Differential occipital responses in early-and late-blind individuals during a sound-source discrimination task[END_REF]Bedny et al. 2012;[START_REF] Collignon | Impact of blindness onset on the functional organization and the connectivity of the occipital cortex[END_REF]. In a recent study we explored the resting-state functional connectivity between Broca area and early visual cortex in normally sighted, blind individuals from pigmentary retinopathy and individuals with an intermediate stage of pigmentary retinopathy exhibiting concentric peripheral visual loss and preserved central "tunnel vision" (see Figure 20). Interestingly, we found that functional connectivity starts in deafferented early visual cortex, namely the peripheral V1 and progresses to the entire early visual cortex and certain extrastriate areas after the complete visual loss [START_REF] Sabbah | Increased functional connectivity between language and visually deprived areas in late and partial blindness[END_REF]. The gradual increase in functional connectivity between Broca and visual cortex suggests that residual visual input limits the multimodal interactions between language and visual areas.

The presence of plasticity and especially of multimodal plasticity should be considered carefully both in sensory restoration and sensory substitution attempts, as it could both enhance and hamper their succes. One example is the case of blind patients from pigmentary retinopathy fitted with camera-connected retinal prosthesis. As the head-mounted camera requires head movements to scan the environment, the vestibulo-ocular reflex inherently induces a misalignment between head and eyes impairing the perceptual localization of the generated image and the visuomotor coordination [START_REF] Sabbah | Importance of eye position on spatial localization in blind subjects wearing an argus II retinal prosthesis[END_REF]. To attenuate the impact of these effects, the patients are constrained employ different strategies of visually guided movements.

In terms of structural changes, late visual loss seems to induce only a thinning of visual areas, mostly the early visual cortex [START_REF] Park | Morphological alterations in the congenital blind based on the analysis of cortical thickness and surface area[END_REF] ; Voss andZatorre 2012; Voss et al. Partie I, Chapter 3 -Visual loss 2014) even though there are some controversies [START_REF] Schoth | Diffusion tensor imaging in acquired blind humans[END_REF][START_REF] Jiang | Thick Visual Cortex in the Early Blind[END_REF]. In acquired, late blindness, optic tracts and optic radiations present reductions in fractional anisotropy that are likely dependent on the etiology of blindness, optic neuropathies being more likely to affect the retinofugal pathways (i.e. glaucoma) [START_REF] Wang | Altered White Matter Integrity in the Congenital and Late Blind People[END_REF]Dietrich et al. 2015;Rokem et al. 2016). Interestingly, in late blind the Voss et al [START_REF] Voss | Evidence for both compensatory plastic and disuse atrophy-related neuroanatomical changes in the blind[END_REF]) find a reduction of the magnetization transfer ratio, a marker of myelination, in the occipital areas with decreased cortical thickness, but these differences didn't survived after correction for multiple comparisons. The effects of late blindness on cortico-cortical connections is unclear. Several studies explored these connectivity: Wang et al. (Wang et al. 2013) found widespread alterations in corpus callosum, anterior thalamic radiations, frontal and parietal white matter regions, Reislev et al. (Reislev et al. 2016) noted instead a reduction in fractioned anisotropy in inferior longitudinal fasciculus and inferior frontooccipital fasciculus while others found no difference in cortio-cortical white matter tracts between late blind and sighted [START_REF] Schoth | Diffusion tensor imaging in acquired blind humans[END_REF].

Plastic changes in blindness occurring after the maturation of visual function likely employs and reinforces preexisting pathways that are inhibited by the visual input in normally sighted. The effects of this plasticity are less dramatic than in congenitally blind as it develops in a mature system with stronger homeostatic mechanisms. Moreover, in late blind there are multiple controversies about how plasticity occurs. Understanding plasticity in these patients is crucial for the design of effective rehabilitation strategies, as well as sensory restitution or sensory substitution.

Overview

Plasticity in partial visual loss

In congenital defects limited to the central part of the visual field, namely in rod monochromats, Morland et al (Morland et al. 2001) and Baseler et al [START_REF] Baseler | Reorganization of human cortical maps caused by inherited photoreceptor abnormalities[END_REF] found evidence of cortical reorganization in the central V1 area. These populations however, due to congenital cone absence, present a visual system differently organized than normally sighted and an abnormal foveal structure [START_REF] Fahim | Diagnostic fundus autofluorescence patterns in achromatopsia[END_REF].

In acquired central visual defects a similar reorganization pattern in the visual cortex was claimed [START_REF] Baker | Reorganization of visual processing in macular degeneration[END_REF][START_REF] Baker | Reorganization of visual processing in macular degeneration: Replication and clues about the role of foveal loss[END_REF]), but later challenged [START_REF] Baseler | Large-scale remapping of visual cortex is absent in adult humans with macular degeneration[END_REF]. Other authors (Masuda et al. 2008;Dilks et al. 2009;Masuda et al. 2010) found that adults with either central or peripheral field defects exhibit only task-related activation of the deafferented regions of the visual cortex. Following these findings it was proposed that in partial visual loss, deafferented primary visual cortex contributes to higher-order mechanisms such as attention or mental imagery (Masuda et al. 2008;Dilks et al. 2009;Masuda et al. 2010). It was also suggested that deafferented primary visual cortex might intervene in multimodal sensory processing since in patients with acquired peripheral visual defects, crossmodal activation of V1 was proportional to the extent of the visual impairment (Cunningham et al. 2015).

Since partial visual loss generates sensory deprivation in a part of the visual cortex, structural alterations are also expected. Indeed, acquired central visual field defects associates gray matter thinning in the posterior part of the primary visual cortex [START_REF] Boucard | Changes in cortical grey matter density associated with long-standing retinal visual ield defects[END_REF][START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF]Prins et al. 2016), while peripheral visual field loss apparently induces thinning of the anterior part of the primary visual cortex (Boucard et al. 2009;Yu et al. 2013;[START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF]. Moreover, in a study on patients with central visual loss, Burge et al found no overall cortical thickness reduction in V1, but noted decreased cortical thickness near the border of the scotoma projection zone, on deafferented side and increased cortical thickness on afferented side (Burge et al. 2016).

Overall, the literature on the reorganization of visual cortex following partial or total visual loss remains controversial and sometimes contradictory. In the available studies, factors such as the limited number of participants [START_REF] Baker | Reorganization of visual processing in macular degeneration[END_REF][START_REF] Baker | Reorganization of visual processing in macular degeneration: Replication and clues about the role of foveal loss[END_REF]Masuda et al. 2008;Dilks et al. 2009;Masuda et al. 2010;[START_REF] Baseler | Large-scale remapping of visual cortex is absent in adult humans with macular degeneration[END_REF]) and/ or heterogeneity in the extent of visual field defects in the samples [START_REF] Baker | Reorganization of visual processing in macular degeneration[END_REF][START_REF] Baker | Reorganization of visual processing in macular degeneration: Replication and clues about the role of foveal loss[END_REF]Masuda et al. 2008;[START_REF] Baseler | Large-scale remapping of visual cortex is absent in adult humans with macular degeneration[END_REF] might have contributed to the divergent results and precluded comparisons between the functional reorganization induced by central and peripheral visual loss. To avoid these obstacles when assessing the way brain processes central and peripheral visual information in health and in disease -the lesional level, the etiology and the extent of visual defects should be comparable. Thus, in the studies described herein, we enrolled patients with central and peripheral visual field loss from retinal disorders affecting photoreceptors (Stargardt macular degeneration and pigmentary retinopathy) and presenting comparable, converse visual field defects.

The literature on the reorganization of visual cortex following partial or total visual loss is controversial and sometimes contradictory. Better designs are required to assess the induced plastic changes.

Overview

Visual input and peculiar perceptive phenomena

As developed above, sensory input is crucial for the adequate cerebral wiring during development. Early, external fluctuations in sensory input or a particular genetic background modulating sensory input may result in different perceptive phenotypes, such as synesthesia (Safran and Sanda 2015). In synesthets, stimulation in a given sensory modality triggers additional experiences in one or multiple domains (Hochel et al. 2009). Concerned individuals have better performances in certain domains and worse in others. While visual synesthets have a better colour perception, they exhibit altered motion and speech perception [START_REF] Banissy | Personality traits in people with synaesthesia: do synaesthetes have an atypical personality profile?[END_REF]McCarthy and Caplovitz 2014;Sinke et al. 2014). It is believed that brain wiring in synesthesia involves more short-range connections between sensory regions and less long-range connections with remote regions like the frontal cortex (van Leeuwen et al. 2011). This connectivity profile might be determined by the abnormal synaptic pruning due to anomalous sensory input (Safran and Sanda 2015).

In partial visual loss, a common form of illusion, namely the "filling-in", occults the circumscribed visual field defects by completing them with a percept embodying visual attributes (i.e., luminance, contrast, texture, Safran and Landis 1996). However, the resulting percept is not accurate and the objects crossing the filled-in area may appear squeezed and distorted (Safran et al. 1999a;Mavrakanas et al. 2009).

An analogous visual completion phenomenon known as "filling-out" (Wittich et al. 2011) occurs with peripheral non-circumscribed field defects (e.g. those occurring in retinitis pigmentosa) and results in a stretching of perceived space and objects at the limit of the residual visual field [START_REF] Temme | Eccentricity perception in the periphery of normal observers and those with retinitis pigmentosa[END_REF][START_REF] Dilks | Human adult cortical reorganization and consequent visual distortion[END_REF].

Acquired partial or total visual loss or even temporal visual sensory deprivation in normally sighted (blindfolding) may induce a particular type of visual hallucinatory phenomenon -the Charles Bonnet syndrome [START_REF] Merabet | Visual hallucinations during prolonged blindfolding in sighted subjects[END_REF]Singh and Sørensen 2012;[START_REF] O'hare | Charles Bonnet Syndrome in Advanced Retinitis Pigmentosa[END_REF]. Charles Bonnet syndrome has a particular perceptual pattern and the restoration of the visual function, when possible, represents the best treatment [START_REF] Santhouse | Visual hallucinatory syndromes and the anatomy of the visual brain[END_REF]ffytche 2005;ffytche 2007) (see also Figure 15C).

Visual input has a major role in shaping visual pathways and normal visual perception. Disruption of visual input in early life or later in life may associate specific sensory phenomena like synesthesia, filling-in of visual field defects or hallucinations.

Overview

Part II

Experimental contributions

Chapter 1

Morphological changes: "Visual brain plasticity induced by central and peripheral visual field loss"

Both central and peripheral visual loss generate sensory deprivation in the correspondent regions of the visual cortex. Therefore, it is expected that this deafferentation induces structural alteration. Several studies have explored the morphological changes developed following partial visual loss and found that disorders affecting the central visual field seem to induce thinning in the posterior, deafferented part of V1 (Boucard et al. 2009;[START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF][START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF]Prins et al. 2016) and that disorders affecting peripheral visual field induce thinning in the anterior, deafferented part of V1 (Boucard et al. 2009;Yu et al. 2013;[START_REF] Yu | Morphologic changes in the anterior and posterior subregions of V1 and V2 and the V5/MT+ in patients with primary open-angle glaucoma[END_REF]. Interestingly, in a population with central visual defects of various etiologies, Burge et al found no overall change in V1 cortical thickness, but noted cortical thickness alterations in areas adjacent to the border of scotoma projection zone, namely decreased cortical thickness on deafferented side and increased in cortical thickness on afferented side (Burge et al. 2016).

Herein, we studied the long-term effect of central and peripheral visual loss on the occipital lobe structure in two models of retinal degeneration described in the previous chapters -Stargardt macular degeneration and pigmentary retinopathy (retinitis pigmentosa). For this purpose, in a population composed of twelve subjects with Stargardt macular degeneration, twelve subjects with pigmentary retinopathy and fourteen normally sighted, we employed two complementary approaches -the measure of cortical thickness and of the cortical entropy. Cortical thickness can be influenced by various factors (e.g. neuronal apoptosis, variation in cortical myelination, the degree of synaptic complexity) therefore was interpreted in association with the cortical entropy a marker of neural and synaptic complexity. Increased entropy reflects higher connective properties and increased synaptic complexity (Sokunbi et al. 2013;Yao et al. 2013;Thiebaut de Schotten et al. 2016) while the reduction in entropy, synaptic and dendritic degeneration (Sokunbi et al. 2013). The occipital lobe was partitioned in the corresponding cytoarchitectonic regions, using cytoarchitectonic probability maps [START_REF] Amunts | Cytoarchitecture of the cerebral cortex-More than localization[END_REF]Zilles K 2010;[START_REF] Mohlberg | A new processing pipeline and release of cytoarchitectonic probabilistic maps -JuBrain[END_REF].

Compared to normally sighted, we found that central visual field loss associates de-

Partie II, Chapter 1 -Morphological changes: "Visual brain plasticity induced by central and peripheral visual field loss" creased cortical thickness in dorsal areas V3d and V3a while peripheral visual field loss determined more widespread alterations including thinning of the early visual cortex (V1 and V2), dorsal area V3d and ventral area V4. None of these areas had altered cortical entropy suggesting that the remaining networks exhibit preserved synaptic complexity.

The study of the occipital lobe cortical entropy reveled increased values in areas LO-2 and FG1 in central visual field los compared with normally sighted and in FG1 compared with peripheral visual field loss. Theses areas are involved in object recognition and the observed differences may represent an adaptive increase in synaptic complexity to compensate the loss of the central vision and its high spatial resolution.

• La perte de champs visuel central et périphérique produite par une atteinte rétinienne entraine une déafférentation dans les régions correspondantes du cortex visuel. Par conséquent, on peut s'attendre à des anomalies structurelles dans ces régions. Plusieurs études ont exploré les altérations morphologiques induites par la déafférentation et ont démontré que la perte visuelle centrale s'accompagne d'un amincissement du cortex dans la partie postérieure, déafférentée du cortex visuel primaire (Boucard et al. 2009;[START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF][START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF]Prins et al. 2016) et que la perte visuelle périphérique induit un amincissement dans la partie antérieure, déafférentée, du cortex visuel primaire (Boucard et al. 2009;Yu et al. 2013;[START_REF] Yu | Morphologic changes in the anterior and posterior subregions of V1 and V2 and the V5/MT+ in patients with primary open-angle glaucoma[END_REF]. Plus intéressant encore, en étudiant une population avec perte visuelle centrale causée par des étiologies variées, Burge et al, retrouvent un amincissement du cortex visuel primaire seulement dans la vicinité de la limite du scotome, du côté déafférenté, et un épaississement cortical limité aux alentours des bords du scotome, du coté afférenté (Burge et al. 2016).

• Dans cette étude, nous avons étudié l'effet à long terme de la perte du champs visuel central ou périphérique sur la structure du lobe occipital, en employant deux modèles de dégénérescences rétiniennes, que nous avons détaillés dans les chapitres antérieursla maculopathie de Stargardt et la rétinopathie pigmentaire. Dans un groupe de sujets composé de douze patients avec maculopathie de Stargardt, douze patients avec retinopathie pigmentaire et quatorze contrôles avec une vision normale, nous avons évalué l'épaisseur corticale et l'entropie corticale. La mesure de l'épaisseur corticale peut être influencée par plusieurs facteurs (par ex. l'apoptose neuronale, des variations dans la myéline corticale, le dégrée de complexité synaptique), et par conséquent elle fut interprétée à l'aide de l'entropie corticale qui représente une mesure indirecte de la complexité neurale et synaptique. Une augmentation de l'entropie corticale traduit une amplification des capacités de connexion et de la complexité synaptique (Sokunbi et al. 2013;Yao et al. 2013;Thiebaut de Schotten et al. 2016), tandis qu'une diminution de l'entropie corticale, une dégénérescence synaptique et dendritique (Sokunbi et al. 2013).

Résumé

Partie II, Chapter 1 -Morphological changes: "Visual brain plasticity induced by central and peripheral visual field loss" Pour réaliser ces mesures, en respectant l'anatomie et la cytoarchitecture du lobe occipital, nous avons conduit les analyses en utilisant des cartes cytoarchitectoniques de probabilité (Amunts et al. 2007;Zilles K 2010;[START_REF] Mohlberg | A new processing pipeline and release of cytoarchitectonic probabilistic maps -JuBrain[END_REF]).

• Par rapport aux sujets normovoyants, nous avons observé que la perte de la vision centrale induit une réduction de l'épaisseur corticale dans les régions V3d et V3a du flux dorsal, tandis que la perte de la vision périphérique induit des altérations plus complexes, en particulier un amincissement du cortex visuel primaire, du V2, de la région du flux dorsal V3d et la région du flux ventral V4. On note que l'entropie corticale ne présentait des modifications dans aucune de ces régions ce qui suggère que malgré une perte neuronale vraisemblable, la complexité synaptique des réseaux résiduels reste inchangée. L'étude de l'entropie corticale dans les mêmes régions cytoarchitectoniques a révélé que par rapport aux normo-voyants, les patients avec une perte du champs visuel central présentent une augmentation des valeurs de l'entropie dans les aires LO-2 et FG1, et que par rapport au sujets avec une perte de la vision périphérique, les sujets avec une perte de la vision centrale présentent une augmentation des valeurs de l'entropie dans l'aire FG1. Ces régions sont impliquées dans la reconnaissance des objets et les différences observées pourraient traduire une amplification de la complexité synaptique visant de compenser la perte de la vision centrale et sa haute résolution spatiale.

Résumé

Introduction

Vision is the most elaborated sensorial input in the human brain. Central vision is captured at retinal level by the macula, which samples about 20°of the central visual field and provides a high spatial resolution. The peripheral visual field is collected by the remaining of the retina and has a low spatial resolution. The distinction between central and peripheral vision is also maintained within the brain. Particularly, dorsal visual areas receive relatively more projections from areas 1 of 17 Submitted manuscript processing peripheral visual field representations, whereas ventral visual areas are more densely connected to those processing central representations (Ungerleider and Desimone, 1986;Gattass et al., 2005). Hence, the loss of central or peripheral visual field should impair in different ways the visual brain and its neuroanatomy. Yet, little is known on the anatomical consequences and compensation mechanisms occurring after central or peripheral visual deprivation.

Central visual field loss prevents the central fixation, compelling patients to employ strategies of fixation in the peripheral retina, near the limit of the field defect (Duret et al., 1999). Whilst the remaining of visual field allows for an appropriate spatial orientation and navigation, its low spatial resolution impairs drastically object, face recognition and reading (Safran et al., 1999;Boucart et al., 2010). Reversely, peripheral visual field loss excludes the use of covert visual attention, constraining the affected individuals to increase their saccade rate in order to laboriously explore their environment [START_REF] Authié | Adaptive gaze strategies for locomotion with constricted visual field[END_REF]. Affected individuals preserve functions related to the high spatial resolution of the residual central vision like face and small objects recognition but exhibit impaired spatial orientation (Wittich et al., 2011) and scene perception [START_REF] Fortenbaugh | Losing sight of the bigger picture: Peripheral field loss compresses representations of space[END_REF], altered postural control [START_REF] Berencsi | The functional role of central and peripheral vision in the control of posture[END_REF] and increased risk of object-collision during locomotion [START_REF] Turano | Perceived visual ability for independent mobility in persons with retinitis pigmentosa[END_REF](Turano et al., , 2002) ) due to the limited coverage of the residual visual field. However, little is known on the brain reorganization consequent to the adjustment of these behaviors.

Preliminary evidence suggests that following a visual defect, the deafferented primary visual cortex alters its connections and the residual afferented primary visual cortex reinforces preexistent functional connections [START_REF] Sabbah | Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss[END_REF]. The latter is presumably an attempt to compensate for the loss of the former, to sustain higher order visual mechanisms. As central or peripheral visual loss generates sensory deprivation in a part of the visual cortex, structural alterations are also expected. This has been previously reported for central visual field defects associated gray matter thinning in the posterior part of the primary visual cortex (Boucard et al., 2009;[START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF][START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF]Prins et al., 2016), while peripheral visual field loss induced thinning of the anterior part of the primary visual cortex (Boucard et al., 2009;Yu et al., 2013) . However, above-mentioned studies evaluate disorders like glaucoma and age-related macular degeneration that are not limited to the eye but imply widespread neurodegenerative cerebral alterations (McKinnon, 2003;Pham et al., 2006;[START_REF] Woo | Cognitive Impairment in Agerelated Macular Degeneration and Geographic Atrophy[END_REF]Chen et al., 2013;[START_REF] Cheung | Is age-related macular degeneration a manifestation of systemic disease? New prospects for early intervention and treatment[END_REF]. Such approaches may have hampered the identification of differences strictly related to early visual deafferentation and further research on disorders restricted to the retina may clarify the brain modification occurring after a pure early visual deprivation.

In the current study, we investigated long-term brain changes associated to two well-described pure and progressive retinal disorders that induce bilateral, converse visual field defects -Stargardt macular degeneration, for central visual loss, and non-syndromic retinitis pigmentosa, for peripheral visual field loss. Stargardt macular degeneration is an hereditary cone-rod dystrophy that, in advanced stages, destroys the macular region, constraining affected individuals to rely only on the peripheral vision (Stargardt, 1909). Reversely, retinitis pigmentosa -a rod-cone dystrophy -primarily affects peripheral retina and results in a progressive constriction of the visual field. It leads to a "tunnel vision" stage, with retained central vision, and later, in the most advanced stage, to blindness (Donders, 1857;Sahel et al., 2015).

To evaluate the effects of the remote loss of central or peripheral vision, we estimated the cortical morphology derived from measures of cortical thickness [START_REF] Das | Registration based cortical thickness measurement[END_REF]. However, the specific cellular mechanisms underlying the variations in cortical thickness remain obscure. They may be related to neuronal apoptosis, variations in cortical myelination, alterations of the synaptic complexity or a summation of these events [START_REF] Wagstyl | Cortical thickness gradients in structural hierarchies[END_REF]Zilles and Amunts, 2015;Burge et al., 2016). To explain the eventual differences in cortical thickness we measured the functional MRI entropy during resting state session (rs-CoEn). rs-CoEn is a method derived from information theory, and linked to neural and synaptic complexity [START_REF] Tononi | Complexity and coherency: integrating information in the brain[END_REF]. According to this approach, increased entropy corresponds to higher connective properties [START_REF] Sokunbi | Inter-individual Differences in fMRI Entropy Measurements in Old Age[END_REF]Yao et al., 2013;Thiebaut de Schotten et al., 2016), while the reduction in entropy may imply synaptic and Table 1. Cytoarchitectonic areas showing significant differences in cortical thickness. NS -normally sighted; cVfL -central visual field loss (SMD); pVfL -peripheral visual field loss (RPTV). The significant differences are in BOLD.

dendritic degeneration (Sokunbi et al., 2013).

To intimately respect its anatomy, the occipital lobe was partitioned in its corresponding cytoarchitectonic regions using cytoarchitectonic probability maps (Amunts et

Results

Cortical thickness analysis

The measured CoTks of occipital lobe cytoarchitectonic areas was normalized with the average CoTks of the occipital lobe. The ratio between each cytoarchitectonic area CoTks and the average CoTks of the occipital lobe was further employed in the subsequent analysis (Ferreira et al., 2016). ANOVA revealed a significant group effect for the cytoarchitectonic areas hOc1 [F (2,35)

Visual brain CoTks in visual field loss compared to normally sighted

All the following post hoc comparisons were Bonferroni corrected for multiple comparisons.

Compared to normally sighted we found a significant reduction of CoTks in the dorsal region hOc3d for both central (p= 0.005) and peripheral (p= 0.015) visual field defects (see Table 1). In central visual field loss/ SMD we also noted significant reduction in dorsal area hOc4d (p= 0.05) (see Figure 1A.1, and Table 1) and in peripheral visual field loss/ RPTV in early visual cortex [hOc 1 (p= 0.036), hOc2 (p= 0.022)] and the ventral region hOc4v (p= 0.017) (see Figure 1A2 and Table 1).

Visual brain CoTks differences in central and peripheral visual field loss

There was no CoTks difference between central and peripheral visual loss (see Table 1).

Resting-state cortical entropy analysis

The measured rs-CoEn of occipital lobe cytoarchitectonic areas was normalized with the average rs-CoEn of the occipital lobe. The ratio between each cytoarchitectonic area rs-CoEn and the average rs-CoEn of the occipital lobe was further employed in the subsequent analysis. ANOVA revealed a significant group effect for the cytoarchytectonic areas hOc4la (F (2, 35) = 3.856 ; p=0.031) and FG1 (F (2, 35) = 6.566; p= 0.004). There was no significant effect for the factor hemisphere [occipital LH, F (2,35) = 0.43, p= 0.654; occipital RH, F (2, 35) = 0.082; p= 0.922]. Note that none of the areas with altered CoTks compared to normally sighted exhibited significant rs-CoEn alterations. Post-hoc independent-sample t-tests (Bonferroni corrected for multiple comparisons) are summarized in Table 2 and in the following paragraphs.

Visual brain rs-CoEn in visual field loss compared to normally sighted

Compared to normally sighted we found in central visual field defect/ SMD group a significant increase of rs-CoEn in areas hOc4la (p= 0.031) and FG1(p= 0.025) (see Figure 1B.1 and Table 2). There was no rs-CoEn difference between peripheral visual loss / RPTV and the normally sighted.

Visual brain rs-CoEn differences in central and peripheral visual field loss

Compared to the peripheral visual field loss/RPTV group, central visual field loss/SMD exhibited significantly higher rs-CoEn in the area FG1 (p= 0.005) (see Figure 1B.2 and Table 2).

Impact of age and duration deficit on CoTks and rs-CoEn

There was no impact of age and deficit duration on the CoTks and rs-CoEn in areas exhibiting differences between groups (for regression differences in other areas see Supplementary Table 1).

Discussion

We assessed the impact of central and peripheral vision loss on the cortical morphology (i.e. cortical thickness, CoTks) and neural and synaptic complexity (i.e. rs-f MRI entropy, rs-CoEn). Three findings emerge from our work. First, compared to normally-sighted both groups with visual field defects exhibited reduced CoTks in the dorsal region hOc3d; peripheral visual field defect group also presented reduced CoTks in early visual cortex (hOc1 and hOc2) and the ventral region hOc4V, while central visual field defect group in the dorsal region hO4d. Second, compared both to normally sighted and peripheral visual field defect groups, central visual field defect group showed increased rs-CoEn in FG1 area; also, compared with normally sighted, central visual field defect group exhibited increased rs-CoEn in hOc4la area. Finally, areas with altered CoTks had normal rs-CoEn and conversely.

Differences in cortical thickness

Compared to normally sighted only the subjects with peripheral visual loss showed decreased CoTks in hOc1 and hOc2, which correspond to the functional regions V1 and V2 of the early visual cortex [START_REF] Amunts | Brodmann's Areas 17 and 18 Brought into Stereotaxic Space-Where and How Variable[END_REF]. Previous studies noted decreased CoTks in the early visual cortex both in central and visual loss, but the anomalies were mainly concentered in their deafferented regions (Boucard et al., 2009;[START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF]Yu et al., 2013;[START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF]Prins et al., 2016). The fact that in our study only peripheral visual loss was associated with a thinning of the early visual cortex suggests that peripheral input has a greater trophic impact on this area, despite its lesser cortical representation. The loss of the peripheral vision represents the loss of an extensive visual field area and affects the output of numerous wide-field retinal informational channels (Ölveczky et al., 2003;Roska and Werblin, 2003;[START_REF] Hosoya | Dynamic predictive coding by the retina[END_REF][START_REF] Münch | Approach sensitivity in the retina processed by a multifunctional neural circuit[END_REF][START_REF] Masland | The Neuronal Organization of the Retina[END_REF]). Yet poorly understood, these channels might play an important role in the functioning of the early visual cortex. Moreover, retinitis pigmentosa, which affects primarily rods and secondary cones, also concerns central visual field despite the visual preservation. Photoreceptor degeneration induces local retinal plasticity and likely impairs certain channels and functions [START_REF] Jones | Retinal remodeling during retinal degeneration[END_REF][START_REF] Jones | Retinal remodeling triggered by photoreceptor degenerations[END_REF].

The reduced hOc3d CoTks in both visual field defects when compared to normally sighted, suggests a comparable contribution of central and peripheral visual field to the dorsal portion of V3 (V3d), which is canonically included in the dorsal stream (Kujovic et al., 2013). Anatomical and functional data indicate that the primarily role of V3d area is the processing kinetic information (Gegenfurtner et al., 1997;[START_REF] Felleman | Cortical connections of areas V3 and VP of macaque monkey extrastriate visual cortex[END_REF]Rosa and Manger, 2005), the extraction of kinetic contours (Zeki, 2003), and 3D form (Vanduffel, 2002). Moreover, V3d has the particularity that its retinotopical map represents only the lower quadrant of the visual field, while the upper quadrant is being represented in the ventral part of V3, area V3v (hOc3v) [START_REF] Rottschy | Ventral visual cortex in humans: Cytoarchitectonic mapping of two extrastriate areas[END_REF]Kujovic et al., 2013). It is possible that the spatial nature of information processing in hOc3d/ V3d is responsible for the decreased CoTks observed with both central and peripheral visual field loss. Indeed, the build-up of an accurate referential system, essential for functions like stereopsis (i.e. 3D perception), requires both central vision, which provides high spatial resolution and fixation, and peripheral vision, which provides wide-field sampling (Goldstein and Clahane, 1966;Luria, 1971;[START_REF] Causer | Quiet eye training in a visuomotor control task[END_REF][START_REF] Dessing | Gaze fixation improves the stability of expert juggling[END_REF].

In central visual loss, the physiological foveal fixation lacks and compels to fixation in the vicinity of the visual field defect, in the residual functional periphery. These eccentric fixation loci (usually multiple) are used both for detection (Duret et al., 1999) and visuomotor coordination [START_REF] Timberlake | Preferred retinal locus-hand coordination in a mazetracing task[END_REF] and occur in different retinal positions for each eye. These peculiarities lead to an inadequate extraction of fixation disparities [START_REF] Wheatstone | On some remarkable and hitherto unobserved phenomena of binocular vision[END_REF] impairing the very mechanism of the stereopsis.

In peripheral visual field loss, foveal vision, physiologic fixation and visual acuity are preserved, but stereopsis is nevertheless impaired through mechanisms like a non-uniform drifting of the two eyes in the absence of the peripheral visual field superposition, the loss of fusion due to brief occlusions (i.e eye-blinks) (Fender and Julesz, 1967) or "empty-field myopia" (i.e. accommodation impairment due to increased amplitude oscillation of accommodation in the absence of peripheral clues resulting in increased difficulty for detection) [START_REF] Whiteside | Effect of empty-field myopia upon the minimum visual angle for a distant target[END_REF][START_REF] Campbell | Fluctuations of accommodation under steady viewing conditions[END_REF].

Interestingly, compared to normally sighted, central visual field loss also exhibited decreased CoTks in the dorsal area hOc4d, corresponding to the functional region V3A. This area seems to be involved in the processing of kinetic and static 3D shapes (Georgieva et al., 2009), especially contour curvature [START_REF] Caplovitz | V3A Processes Contour Curvature as a Trackable Feature for the Perception of Rotational Motion[END_REF], stereoscopic and chromatic motion [START_REF] Mckeefry | The contribution of human cortical area V3A to the perception of chromatic motion: A transcranial magnetic stimulation study[END_REF][START_REF] Anzai | Coding of Stereoscopic Depth Information in Visual Areas V3 and V3A[END_REF], perceptual stability during eye movements [START_REF] Braddick | Brain Areas Sensitive to Coherent Visual Motion[END_REF][START_REF] Fornazzari | Blue is music to my ears': multimodal synesthesias after a thalamic stroke[END_REF], the prediction of the visual motion (Maus et al., 2010), its structural damage commonly resulting in simultanagnosia, namely the inability to interpret complex visual displays despite the preserved capacity to recognize single objects [START_REF] Coslett | Simultanagnosia. To see but not two see[END_REF]. Impaired fixation and stereoscopic vision in patients with central visual loss may account for the CoTks loss in this area.

Another intriguing result was the decreased CoTks in area hOc4v in peripheral field loss, when compared to normally sighted. Area hOc4, to the best of our knowledge, probably corresponds to human V4 (hV4) or at least to its ventral subdivision V4v (hV4v). The role of hV4 in color perception is still debated (Bartolomeo et al., 2014), but its central participation in the figureground segmentation through the integration of multiple stimulus properties (i.e. contour, shape, texture, motion, color, disparity) by bottom-up salience driven attentional mechanism or top-down proactive spatial or feature selection makes consensus [START_REF] Reynolds | Interacting roles of attention and visual salience in V4[END_REF][START_REF] Qiu | Figure-ground mechanisms provide structure for selective attention[END_REF][START_REF] Poort | The role of attention in figure-ground segregation in areas V1 and V4 of the visual cortex[END_REF][START_REF] Roe | Toward a Unified Theory of Visual Area V4[END_REF]. Peripheral visual field loss and the resulting severely constricted visual field, may limit covert visual attention, reduces the sensory input in area hOc4 and consequently its CoTks.

Differences in cortical entropy

Compared to normally sighted, central visual field loss group exhibited increased rs-CoEn in area hOc4la that likely corresponds to functionally defined LO-2 region [START_REF] Larsson | Two retinotopic visual areas in human lateral occipital cortex[END_REF] involved in shape processing, object and face recognition, visual attention, action observation, visual tracking, spatial location discrimination, mental imagery and subjective emotional picture discrimination [START_REF] Malikovic | Cytoarchitecture of the human lateral occipital cortex: mapping of two extrastriate areas hOc4la and hOc4lp[END_REF]. The increased rs-CoEn in area hOc4la/ LO-2 suggests an adaptive increase in synaptic complexity points in this area, which is crucial for shape perception, figure-ground segregation and visuomotor coordination [START_REF] Malikovic | Cytoarchitecture of the human lateral occipital cortex: mapping of two extrastriate areas hOc4la and hOc4lp[END_REF]. Moreover, in a previous study exploring the resting state functional connectivity of central and peripheral V1 in the exact populations explored here, we found that in central visual field loss, isolated afferented peripheral early visual cortex exhibited increased functional connectivity with LOC compared to corresponding region in normally sighted [START_REF] Sabbah | Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss[END_REF].Therefore, in central visual loss the increased rs-CoEn in LO-2 might be linked to the increased functional connectivity of this area with the residually afferented peripheral early visual cortex.

Subjects with central visual field loss presented increased rs-CoEn in area FG1 when compared to normally sighted and peripheral visual field loss participants. This area, located in the posterior part of the fusiform gyrus, medial to the middle fusiform sulcus (Caspers et al., 2013;Lorenz et al., 2015) exhibits a bias for the peripheral visual field representations. More precisely, FG1 and the anteriorly situated FG3 overlap with places, inanimate large objects and peripheral biased representations (Lorenz et al., 2015). This line of evidences suggests that the observed difference in rs-CoEn may relate to an enhanced peripheral visual field treatment in FG1 area in order to compensate for the central visual field loss. In the above mentioned resting-state study, we also noted that compared to afferented peripheral early visual cortex in normally sighted, isolated afferented peripheral early visual cortex in central visual field group showed increased resting-state functional connectivity with fusiform gyrus.

Combined cortical thickness and cortical entropy data

Interestingly, the regions with altered CoTks had normal rs-CoEn and conversely. The decreased CoTks in the early visual cortex (HoC1/ V1 and hOc2/V2), hOc3d (V3d), hOc4v in peripheral visual field loss, and the decreased CoTks in hOc3d (V3d) and hOc4d (V3A) in central visual loss compared with normally sighted, corroborated with the normality of the CoEn indicate a possible mixture of apoptotic neuronal loss and variation in myelination but with preserved synaptic complexity in the remaining networks.

The increased rs-CoEn in FG1 in central visual field loss compared with both normally sighted and peripheral visual loss, in hOc4la (LO-2) in central visual field loss compared with normally Submitted manuscript sighted, suggest an increase in synaptic complexity possibly to compensate for the impairment of certain functions associated with the central visual field loss. Therefore, the normal cortical thickness in these regions may obscure an eventual neuronal loss induced by deafferentation, compensated by the increase in synaptic complexity.

Limitations

Cytoarchitectonic areas are highly variable across subjects (Amunts et al., 1999). Herein, we extracted occipital cytoarcitectonic areas from an atlas based on observer-independent probabilistic mapping of 10 post mortem brains (Zilles and Amunts, 2015;[START_REF] Mohlberg | A new processing pipeline and release of cytoarchitectonic probabilistic maps -JuBrain[END_REF]. To reduce the effect of inter-individual variability, CoTks and rs-CoEn were sampled only in voxels where the same cytoarchitectonic area overlaps in more than 5 out of 10 of the post-mortem brains investigated.

Myelin density in the cortex and various technical parameters (field strength, tissue segmentation methods, smoothing, etc) may influence the MRI measure of cortical thickness and lead to incorrect estimations [START_REF] Salimi-Khorshidi | Automatic denoising of functional MRI data: Combining independent component analysis and hierarchical fusion of classifiers[END_REF]. These effects can be particularly deceptive in disorders that impact myelination (i.e. multiple sclerosis) or in physiological states exhibiting different degrees of cortical myelination (i.e. development or aging) (Westlye et al., 2010;Zilles and Amunts, 2015). Both models of visual loss we employed in this study have no known association with developmental myelination anomalies or active demyelination. Therefore, we can consider that the above-mentioned biases of cortical thickness by MRI had little, if no impact on the results.

Resting-state f MRI signal is notoriously affected by motion (Van Dijk et al., 2012). Increased movements would virtually increase measures of entropy. To reduce this effect, we regressed out the motion related signal from the f MRI data prior to the calculation of entropy. In this way we maximized the likelihood that the entropy measures reflect the spontaneous hemodynamic fluctuations related to brain activity.

Overall, central and peripheral visual loss induced complex structural changes unpredicted by the canonical segregation central vision -ventral visual field, peripheral vision -dorsal visual field. We found that central visual field loss induces a thinning in dorsal stream areas hOc3d (V3d) and hOc4d (V3A) and peripheral visual field loss in early visual cortex (hOc1/V1 and hOc2/V2), dorsal stream area hOc3d (V3d) and ventral stream area hOc4v (V4). Central visual field loss also induces an increase in synaptic complexity in areas hOc4la (LO-2) and FG-1 reflecting possible alternative, compensatory processing. These results offer a new and interesting insight on the effect of central and peripheral visual field deafferentation and also invite to revisit the canonical concepts of "ventral" and "dorsal" stream. Moreover, this data suggests complex adaptive changes that should be considered in the development of new visually rehabilitation strategies, sensory substitution devices or visual restitution attempts.

Methods and Materials

Participants : The Ethics Committee (Comité de protection des personnes, Ile de France V, and Agence Nationale de Sécurité du Médicament et des Produits de Santé) approved the study protocol (number 12873). 38 subjects gave their written informed consent prior to inclusion. Twelve subjects suffered from Stargardt macular dystrophy (SMD) (six women; all right-handed, age range from 18 to 58 year-old, mean 38.4 ± 12, median 39). This group presented a central scotoma, 10-20 degrees in diameter (as evaluated by Goldmann III/4 kinetic perimetry), without foveal sparing, with a best-corrected visual acuity equal or superior to 20/400 (measured by EDTRS charts). Twelve subjects suffered from retinitis pigmentosa, tunnel vision stage (RPTV) (six women; nine right-handed, age-range from 18 to 62 year-old, mean 41.7 ± 16.7, median 40), and presented a central residual visual field limited to a 10-20 degree diameter (as evaluated by Goldmann III/4 kinetic perimetry) with a best-corrected visual acuity equal or superior to 20/40 (measured by EDTRS charts). Additionally, fourteen normally sighted controls (seven women; all right-handed, age-range from 18 to 59 year-old, 41.6 ± 14.6, median 41), with normal routine ophthalmological examinations were also recruited for this study. Groups were matched for age and no significant difference between groups was observed (Kruskal-Wallis, c2(2)=.445, p= .801, mean rank age 19.83 in SMD group,20.79 in RPTV group and 19.82 in normally sighted group) (see for details Table 3).

Neuroimaging: MRI was performed with a whole-body 3T clinical imager (Sigma Horizon) using an 8-channel head coil.

T1-weighted gradient-echo images were acquired with the following parameters TE/TR/flip angle, 3.9 ms/9.5 ms/20°; FOV, 25.6 x 25.6 mm; matrix, 512 x 512; source voxel size, 1.2 x 0.5 x 0.5 mm; thickness, 1.2 mm, no gap.

Additionally, 32 contiguous axial T2*-weighted gradient-echo echo-planar images (TE/TR, 93 ms/3000 ms; FOV, 240 x 240 mm; matrix, 64 x 64; voxel size, 4 x 3.75 x 3.75 mm converted to 3 x 3 x 3 mm; thickness, 4 mm; no gap; NEX, 1) were recorded to encompass the entire brain. 184 volumes were acquired including 4 "dummy" volumes obtained at the start of the session. Scan duration was 9.25 minutes for the whole sequence. No explicit task was required, and subjects were instructed to keep their eyes closed.

Cortical thickness analysis (CoTks):

A registration-based method (Diffeomorphic Registration based Cortical Thickness, DiReCT) was employed to estimate the cortical thickness [START_REF] Das | Registration based cortical thickness measurement[END_REF] from the T1-weighted imaging dataset. The first step of this method consists in creating a two voxel thick sheet, one that lies just between the grey matter and the white matter and a second lying between the grey matter and the cerebrospinal fluid. Then, the grey/white interface is expanded to the grey/cerebrospinal fluid interface using diffeomorphic deformation estimated with ANTs [START_REF] Avants | Multivariate Normalization with Symmetric Diffeomorphisms for Multivariate Studies[END_REF]Klein et al., 2009;[START_REF] Tustison | Explicit B-spline regularization in diffeomorphic image registration[END_REF]. The registration produces a correspondence field that allows an estimate the distance between the grey/white and the grey/cerebrospinal fluid interfaces, and thus cortical thickness. This approach has good scan-rescan repeatability and good neurobiological validity as it can predict, with high statistical power the age and gender of the participants [START_REF] Tustison | Large-scale evaluation of ANTs and FreeSurfer cortical thickness measurements[END_REF]. All these steps were carried on automatically using BCBtoolkit (http://toolkit.bcblab.com). Average cortical thickness of the occipital lobes of each subject was also measured to account for the inter-individual variability (Ferreira et al., 2017). Entropy analysis (rs-CoEn): First, T1-weighted gradient-echo images were skull stripped using Brain Extraction Tool (BET) as part of the FMRIB software package (FSL, http://fsl.fmrib.ox.ac.uk). T2*-weighted images were subsequently registered to the anatomical (T1-weighted) image using affine deformations. Skull stripped T1-weighted gradient-echo images were registered to the MNI152 template (http://nist.mni.mcgill.ca/?p=904) using affine and diffeomorphic deformations (http://stnava.github.io/ANTs) (Klein et al., 2009;[START_REF] Avants | A reproducible evaluation of ANTs similarity metric performance in brain image registration[END_REF]. The latter deformations were applied to the T1 registered T2*-weighted images. Since the resting-state f MRI signal can be heavily affected by motion, even following motion correction between temporally-adjacent volumes (Van Dijk et al., 2012), we estimated the signal fluctuation associated with motion and regressed it out from the f MRI data prior to the calculation of entropy. To this aim, we employed a recently developed and validated procedure based on data-driven Independent Component Analysis (ICA), termed ICA-Aroma (Pruim et al., 2015). This method performs an ICA decomposition of the data and estimates which components reflect motion-related artifacts in the f MRI signal on the basis of a robust set of spatial and temporal features. This is made possible due the distinctiveness of the motion-related components isolated by ICA on the f MRI signal [START_REF] Salimi-Khorshidi | Automatic denoising of functional MRI data: Combining independent component analysis and hierarchical fusion of classifiers[END_REF]. This approach outperforms other methods like the regression of the motion parameter estimates, while limiting in the same time the loss in degrees of freedom (Pruim et al., 2015). Compared to spike-removal methods such as scrubbing (Power et al., 2012), ICA-Aroma has the advantage of preserving the temporal structure of the f MRI signal. Finally, the resting-state cortical entropy (rs-CoEn) was estimated using FSL fslstats by first binning -using a fixed amount of 1,000 bins -the preprocessed f MRI signal within each region of interest (ROI), and subsequently estimating the mean Shannon entropy over the entire ROI. Like in the case of CoTks, to account for inter-individual variability, we extracted the average cortical entropy for each subject. These values were estimated on a grey matter mask from the MNI single subject template, in turn obtained from FAST segmentation, and subsequent thresholding at 0.4 the partial volume estimate map of the grey matter. In addition, we removed deep-brain structures and the cerebellum (which remain after segmentation) using the group-level template of subcortical structures provided by the Harvard-Oxford subcortical atlas contained in FSL.

Regions of interest:

To intimately respect the anatomy and cytoarchitecture of the cerebral cortex, we used probabilistic cytoarchitectonic maps of the occipital lobe [START_REF] Amunts | Cytoarchitecture of the cerebral cortex-More than localization[END_REF][START_REF] Zilles | Centenary of Brodmann's mapconception and fate[END_REF][START_REF] Mohlberg | A new processing pipeline and release of cytoarchitectonic probabilistic maps -JuBrain[END_REF] to extract region specific measures of cortical thickness and entropy. These regions included hOc1 (V1), hOc2 (V2), hOc3d (V3d), hOc4d (V3A), hOc3v (VP/V3v), hOc4v (V4/V4v), hOc5 (V5/ hMT+), hOc4la (LO-2), hOc4lp (LO-1), FG1, FG2 and FG4 (http://www.fz-juelich. de/inm/inm-1/EN/Forschung/_docs/SPMAnatomyToolbox/SPMAnatomyToolbox_node.html).

Statistical analysis:

We confirmed the Gaussian distribution of the data for the three groups using the Shapiro-Wilk test [START_REF] Shapiro | An analysis of variance test for normality[END_REF], as well as the homogeneity of variance with the Levene test (Levene, 1960).

Statistical analysis was performed with SPSS 20 (SPSS, Chicago, IL). Two consecutive repeated measures ANOVA were employed to assess differences in CoTks and rs-CoEn between the three groups. Cytoarchitectonic areas were considered as between subject factors and hemisphere as within subject factor. Post-hoc analyses Bonferroni corrected for multiple comparisons were performed when statistically appropriate.

The relation between age, visual deficit duration and the cortical thickness and cortical entropy of each cytoarchitectonic ROI was analyzed through linear regression in SPSS 20 (SPSS, Chicago, IL).

Functional changes: "Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss"*

Besides the morphological impact of the sensory deafferentation, another important question concerns the way the residually afferented early visual cortex and deafferented early visual cortex reorganize their networks following central or peripheral visual loss. To explore these changes, we analyzed the resting-state functional connectivity of central and peripheral early early visual cortex (V1 and V2) 1 . This functional analysis was conducted on same subjects as the first study, which investigated the morphological changes induced by visual loss (e.g. twelve subjects with Stargardt macular degeneration, twelve subjects with pigmentary retinopathy and fourteen normally sighted subjects). As developed in Chapter 3.2.3, resting-state f MRI, is a very low demanding technique, easily accepted by patients [START_REF] Wang | Relationship between ventral stream for object vision and dorsal stream for spatial vision: An fMRI+ERP study[END_REF]Butt et al. 2013;Striem-Amit et al. 2015). Herein, to selectively explore the resting-state functional connectivity of the central and peripheral early visual cortex, we employed a partial correlation method (Striem-Amit et al. 2015;Zeharia et al. 2015). Unlike simple correlation, partial correlation holds a grater ability to identify false positives when looking for direct connections. This method applies linear regression to remove fluctuations induced by a specific brain area in the functional connectivity network of the seed region, thus rendering a predicted functional connectivity that reflects more precisely a direct link between seed region and other brain areas. Partial correlation is of particular interest for the exploration of the functional connectivity of the central and peripheral early visual cortex since the strong interconnectivity between these two regions could mask some of their specific connections (Falchier et al. 2002).

We found that compared to normally sighted, afferented central and peripheral early visual cortex in patients with visual field loss enhance their functional connectivity in Partie II, Chapter 2 -Functional changes: "Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss"* occipital lobe, whereas deafferented central and peripheral early visual cortex increase their functional connectivity with more remote regions. The functional connectivity pattern of the part of the early visual cortex receiving the remaining visual input suggests that the isolated afferented early visual cortex strengthens local connections, presumably to tune-up visual information processing. In deafferented early visual cortex, remodeling affects more remote connections, suggesting that deafferented early visual cortex likely diverts its processing capacity to higher-order functions (top-down) that could optimize the residual visual function. The absence of increased local connectivity in the deafferented compared to the normally afferented early visual cortex or its decreased local connectivity when compared to the isolated afferented early visual cortex imply that deafferented early visual cortex rewires different type of information than the afferented early visual cortex. It is unlikely that increased functional connectivity of the sensory deprived visual cortex represents noise generated by aberrant autonomous activity, because this would imply strengthened connections between the deafferented early visual cortex and regions to which they are strongly linked in normal vision, effect not confirmed by our data. Rather, the enhanced connectivity of the deafferented primary visual cortex concerned long-range connections involved in higher-order processing. Therefore, the connectivity pattern of afferented early visual cortex suggests adaptive changes that might enhance the visual processing capacity whereas the connectivity pattern of deafferented early visual cortex may reflect the involvement of these regions in high-order mechanisms.

The current study also brings some light into the current debate on the plasticity of deafferented early visual cortex following a partial visual loss (Backer et al. 2005, Backer et al. 2008[START_REF] Baseler | Large-scale remapping of visual cortex is absent in adult humans with macular degeneration[END_REF], Masuda et al. 2008, Dilks et al. 2009, Masuda et al. 2010) by showing that both afferented and deafferented regions of early visual cortex reorganize, that their reorganization is different and that it likely backs different functions.

• Outre que les changements structurels induits par la déafférentation sensorielle, le mode dont les régions du cortex visuel primaire qui reçoivent les afférences visuelles résiduelles et respectivement le mode dont les régions déafférentées réagissent réorganisent leurs connections fonctionnelles, exigent également des réponses . Afin d'étudier ce type de plasticité nous avons analysé la connectivité fonctionnelle de région centrale et périphérique du cortex visuel primaire (V1 et V2) en IRM fonctionnel de repos. Cette étude fonctionnelle fut menée sur la même population que la première étude, c'est à dire douze sujets avec maculopathie de Stargardt, douze sujets avec rétinopathie pigmentaire et quatorze sujets avec une vision normale. L'IRM fonctionnelle de repos est une technique facilement acceptée par les patients car elle présume une participation passive, le sujet étant allongé dans la machine d'IRM, avec les yeux fermés pendant toute la durée de l'acquisition (voire Chapitre 3.2.3, Wang et al. 2008;Butt et al. 2013;Striem-Amit et al. 2015). Afin d'explorer de manière spécifique la connectivité fonctionnelle des régions déafférentées et recevant les afférences visuelles résiduelles, nous avons employé une méthode de corrélation partielle qui présente une fiabilité supérieure par rapport à la corrélation simple, notamment puisqu'elle permet l'indentification des faux positives (Striem-Amit et al. 2015;Zeharia et al. 2015). Pour soustraire les fluctuations induites dans le réseau neuronal de la région d'intérêt par une autre région corticale, la méthode de corrélation partielle utilise une régression linéaire. Par conséquent, le signal obtenu reflète mieux la connectivité fonctionnelle de la région d'intérêt. Cette méthode est particulièrement intéressante dans l'étude de la connectivité fonctionnelle de la partie centrale et périphérique du cortex visuel primaire, car la forte interconnexion physiologique de ces régions pourrait masquer certaines connections qui leur sont propres (Falchier et al. 2002).

• Nous avons trouvé que par rapport régions corespondantes des sujets normovoyants, les régions centrale et périphérique du cortex visuel primaire qui reçoivent les afférences résiduelles, augmentent leur connectivité fonctionnelle locale, au niveau du lobe occipital, tandis que les régions déafférentées renforcent des connections à distance. Le pattern de connexion du cortex afférenté avec des régions Résumé voisines suggère une réorganisation qui pourrait avoir comme finalité l'augmentation de la capacité de traitement de linformation visuelle. De l'autre côté, le pattern de connexion du cortex déafférenté avec des régions lointaines suggère une potentielle réorientation de la capacité de traitement de l'information vers des fonctions supérieures et donc pourraient optimiser indirectement la fonction visuelle résiduelle. L'absence de renforcement de la connectivité fonctionnelle locale du cortex déafférente par rapport aux cortex recevant des afferences normales et la diminution de sa connectivité fonctionnelle par rapport au cortex recevant les afférences résiduelles, indique que le cortex déafférenté traite un type diffèrent d'information que le cortex afférenté. Il est fort improbable que la connectivité du cortex déafferenté soit du bruit généré par une activité autonome aberrante, puisque cette supposition demande un renforcement des connections de proximité que nous n'avons pas retrouvé. Il est donc plus vraisemblable que l'activité du cortex déafférenté reflète des connections à distance qui participent aux fonctions supérieures.

• Au total, le pattern de connectivité du cortex qui reçoit les afferences résiduelles suggère une réorganisation qui pourrait améliorer le traitement de l'information visuelle et le pattern de connectivité du cortex déafférenté suggère une possible rôle dans des fonctions supérieures.

• Cette étude apporte également un éclairage dans la dispute sur la réorganisation du cortex visuel primaire après la perte d'une partie du champ visuel (Backer et al. 2005, Backer et al. 2008[START_REF] Baseler | Large-scale remapping of visual cortex is absent in adult humans with macular degeneration[END_REF], Masuda et al. 2008, Dilks et al. 2009, Masuda et al. 2010)

Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss

Norman sabbah 1,2,3,4,* , Nicolae sanda 1,2,3,4,5,* , Colas N. Authié 1,2,3,4 , saddek Mohandsaïd 1,2,3,4 , José-Alain sahel 1,2,3,4,6,7,8 , Christophe Habas 1,2,3,9 , Amir Amedi 1,2,3,10,11,12 & Avinoam B. safran 1,2,3,4,13 Behavioral alterations emerging after central or peripheral vision loss suggest that cerebral reorganization occurs for both the aferented and deaferented early visual cortex (EVC). We explored the functional reorganization of the central and peripheral EVC following visual ield defects speciically afecting central or peripheral vision. Compared to normally sighted, aferented central and peripheral EVC enhance their functional connectivity with areas involved in visual processing, whereas deaferented central and peripheral EVC increase their functional connectivity with more remote regions. The connectivity pattern of aferented EVC suggests adaptive changes that might enhance the visual processing capacity whereas the connectivity pattern of deaferented EVC may relect the involvement of these regions in high-order mechanisms. Characterizing and understanding the plastic changes induced by these visual defects is essential for any attempt to develop eicient rehabilitation strategies.

he macular and peripheral parts of the retina constitute an intricate functional unit. heir combined input is responsible for the impression of a homogenous image over the entire visual ield. his functional unity is not present from birth since ontogenically, the central and peripheral parts of the retina mature sequentially. Unlike the periphery, the central retina is immature at birth and only develops completely years later 1-3 . Ater the visual function matures, damage to the central or peripheral retina impairs not only its speciic functions related to the afected region, but also lessens the performance of the other retina 4 . How the brain behaves and potentially adapts to this challenge remains unclear. Nevertheless, a number of potential response mechanisms have been suggested: (1) the remaining aferented visual cortex tunes-up its processing capacity and compensates to a certain extent for the limited retinal input, whereas the deaferented visual cortex might (2) rewire and receive sensory input from the spared retina and end up treating roughly the same type of information as the aferented visual cortex; (3) divert its processing capacity to speciic higher-order functions or multisensory processing; (4) supply the rest of the brain with meaningless input generated from aberrant intrinsic activity. 5 Service de neurologie, Hôpital Foch, Suresnes, France. 6 Institute of Ophthalmology, University College of London, United Kingdom. 7 Fondation Ophtalmologique Adolphe de Rothschild, Paris, France. 8 Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, US.

Adaptive strategies such as the eccentric ixation employed in the case of central visual ield defects induce proportional functional changes in the peripheral early visual cortex (EVC) 5,6 , thus providing some support for the irst hypothesis that the residual aferent visual cortex reorganizes to compensate for the loss in sensory input. In support of the second, rewiring hypothesis, Morland 7 and Baseler 8 found that in rod monochromats, deaferented regions of the visual cortex respond to visual stimulation of the functional retina, but that these populations present a diferently organized visual system and an abnormal foveal structure 9 due to the congenital absence of cones. In acquired visual ield defects a similar reorganization was reported 10,11 , but later challenged 12 . Other authors 13-15 reported that adults with conditions inducing either central or peripheral ield defects only exhibited task-related activation of the deaferented regions of the visual cortex. his led to the third hypothesis of another type of reorganization in which the sensory-deprived visual regions contribute to higher-order mechanisms such as attention or mental imagery 13-15 or intervene in multisensory processing 16 . he occurrence of visual hallucinations (i.e. the Charles Bonnet syndrome) following both central and peripheral visual loss and their induction through blindfolding in the normally-sighted advocate for the presence of aberrant intrinsic activity in sensory deprivation (the fourth hypothesis) 17-19 . hus overall, the literature on the reorganization of visual cortex subsequent to partial or total visual loss remains fraught with controversy. In previous studies, factors such as the limited number of participants 10-15 and/or heterogeneity in the extent of visual ield defects in the samples 10-13 may have contributed to these divergent results and preclude comparisons between the functional reorganization induced by central and peripheral visual loss. To avoid these obstacles, samples must consist of subjects with comparable, converse visual ield defects. In this study, we selected participants sufering from a condition that induces progressive visual loss in either the central retina; i.e., Stargardt macular dystrophy, or the peripheral retina; i.e. retinitis pigmentosa and whose visual ield defects met the selection criteria for our experiments.

Stargardt macular dystrophy (SMD) is a well-documented bilateral, inherited retinal disorder that induces well-circumscribed, central visual defects 20,21 . In its advanced stages, patients afected by this hereditary cone-rod dystrophy end up losing macular vision and in daily life can only rely on their residual peripheral vision. hey are able to orient and navigate, but are markedly impaired for object or face identiication and reading 22,23 . In contrast, retinitis pigmentosa -a rod-cone dystrophy -is a disorder that primarily afects the peripheral retina, causes progressive bilateral constriction of the visual ield and eventually, in its most advanced stages, leads to complete blindness 20 . In the "tunnel vision stage" (RPTV), when the macular function is still preserved, these patients are able to correctly analyze relatively small images but experience diiculties in spatial orientation and scene perception 24-26 .

We explored the changes induced by partial visual loss by analyzing resting-state functional connectivity (rs-FC), a method that places few demands on patients since they perform no task during scan acquisition. Resting-state luctuations are well-organized into networks previously identiied in a range of cognitive tasks 27-36 , and are of particular interest when attempting to detect interactions between early visual areas, higher order visual areas, and non-visual brain regions both in normal and altered visual function 37-39 . To selectively explore the resting-state FC of central and peripheral early visual cortex, we employed a partial correlation method 39,40 . his method is used extensively as a research tool because it is suiciently sensitive to recover retinotopic or mototopic maps from the resting-state both in the sighted 39-42 and the blind 38,39,43 . It constitutes a highly useful technique when aiming for a global view of these interactions and a detailed map of the background brain FC, a crucial irst step in exploring the brain's response to visual loss. However, to the best of our knowledge, only a few studies have explored the rs-FC of EVC in the visually impaired 44,45 , but none have diferentiated between its central and peripheral regions 44,45 . Given the nature of these patients' deprivation, it is clearly worth inquiring whether these FC changes are unique to the visual system. herefore, as a control, we also investigated the possible FC changes in another topographic system, the somatosensory system.

Materials and Methods

subjects and ethics. Subjects were recruited and assigned to the three groups as follows:

• Twelve Stargardt macular dystrophy (SMD) subjects (six women and six men; all subjects were right-handed), presenting a central scotoma, 10-20 degrees in diameter (as evaluated by Goldmann III/4 kinetic perimetry), without foveal sparing, and best-corrected visual acuity equal or superior to 20/400 (measured by EDTRS charts). Ages ranged from 18 to 58 years (average: 38.4, median: 39). • Twelve retinitis pigmentosa tunnel vision (RPTV) subjects (six women and six men; nine subjects were righthanded), presenting a central residual visual ield limited to a 10-20 degree diameter (as evaluated by Goldmann III/4 kinetic perimetry), and best-corrected visual acuity equal or superior to 20/40 (measured by EDTRS charts). Ages ranged from 18 to 62 years (average: 41.8, median: 40.0). • Fourteen normally sighted controls (seven women and seven men; 14 subjects were right-handed), with normal routine ophthalmological examinations. Ages ranged from 18 to 59 years (average: 41.6, median: 41.0).

Subjects were matched for age, and no subject had any reported neurological or psychiatric diseases (see Table 1). he Ethics Committee (Comité de protection des personnes, Ile de France V, and Agence Nationale de Sécurité du Médicament et des Produits de Santé) approved the experimental protocol (number 12873), and all subjects gave their written informed consent before participating. All methods were performed in accordance with the relevant guidelines and regulations.

Functional imaging. fMRI was conducted with a whole-body 3T clinical imager (Sigma Horizon) using an eight-channel head coil. In each scanning sequence, 32 contiguous axial T2*-weighted gradient-echo echo-planar images (TE/TR, 93 ms/3000 ms; FOV, 240 × 240 mm; matrix, 64 × 64; voxel size, 3.75 × 3.75 × 4 mm; thickness, 4 mm; interslice spacing, 0 mm; NEX, 1) were recorded to encompass the entire brain. 180 volumes were acquired including 4 "dummy" volumes obtained at the start of the session. Scan duration was 9.25 minutes for the EPI sequence. Of-line, T2*-weighted images were co-registered and overlaid on the corresponding anatomic T1-weighted gradient-echo images (TE/TR/lip angle, 3.9 ms/9.5 ms/20°; FOV, 25.6 × 25.6 mm; matrix, 512 × 512; source voxel size, 1.2 × 0.5 × 0.5 mm converted to 1 × 1 × 1 mm; thickness, 1.2 mm; interslice spacing, 1.2 mm). During the scan, subjects were supine in the MRI scanner and wore earplugs to compensate for the noisy environment. Subjects were instructed to keep their eyes closed. No explicit task was required. fMRI preprocessing. fMRI data were preprocessed using the BrainVoyager QX 2.8 software package (Brain Innovation, Maastricht, Netherlands) and complementary sotware written in MATLAB R2009a (he MathWorks, USA). Preprocessing of functional scans successively included: 3D motion correction (no head motion exceeded 2 mm/2 degrees in any of the six movement directions i.e. X, Y, Z translations, X, Y, Z rotations), slice-time correction, band-pass iltering between 0.01 and 0.1 Hz, voxel-to-voxel linear regression 46 of spurious signals from the white matter and ventricle regions anatomically deined for each subject, normalization in the Talairach coordinate system in the volume 47 , and spatial smoothing with a 6 mm Gaussian ilter kernel full-width-at-half-maximum. We did not include global signal removing to avoid the possible introduction of false negative correlations 48 . For the between-group comparison, we tested and found no signiicant diference

External functional localizers.

External functional localizers were used to define the seed region-of-interest (ROI) from visual localizers (central EVC, peripheral EVC) in the volume. Each of these localizers was extracted from a group of normally sighted controls and analyzed in normalized Talairach space using a random efect GLM which enabled generalization of the indings to the population (see below; Friston et al. 1999).

To deine the primary visual cortex seeds, a separate population of thirteen control subjects (seven women; six male; aged [22][23][24][25][26][27][28][29][30][31][32][33][34][35] was scanned in a standard phase-encoded retinotopic mapping experiment, using ring (eccentricity mapping) and wedge (polar mapping) stimuli 39,50 delivered during two separate sessions. he stimuli were projected via an LCD screen positioned over the subject's forehead and watched through a tilted mirror. In the irst session an annulus was projected, expanding in 30 seconds from 0° to 34° of the subject's visual ield; the procedure was repeated ten times. he second session included a wedge stimulus with a 22.5° polar angle that rotated around the ixation point; each cycle was completed in 30 seconds, and repeated 20 times. Both the annulus in the irst session and the wedge in the second session contained a lickering (6 Hz) radial checkerboard pattern with respect to standard retinotopic procedures 50 for the delineation of ield maps. In both cases, there was a 30 second mute period before and ater the visual stream for baseline. Group phase analysis was conducted on the two sessions 51 resulting in group maps of eccentricity and angle mapping. Angle mapping was then used to deine the borders of EVC, and the two maps were used to segregate it according to eccentricity (center or periphery of the visual ield). he central EVC was considered under an eccentricity of 5 degrees and the peripheral EVC higher than 15 degrees.

For supplementary ROI analyses, we also used external functional localizers from previous studies by our team 40,42,52 i.e. let hemisphere S1 lip and foot areas.

To validate the localizer deinitions, we also ran a control analysis (see supplementary Figure S7) at the individual subject level to test for the time course correlations between seed regions deined based on external functional localizers and seed regions deined based on anatomical localizers (as deined by 7 mm spheres on the posterior and anterior portions of the calcarine sulcus of each subject).

Seed ROI deinition and analysis.

(1) A partial correlation analysis 39,53 was conducted as follows. For each subject, a seed region of interest (ROI) based on external functional localizers (e.g., the central EVC) served to extract and z-transform the blood-oxygen-level dependent time course of this region in volume 54 while regressing out the time course of the complementary part of the visual ield component (e.g., the peripheral EVC) to suppress the shared variance and conserve only the unique variance corresponding to the ROI predictor. (2) A random-efect analysis based on the general linear model (GLM) 55 was conducted for each group. his pair-wise correlation analysis led to four maps for each group: (a) the central EVC (regressed peripheral EVC), (b) the peripheral EVC (regressed central EVC), (c) the let S1 -lip area (regressed S1 -foot area) and (d) the let S1 -foot area (regressed S1 -lip area) with a signiicance level of p < 0.05, corrected for multiple comparisons using cluster-size thresholding 39,56 , implemented in BrainVoyager using the Monte Carlo simulation approach (1000 iterations). his method directly takes into account the data contiguity of neighboring voxels and corrects for the false-positive rate of continuous clusters (a set-level statistical inference correction; corrected to p < 0.05). ( 3) For each patient group, we also tested the correlations between the following variables (i) the age at disease onset and, (ii) the duration of the visual deicit (Pearson Product-Moment Correlation, corrected for false discovery rate (FDR) for multiple comparisons) and the FC patterns found in the between-group maps (pairs of regions signiicantly connected; e.g. peripheral EVC and lingual gyrus). ( 4) To test for the main efect, a random-efect ANOVA was run on all the subjects with a between-subject factor enabling separation between groups with a signiicance level of p < 0.05, corrected for multiple comparisons using cluster-size thresholding. (5) To establish contrasts between groups, second-level analyses (post-hoc) were performed.

To summarize, an ROI-based functional connectivity analysis applied to the brain resting-state fMRI data was conducted on all groups. We used data from the seeded regions to establish resting-state functional connectivity maps intra-group. We then ran an ANOVA on all the subjects and post-hoc analysis to determine diferences between groups in volume. he maps were then converted and displayed on the surface (data integrated in depth along vertex normals from -1 mm to 3 mm), enabling a complete view of the brain.

Results

All the results presented below were statistically signiicant (p < 0.05; corrected for multiple comparisons).

Intra-group analysis -Functional connectivity seeded from the central EVC. Aferented central

EVC in the normally sighted exhibited a positive FC with the bilateral inferior and middle occipital and bilateral posterior part of the lingual gyri, bilateral orbitofrontal cortex but a negative FC with the bilateral inferior frontal gyrus, insula, cuneus, parieto-occipital sulcus, precuneus, cingulate sulcus, superior temporal and frontal gyrus, let intraparietal sulcus, inferior parietal lobule, precentral gyrus and right superior frontal sulcus (see Fig. 1A).

Isolated aferented central EVC in the RPTV exhibited a positive FC with the bilateral posterior part of the lingual gyrus, bilateral inferior and middle occipital and posterior fusiform gyri. It exhibited a negative FC with the bilateral inferior parietal lobule (supramarginal gyrus), insula, right anterior cingulate gyrus and right cuneus, right intraparietal sulcus, precentral sulcus and the posterior part of superior, middle and inferior frontal gyri (see Fig. 1B).

Deaferented central EVC in the SMD exhibited a positive FC with the bilateral posterior part of the lingual gyrus, bilateral inferior occipital gyrus, middle occipital gyrus, let superior parietal lobule, precuneus, bilateral anterior and posterior thalami. It exhibited a negative FC with the bilateral insula and postcentral gyrus, right posterior part of cingulate sulcus and the medial part of the precentral gyrus, right cuneus, anterior part of the lingual and parahippocampal gyri (see Fig. 1C).

here were no signiicant correlations for any group between either the age at disease onset or the duration of the visual deicit, and the FC of the central EVC with any other signiicant regions in the intra-group maps (Pearson correlations, FDR corrected; all ps > 0.05).

Intra-group analysis -Functional connectivity seeded from the peripheral EVC. Afferented peripheral EVC in the normally sighted exhibited positive FC with the bilateral cuneus, precuneus, posterior cingulate, lingual, parahippocampal, fusiform, superior and middle occipital gyri, posterior middle temporal gyrus and superior temporal sulcus, anterior superior temporal gyrus and right orbitofrontal and anterior cingulate cortex. It exhibited a negative FC with the bilateral inferior and middle frontal gyri, precentral sulcus, inferior frontal sulcus, inferior parietal lobule (supramarginal gyrus) and let superior frontal gyrus (see Fig. 2A).

Isolated aferented peripheral EVC in SMD exhibited a positive FC with the bilateral cuneus, lingual gyrus, parahippocampal gyrus, fusiform gyrus, precuneus, posterior cingulate, superior occipital gyrus, right middle occipital gyrus, bilateral inferior parietal lobule, right posterior superior parietal lobule and intraparietal sulcus, bilateral posterior middle temporal gyrus and superior temporal sulcus, bilateral lateral occipital complex, right superior, middle and temporal gyri and right superior and inferior temporal sulci, right pre and post central gyri, right central sulcus and bilateral orbitofrontal cortex. It exhibited a negative FC with the bilateral insula, inferior and middle frontal gyri, inferior and superior frontal sulci, right superior frontal gyrus and let anterior cingulate cortex (see Fig. 2B).

Deaferented peripheral EVC in RPTV exhibited a positive FC with the bilateral cuneus, lingual and parahippocampal gyri, precuneus, posterior cingulate, anterior cingulate, inferior parietal lobule, posterior thalamus, right posterior superior temporal sulcus and superior frontal gyrus and sulcus. It exhibited a negative FC with the bilateral inferior occipital gyri, precentral gyri, postcentral sulci, the anterior part of intraparietal sulci and the let middle occipital gyrus (see Fig. 2C).

here were no signiicant correlations for any group between either the age at disease onset or the duration of the visual deicit, and the FC of peripheral EVC with any other signiicant regions in the intra-group maps (Pearson correlations, FDR corrected; all ps > 0.05).

Between group analysis -Functional connectivity diferences seeded from the central EVC.

As compared to normally sighted, the RPTV subjects showed increased FC of the aferented central EVC with the let middle occipital and let superior temporal gyri. here was also reduced central EVC FC with the anterior part of the right middle temporal gyrus, as well as the bilateral ventral anterior cingulate cortex (see Fig. 3A and Table 2). SMD subjects presented increased FC of the deaferented central EVC with the let inferior parietal lobule, bilateral cuneus, intraparietal sulcus, regions of the dorsal pathway, as well as the right precuneus (see Fig. 3B and Table 2). hey also exhibited decreased central EVC FC with the ventral anterior cingulate cortex, the right superior and the middle temporal gyri.

A comparison of the two groups of visually deprived subjects indicated that the SMD subjects presented increased FC between the deaferented central EVC and the right cuneus and precuneus, the right inferior parietal lobule and the let superior parietal lobule (see Fig. 3C and Table 2). RPTV subjects showed increased FC with the let posterior fusiform, the inferior occipital gyri as well as with the let supramarginal gyrus and the postcentral gyrus.

Between group analysis -Functional connectivity differences seeded from the peripheral EVC. As compared to normally sighted, the RPTV group exhibited increased FC with the right inferior parietal lobule, as well as with the posterior and anterior regions of the medial frontal gyrus (see Fig. 4A and Table 2).

In contrast to the central EVC FC, the peripheral sensory deprived EVC of RPTV subjects showed decreased FC with the central sulcus let anterior middle temporal gyrus and the middle occipital gyrus as well as with the bilateral superior occipital gyrus, the right middle and the inferior occipital gyrus. he SMD group showed increased FC of their peripheral aferented EVC with regions of the ventral and dorsal pathway such as the right lateral occipital cortex, the bilateral lingual gyri, the right inferior occipital, fusiform, parahippocampal gyri as well as the right inferior temporal gyrus (see Fig. 4B and Table 2). here was decreased FC with the bilateral superior part of the cuneus, the right precuneus and the let dorsal anterior cingulate.

Comparing both groups of visually-deprived subjects showed increased FC of the SMD subjects' still aferented, peripheral EVC with both ventral and dorsal stream regions -the bilateral middle occipital, inferior occipital gyri, the right superior occipital gyrus, the right lateral occipital cortex, the bilateral lingual and fusiform gyri as well as the right parahippocampal gyrus (see Fig. 4C and Table 2). FC was also increased with the right sensorimotor cortex. By contrast, RPTV subjects had increased FC of their sensory deprived peripheral EVC with the bilateral cuneus on the dorsal pathway, the bilateral middle frontal and the right superior frontal gyri well as with the entire let anterior cingulate cortex.

Intra-group analysis -Functional connectivity seeded from the left S1 lip area and the left S1 foot area. Both S1 respective lip and foot areas were perfectly connected between hemispheres in the three groups (see Figs 5 and6). he lip area was functionally connected to the bilateral post central gyrus, precentral gyrus, premotor cortex, insula, superior temporal gyrus and the let LOC/V5/hMT+ in all three groups. here was negative FC between the lip area and IPL, anterior cingulate cortex (aCC), anterior MTG, and fronto-orbital cortex, precuneus and cuneus. Continued he let foot area was functionally connected with bilateral post central gyrus, precentral gyrus, premotor cortex, and precuneus in all three groups. In all groups the let foot area also exhibited negative FC with bilateral IFG and in peripheral visual ield defect (RPTV) and in normal vision also with the anterior insula as well. Moreover, the central visual ield group (SMD) exhibited increased FC between the let foot area and the let SOG and the right inferior occipital gyrus whereas the peripheral visual ield defect group (RPTV) exhibited increased FC with the right peripheral EVC, LOC, superior temporal gyrus and bilateral SPL (see Fig. 6B andC).

Between group analysis -Functional connectivity seeded from the left S1 lip area and the left S1 foot area. In patients with a peripheral visual ield defect compared to normal vision, the let S1 lip area showed increased FC with STG and decreased FC with an area that overlaps V5/hMT+ and EBA as well as SPL (see Fig. 7A). In patients with central visual loss compared to normal vision, there was an increased FC of the lip area with MTG and anterior EVC (see Fig. 7B). In patients with central visual loss compared with patients with peripheral visual loss there is an increased FC of the let lip area with the posterior part of inferior and middle frontal gyri (posterior part of Broca area) and IPS (see Fig. 7C).

We found no FC diference for the let foot area between normally sighted and patients with peripheral visual ield loss (RPTV) (see Fig. 8A). In patients with central visual ield loss (SMD) compared to the normally sighted, there was increased FC with the right posterior superior temporal gyrus, SPL, postcentral gyrus, fusiform and lingual gyri (see Fig. 8B). Compared to central visual ield loss (SMD), in peripheral visual ield loss, the let foot area exhibited increased FC with the right anterior EVC, cuneus and let lingual and fusiform gyri and decreased FC with let MOG (see Fig. 8C).

he main results were summarized in Fig. 9.

Discussion

SMD and RPTV models were implemented to evaluate the efects of central and visual loss on the FC of the EVC. he ive main indings can be summarized as follows: (1) in both patient groups, deaferented EVC exhibited a diferent FC pattern than the corresponding regions in normally sighted, suggesting that either the central or peripheral EVC could reorganize ater deaferentation but more interestingly (2) we also found a diferent FC pattern in the patients' EVC that still received the residual visual input, implying that such reorganization also impacts aferented visual areas;

(3) we found more changes in FC to peripheral than to central EVC (in both aferented and deaferended states); ( 4) compared to normal vision, the patients' aferented central or peripheral EVC demonstrated increased FC with many areas involved in visual processing whereas the deaferented central or peripheral EVC showed increased FC with remote regions; (5) he contrast between deaferented and isolated aferented early visual cortex revealed patterns of FC diferences that were similar, but more complex compared to those observed in comparison to normally aferented visual cortex.

The functional connectivity of the normally aferented central and peripheral early visual cortex. In the normally sighted, the central and peripheral early visual cortex exhibited a positive FC with areas of the dorsal and ventral stream. he positive FC of the central and peripheral EVC was roughly similar to previous descriptions of the entire EVC connectivity with the exception of the primary sensorimotor cortex 37 . However, we found a weak positive FC between the early visual cortex (central and peripheral) and the primary sensorimotor cortex (mostly in the right hemisphere) that did not survive the correction for multiple comparisons (data not shown).

FC diferences between isolated aferented and normally aferented EVC.

Compared to the subjects with normal vision, the aferented central EVC in RPTV exhibited increased FC with the let MOG and STG, whereas their deaferented EVC periphery showed decreased FC with these same regions. Interestingly, in normal vision these regions had stronger canonical connections with the peripheral EVC as found in previous studies (see Fig. 2) 57-59 . It is conceivable that the increased FC of the central EVC with the let MOG and STS/STG, which are involved in space, scene processing and multisensory integration, relects an adaptive process to partially compensate for the loss of peripheral vision 60-63 .

Compared to the subjects with normal vision, the aferented peripheral EVC in SMD subjects showed an increased FC with areas of the ventral stream (i.e., the let lingual and inferior occipital gyri, the bilateral fusiform gyrus, the right parahippocampal gyrus) and associated functional areas (i.e., the right lateral occipital complex). Most of these regions are involved in the face perception network 64,65 and even predict performance in multiple face-processing tasks 66 . It is worth noting that in normal vision, face perception is associated with center-biased rather than peripheral-biased representations 64,67 . Hence, the increased FC between isolated aferented peripheral EVC and the ventral stream areas in SMD subjects (as compared to the other groups) may be indicative of a compensatory mechanism for the loss of central vision. Similar results were obtained in an fMRI study exploring the efects of simulated central scotoma on face recognition 68 . Moreover, developmental data on the early ability of neonates to process faces 69 although they have an immature fovea and low visual acuity 1 lend additional support to this hypothesis.

FC diferences between aferented and deaferented EVC.

Compared to the normally sighted, the deaferented peripheral EVC in RPTV group exhibited increased FC with the IPL/IPS and MFG. Interestingly, the isolated aferented central EVC showed decreased FC with the same region. IPS/IPL plays a role in top-down control, attention, multisensory integration, visuomotor coordinate transformation and task-demand in normal subjects 58,70-72 . herefore, the increased FC between the RPTV deaferented peripheral EVC with IPS and other areas involved in eye movements (FEF, SEF), multisensory integration, visuomotor coordinate transformation (IPL) and pre-motor control and planning (middle frontal gyrus) presumably relects adaptive mechanisms to peripheral vision loss. Compared to the normally aferented (sighted) and isolated aferented central EVC (RPTV), the deaferented central EVC of the SMD exhibited increased FC with the cuneus, the parieto-occipital sulcus (POS) and the precuneus. he participation of these regions in switching attention, orientation selectivity and visuomotor processing 73 raises questions about to their possible role in the development of a surrogate overt attention network in subjects lacking central vision. his remains true as well at the intragroup level given the positive FC of the deaferented central EVC not only with the precuneus but also with the MOG (see Fig. 1C), which is involved in space and scene processing 63 . In the normally sighted EVC, the precuneus and MOG exhibit strong coactivation in visual imagery tasks 74 suggesting that the FC changes we observed in the deaferented central EVC might share common mechanisms with mental imagery 74 . Interestingly, in contrast to the deaferented central EVC, the isolated aferented peripheral EVC of SMD patients exhibited decreased FC with the cuneus, the POS and the precuneus (see Fig. 4B) possibly relecting a bufering mechanism to prevent noise and errors 75 .

At the intra-group level, both the deaferented central (SMD) and peripheral (RPTV) EVC showed a positive FC with the posterior thalamus/pulvinar (non-signiicant diference when compared to normally sighted). he pulvinar is involved in attentional processes and is thought to play a fundamental role in cortico-cortical communication 76 . Sensory deprivation imbalances the geniculate and cortical input 13,15 and therefore, the positive FC between the visually deaferented early visual cortex and the pulvinar might unmask preexisting cortico-thalamo-cortical signals for top-down control. Activation found by previous studies in the V1 lesion projection zone (LPZ) during visual stimulus-related judgments but not during passive viewing suggests the participation of attentional mechanisms and supports this hypothesis 13,15 .

Diferences between isolated aferented EVC and deaferented EVC. he contrast between isolated aferented EVC and deaferented EVC is diicult to interpret as it compares two groups with a modiied FC. It was primarily intended to be a control for the comparison to the normally aferented visual cortex. In fact, the diferences in FC between the isolated aferented central EVC in the RPTV and the deaferented central EVC in the SMD group were roughly similar to the diferences observed when compared to the normally aferented central EVC, with the exception of the MOG. he lack of a FC diference in MOG, consistent with the results mentioned above, might relect the increased adaptive connectivity of both the deaferented and isolated aferented central EVC with this region. he isolated aferented central EVC of RPTV also exhibited a relative increase in FC with the IOG and fusiform gyrus, which are areas of the ventral processing stream.

Compared to the deaferented peripheral EVC in the RPTV patients, the isolated aferented peripheral EVC in the SMD patients exhibited an increased FC with the right sensorimotor cortex, superior temporal gyrus and bilateral LOC. hus, this unique contrast between aferented and deaferented peripheral EVC also exposes the multisensory connections of the aferented peripheral EVC with sensorimotor and auditory areas 37,57,58 . Moreover, when seeding from the foot area in SMD patients we found a similar FC pattern, which conirms the multisensory connectivity between aferented peripheral EVC, LOC auditory and somatosensory areas (see Fig. 8).

he maps seeded from the S1 areas. he intra-group ROI analyses based on somatosensory seeds validate our resting-state partial correlation approach by showing that the somatosensory topographic system could be mapped in our sighted population as well as in both groups of visually-impaired patients (see Figs 5 and6). he S1 respective lip and foot areas were perfectly connected between hemispheres in the three groups, see Figs 5 and6). hese results are in line with previous studies showing such a similar organization system in the sighted 40,42 . Moreover, the lip area was functionally connected to bilateral inferior frontal gyrus, insula and the right LOC, which is consistent with the literature 52 . We found very minor between-group diferences, (see Fig. 7). hese results support the claim that observed diferences in the visual cortex (Figs 1 to 4) are related to the plastic changes induced by visual ield loss.

he analysis seeding the foot sensory projection area also yielded consistent results. he regression of the lip projection area resulted in a negative FC between the foot area and the inferior frontal gyrus and insula. In central visual ield loss, the foot area is functionally connected to the isolated aferented peripheral EVC (see Fig. 6c). his coincides with what we found with EVC seeds (see Figs 2b and8). However, there was no signiicant diference with the normally sighted (see Fig. 8b).

Comparison of the FC between congential, late complete blindness and partial blindness. To the best of our knowledge, few studies 39,41 have compared the rs-FC to retinotopic areas of the blind. Bock et al. found that resting-state correlations between V1 and V2/V3 were retinotopically organized in normally sighted, early blind as well as anophthalmic subjects suggesting that retinal waves or visual experience are not necessary to develop a resting-state retinotopic pattern 41 . he team of Striem-Amit seeded both the central and peripheral EVC in congenitally blind subjects and also identiied diferent FC patterns according to the seeds 39 . Interestingly, as compared to sighted controls, they found an increased FC of the peripheral EVC in the congenitally blind group with the same areas that we found in the RP (i.e. IPL/IPS, MFG; see Fig. 4B) and SMD patients (LOC, IOG, ITG, fusiform gyrus; see Fig. 4A). hey attributed their results to cross-modal attention plasticity which is consistent with the hypotheses we put forward for our populations. However, these authors found a FC increase of the central EVC with the let inferior frontal gyrus and a FC decrease of both retinotopic areas with the somatosensory and auditory regions. We did not ind such results here (see Figs 3,7 and 8). his might be explained by the extent of visual loss since in a previous study our team showed that the FC pattern of retinotopic regions with Broca's area difers between RP completely blind and tunnel vision patients 77 . As also shown by the analyses seeding S1 areas (see Figs 5,6,7 and 8), certain robust systems (language, auditory, somatosensory) might need profound loss of vision to start developing plasticity 78-81 .

Overall, the FC pattern of the part of the EVC receiving the remaining visual input supports the irst hypothesis that the isolated aferented EVC strengthens the local connections, presumably to tune-up visual information processing. In the deaferented EVC, remodeling concerns more remote connections, and this pattern lends support to the third hypothesis that deaferented EVC likely diverts its processing capacity to higher-order functions that can optimize the residual visual function. he absence of increased local connectivity in the deaferented compared to the normally aferented EVC or its decreased local connectivity when compared to the isolated aferented EVC do not support the view that deaferented EVC rewires the same type of information as the aferented EVC (2 nd hypothesis). An alternative explanation for the increased FC of the sensory deprived visual cortex is that it represents noise generated by aberrant autonomous activity 82 (4 th hypothesis). his scenario is unlikely because it would imply strengthened connections between the deaferented EVC and regions to which they are strongly linked in normal vision, an efect that was not conirmed by our data. Rather, the enhanced connectivity of the deaferented primary visual cortex concerned long-range connections involved in higher-order processing. However, as suggested by the thinning of the gray matter in the deaferented EVC in conditions inducing similar visual ield defects 83-88 , these long-range connections are not enough to preserve the processing function and structure of the visual areas that lost their sensory input.

Limitations

Direct implications from the present data on patients' everyday life and hypotheses about precise cerebral mechanisms cannot be inferred from rs-FC data alone. herefore, the present results and the hypothesis we advanced require further exploration with behavioral and task-based fMRI studies.

he best way of designing the ROI for central and peripheral EVC is retinotopy. Unfortunately in central visual loss, the ixation is eccentric and unsteady and as a result, retinotopy would have been particularly challenging and subject to errors. To bypass this limitation, we estimated the central and peripheral EVC by extrapolating the ROI from a retinotopy experiment conducted in a second group of normally sighted subjects. In addition, this method avoids the problem of diferences in accuracy when deining EVC across patients and control subjects (see also supplementary Figure S7 for control analysis of localizer deinitions). However, since the deaferented primary visual cortex sufers from structural alterations, primarily in the form of gray matter thinning, both in central 83-86 and peripheral 83,87 visual ield loss, the central and peripheral ROI we employed may not be limited to V1, and overlapped to a certain extent with V2. For this reason we employed the term of "early visual cortex". Rs-fMRI is subject to reliability problems induced by movement 49,89,90 . herefore, we instigated extra measures to control for head movement and to verify that there was no signiicant diference in head movement across groups (see pre-processing section in Materials and methods and Supplementary Figures S1 to S4).

It is a convention in the ield that increases in functional correlations may relect increased functional connectivity. However, increases in the BOLD signal can be unrelated to plasticity as demonstrated by higher resting-state iring in blind animals 91 , or enhanced retinotopic rs-signals in anophthalmic individuals possibly due to metabolism alteration 41 . Furthermore, glucose utilization in the human visual cortex is abnormally elevated in early but decreases in late blindness 92 . We have a degree of certainty that the resting-state iring state was equivalent in our three populations since the control analyses seeding S1 areas (see Figs 5,6,7 and 8) revealed similar symmetric patterns between hemispheres in all the three groups. Moreover, the selection criteria were stringent to avoid the patients with associated disorders that could account for the metabolic disorders.

Despite numerous claims to the contrary in the literature 28,34,93 , we cannot exclude that rs-fMRI relects non neural signals such as blood low 46,94 . It has been shown that the vascular low from the back to the front of the head is highly similar to the neural eccentric retinotopy 95 . In an attempt to reduce the efect of the vascular component, we used the partial correlation method.

Unlike simple correlation, the partial correlation method has the advantage of identifying false positives when looking for direct connections 53,96-101 , but can introduce false negative correlations 48 . Compared to simple correlation analyses (see Supplementary Figures S5 andS6), we found similar negative FC patterns across groups and identiied the false positives. Furthermore, we validated the coherence and speciicity of the resting-state partial correlation approach through somatosensory seeds (see Figs 5,6,7 and 8) and showed that: (1) S1 respective lip and foot areas were perfectly connected between hemispheres as predicted (topographical homologies in the location based on topography) and ( 2) the somatosensory topographic system in our sighted population was similar to the one described in the literature 40,42 and more importantly, to our visually-impaired subjects (3) analyses seeding EVC and S1 areas were coherent since the FC of S1 to EVC was found ater both analyses.

Conclusion

he current study documented the functional reorganization induced in the primary visual cortex by visual loss speciically afecting either central or peripheral vision. he observed changes suggest two types of adaptive processes. he irst involves the aferented parts of the primary visual cortex and engages certain preexisting pathways by enforcing their connections and presumably increasing their processing power to compensate for the loss of the deaferented EVC functions. he second concerns sensory-deprived parts of the primary visual cortex, which strengthens long-range connections, presumably to support high-order mechanisms. hese results provide insights into the behavior of EVC functional regions in disease. A greater understanding of these processes is crucial for any attempt to develop eicient rehabilitation strategies or vision restoration.

Figure S2. Intra-group analysis of functional connectivity seeded from the peripheral EVC (central EVC and movement regressed).

The maps are shown in mesh for the (A) afferented peripheral EVC (normally sighted); * the dotted line on the median aspect of the brain represents the seed region (peripheral EVC) (B) isolated afferented peripheral EVC (Stargardt macular dystrophy) (C) deafferented peripheral EVC (retinitis pigmentosa tunnel vision). Yellow-orange depicts areas of higher positive connectivity for each group, and green-blue higher negative connectivity. LH: left hemisphere, RH: right hemisphere. (Stargardt macular dystrophy). Yelloworange depicts areas of higher positive functional connectivity for each group, and green-blue higher negative functional connectivity. Dashed lines: probable false positive correlations; solid lines: the likely origin of the positive correlations. Red lines: areas that differ with vs. without the partial correlation method in normal vision. Green lines: areas that differ with vs. without the partial correlation method in Stargardt macular dystrophy. Blue lines: areas that differ with vs. without the partial correlation method in retinitis pigmentosa tunnel vision (see also Figure 1). Cn: cuneus; IOG: inferior occipital gyrus; IPL: inferior parietal lobule; MTS: middle temporal sulcus; MOG: middle occipital gyrus. pMTG: posterior middle temporal gyrus. aMTG: anterior middle temporal gyrus.

Supplementary material

Comment to Supplementary Figures S5, S6:

The partial correlation method has the advantage of being able to exclude false positives, which was why it was chosen in the current study. Supplementary Figures S5 andS6 present the intra-group analysis for central and peripheral EVC as well as the intragroup comparisons without partial correlation. Figure S5 depicts certain regions that are likely false positive correlations and we point to their probable origin. These false positive rs-FC may be the cause of the differences in FC between groups as illustrated by the green arrowheads in Figure S6. In addition, at the intra-group level, the negative FC to both central and peripheral EVC is fairly similar with (see Figure 1 and 2) or without (Figure S5) calculating by the partial correlation method.

Synthesis of the principal results

In the current work we explored the structural and functional plasticity induced by the loss of the central and peripheral visual fields in retinal disorders that affect primarily the photoreceptor layer and induce opposite visual field defects: Stargardt macular degeneration for loss of central visual field and non-syndromic pigmentary retinopathy (retinitis pigmentosa) for the loss of peripheral visual field. With visual loss occurring at retinal level, structural and functional changes are likely the direct consequence of deafferentation. To properly compare the different effects of central and peripheral visual field loss, we recruited in each group subjects with a similar extent of visual field defect. Moreover, the area with visual field defect in one group (e.g. central visual field loss in Stargardt macular degeneration) matched the spared visual field of the other group (e.g. resiudual

"tunnel vision" in pigmentary retinopathy).

As a first approach we explored the long-term impact of central and peripheral visual field loss on the structure of the occipital lobe. We measured the cortical thickness and complementary, the cortical entropy, marker of synaptic complexity. Three central findings emerged. First, compared to normally-sighted, central visual field loss exhibited decreased cortical thickness in dorsal areas V3d and V3A, while peripheral visual field loss in early visual cortex (V1 and V2), dorsal area V3d and ventral area V4. Secondly, compared to normally sighted only the central visual loss presented differences in cortical entropy, namely an increase in area FG1 compared both with normally sighted and peripheral visual loss and with LO-2 compared with normally sighted. It is conceivable that increased cortical entropy in theses regions represents adaptive, compensatory, enhanced processing following the loss of central vision and its high spatial resolution. Third, no region with cortical thinning exhibited alterations in cortical entropy and conversely. The normality of cortical entropy in areas with cortical thinning indicate that synaptic complexity in the remaining networks is likely preserved. On the other hand, increased synaptic complexity in areas with normal cortical thickness could actually mask neuronal loss due to sensory deafferentation.

From the available literature on the structural changes induced by central and peripheral deafferentation (Boucard et al. 2009;[START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF]Chen et al. 2013;Yu et al. 2013;[START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF][START_REF] Olivo | Cerebral Involvement in Stargardt's Disease: A VBM and TBSS Study[END_REF]Burge et al. 2016;Ferreira et al. 2016;Prins et al. 2016) some studies emphasized on the cortical thinning in deafferented regions of the early visual cortex (Boucard et al. 2009;[START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF]Yu et al. 2013;[START_REF] Prins | Surface-Based Analyses of Anatomical Properties of the Visual Cortex in Macular Degeneration[END_REF] Partie III, Chapter 1 -Synthesis of the principal results al. 2016) suggesting a retinotopically-related pattern neuronal degeneration (Prins et al. 2015), other found widespread alterations (Chen et al. 2013;[START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF][START_REF] Olivo | Cerebral Involvement in Stargardt's Disease: A VBM and TBSS Study[END_REF] and some failed to find any differences (Ferreira et al. 2016). Interestingly, Burge et al. found no overall change in V1's cortical thickness but noted alterations near the border of the scotoma projection area, namely a decrease on deafferented side and increase on afferented side. The different results recorded by the literature may be related to the heterogeneity of the studied visual field defects or to the peculiarities of the employed models. For example, glaucoma and age-related macular degeneration that were widely explored may represent the visual expression of more wide-spread degenerative disorders (Prins et al. 2015). By using models of visual loss that affect essentially the external retina and by including highly homogenous clinical populations (with very similar extent of the visual field defects) we avoid theses issues. Moreover, by matching the visual defect in one visually impaired group with the spared visual field in the other visually impaired group we were able to isolate and evaluate the plastic changes induced by the loss of central and peripheral vision.

In a second time we explored the long-term impact of central and peripheral visual loss on the functional connectivity between central and peripheral early visual cortex and the rest of the brain. The functional connectivity pattern of the early visual cortex that receives the residual visual input shows a strengthening of its connections with neighboring areas, presumably to tune-up the processing of the visual information. By contrast, remodeling of deafferented early visual cortex imply a strengthening of its connections with more remote areas, possibly reflecting a redeployment of its processing capacity to assist high-order function that may in turn support and optimize the residual vision.

The absence of increased connectivity between deafferented early visual cortex with neighboring areas compared to normally afferented early visual cortex and the decreased functional connectivity of deafferented early visual cortex with the same regions when compared to the isolated afferented early visual cortex argument against a rewiring of deaffereted cortex with information directly diverted from the afferented cortex. Another potential explanation for the increased functional connectivity of deafferented early visual cortex is that it represents noise generated by aberrant autonomous activity. This implies strengthened connections between deafferented cortex and regions to which they are strongly linked in normal vision. However, the increased functional connectivity of deafferented early visual cortex with remote and not with neighboring regions (strongly connected with normally afferented early visual cortex) advocates against this hypothesis.

Interestingly, in a resting-state functional connectivity study seeding from central and peripheral early visual cortex in congenitally blind and sighted controls, Striem-Amit et al (Striem-Amit et al. 2015) found increased functional connectivity of the peripheral early visual cortex in congenitally blind with the same areas we found in peripheral (retinitis pigmentosa) and central visual loss (Stargardt macular dystrophy), namely in the inferior parietal lobule/ intra-parietal sulcus, middle frontal gyrus and LOC, inferior occipital gyrus, inferior temporal gyrus and fusiform gyrus, respectively (see Figure 4A, Chapter B2). For the central early visual cortex, in congenitally blind, these authors found an increase in functional connectivity with the left inferior frontal gyrus (including Broca's area) and a functional connectivity decrease of both retinotopic areas with somatosensory and auditory regions, results that have without correspondence in our study. Both their results on congenitally blind and our study of functional connectivity in central or peripheral visual loss likely reflect cross-modal attention plasticity. The differences between their results and our data may be due to the extent of visual loss in studied populations and to developmental peculiarities due to congenital lack of visual sensory input (Pascual-Leone et al. 2005;Liu et al. 2007;[START_REF] Yu | Altered functional connectivity of primary visual cortex in early blindness[END_REF][START_REF] Qin | The Development of Visual Areas Depends Differently on Visual Experience[END_REF]Burton et al. 2014). Indeed, in retinitis pigmentosa, the extent of visual loss impacts the functional connectivity between retinotopic regions and Broca's area, as we showed in a previous study [START_REF] Sabbah | Increased functional connectivity between language and visually deprived areas in late and partial blindness[END_REF], see also Chapter 3.2.5 and 3.2.6).

Overall, the central visual loss induces cortical thinning in dorsal stream areas, whereas the peripheral visual loss in early visual cortex and both dorsal and ventral stream areas, suggesting a higher negative impact of the peripheral visual loss. Moreover, the study of the cortical entropy, marker of synaptic complexity, shows an increase only in the central visual loss and concerns areas LO-2 and FG-1 involved in shape recognition. This suggests that only the central visual loss induces a compensatory increase in synaptic complexity. Functional connectivity study revealed two types of adaptive processes. The first concernes the afferented parts of the early visual cortex, involves preexisting pathways and presumably enforces their processing power to compensate for the loss of the deafferented early visual cortex functions. The second concerns the sensory deprived early visual cortex that strengthens long-range connections, presumably to support high-order mechanisms.

Overview

Chapter 2

Insight on visual brain plasticity from combined structural and functional data

An important aspect is the corroboration between structural and functional data. Due to the fact that structural data is limited to the occipital lobe, the discussion can only concern this structure.

Combined structural and functional data suggest that some of the thinner regions of the occipital cortex in patients with visual loss correspond to areas that exhibit reduced functional connectivity with peripheral EVC when compared to normally sighted. More precisely, in central visual field loss, thinner dorsal area V3d superpose with the superior part of cuneus that exhibits reduced functional connectivity with the isolated afferented peripheral V1, while in peripheral visual field loss, thinner V2, dorsal V3d and ventral V4 partially superpose with areas in superior, middle and inferior occipital gyrus that exhibit reduced functional connectivity with deafferented peripheral V1 (see Figure 20 A, B and Figure 21B,C). In peripheral visual field loss, thinner dorsal area V3d also partially superposes on a middle occipital gyrus area that has increased functional connectivity with isolated afferented central V1 (see Figure 21 A,B).

The increased cortical entropy in LO-2 and FG1 area in central visual loss (Stargardt macular dystrophy) compared with normally sighted, seems to correspond to lateral occipital complex and the fusiform gyrus that exhibit increased functional connectivity with the isolated afferented peripheral V1 (see Figure 20 B,C).

Overall, combined structural and functional data indicate two connections. First, a possible correspondence between the cortical thinning in several dorsal and ventral stream areas and the decrease in functional connectivity between these areas and peripheral early visual cortex in both types of visual loss, regardless of their afferentation status. Second, compared with normally sighted, the increased cortical entropy, marker of increased synaptic complexity in areas related to object identification in peripheral visual loss, possibly corresponds to the increase of functional connectivity between these areas and the isolated afferented peripheral early visual cortex. Both connections indicate that peripheral visual input and the functional connectivity of peripheral early visual cortex have a higher plastic impact on the occipital lobe. It is possible that this effect relates to the Partie III, Chapter 2 -Insight on visual brain plasticity from combined structural and functional data complex cross-modal connectivity of peripheral V1 (Falchier et al. 2002;[START_REF] Rockland | Multisensory convergence in calcarine visual areas in macaque monkey[END_REF][START_REF] Zhang | A dynamic fMRI study of illusory double-flash effect on human visual cortex[END_REF]. Of course, consequent specially designed studies are required to evaluate the validity of theses possible connections between structural and functional data.

Combined structural and functional data indicate that following partial visual loss peripheral visual input and the functional connectivity of peripheral early visual cortex have a higher plastic impact on the occipital lobe.

Overview

Partie III, Chapter 2 -Insight on visual brain plasticity from combined structural and functional data Regions are indicated through arrowheads filled with colors that correspond to the associated cytoarchytectonic area. Arrow border is colored magenta for the correspondence decreased CoTks -decreased functional connectivity and red for the correspondence decreased CoTks -decreased functional connectivity Chapter 3

Limitations

Study design

Both studies presented in the current work are case-control, cross-sectional observational approaches allowing the detection of morphological and functional connectivity differences between subjects with visual field defects and normally sighted [START_REF] Grimes | Compared to what? Finding controls for casecontrol studies[END_REF]. This type of study can be confounded by other factors and shows false relationships between the studied variables (i.e. central and peripheral visual loss) and the observed differences (i.e. differences in CoTks, CoEn rs-FC, [START_REF] Lawlor | Commentary: The hormone replacementcoronary heart disease conundrum: Is this the death of observational epidemiology?[END_REF][START_REF] Ioannidis | Contradicted and Initially Stronger Effects in Highly Cited Clinical Research[END_REF]. To minimize this risk, we included age-matched subjects with highly homogenous clinical presentation and we also explored the impact of potential confounding factors, like age and deficit duration.

Other limitations of the employed study designs are that they fail to identify in which sequence changes occur and to provide the functional meaning of the observed differences. This investigation is however an essential step that allows consequent experimental studies that could explain how and why these changes occur and what are their perceptual and behavioral consequences.

MRI protocol

As cytoarchitectonic areas are highly variable across subjects, we extracted cytoarchitectonic areas of the occipital lobe from an atlas based on observer-independent probabilistic mapping of 10 postmortem brains, only in voxels where the same cytoarchitectonic area overlapped in more then half of the post-mortem investigated brains (Amunts et al. 1999;Zilles K 2010;[START_REF] Mohlberg | A new processing pipeline and release of cytoarchitectonic probabilistic maps -JuBrain[END_REF]. Through this approach, we aimed to reduce the effect of inter-individual variability. Moreover, for the same purpose, we normalized the cortical thickness of each cytoarchitectonic area with the average cortical thickness of the occipital lobes (Ferreira et al. 2016). This ratio was further employed in subsequent analysis.

Important factors in the MRI measurement of cortical thickness are the cortical myelin density and various technical parameters (i.e. field strength, tissue segmentation methods, Partie III, Chapter 3 -Limitations smoothing, etc). They can influence the measurement of the cortical thickness and lead to incorrect estimation, especially in disorders or particular physiological states (i.e. development or aging, Westlye et al. 2010;Zilles and Amunts 2015). The employed models of central and peripheral visual loss have no known association with developmental or acquired myelination anomalies. Therefore, the above-mentioned biases in the measure of cortical thickness have little or no impact in our study. However, it is unknown if sensory deafferentation per se translates into a certain degree of cortical myelin loss.

The structural study on the plasticity induced by central and peripheral visual was limited to the occipital lobe due to the absence of available cytorchitectonic maps for the entire brain. Therefore, we ignore the structural effects of partial visual loss on remote brain areas and cannot present a global view of the induced plastic changes.

Resting-state f MRI signal, employed in the current work both in the study of the functional connectivity and in the study of the cortical entropy is particularly sensitive to motion (Caceres et al. 2009;Tagliazucchi et al. 2012;van Dijk et al. 2012). For the measure of the cortical entropy, where increased movement virtually increase the measured values, we regressed out the motion-related signal, thus maximizing the likelihood that measurement reflect the spontaneous hemodynamic fluctuations related to brain activity. For the study of the functional connectivity, we instigated extra measures to control for the head movements and to validate the absence of significant differences in head movements across groups.

The most accurate way of designing the ROIs for central and peripheral primary visual cortex is retinotopy, but in the study of the functional connectivity this approach was impossible due to the fixation peculiarities of the patients with central visual field loss. Therefore, we by-passed this limitation by extrapolating the ROIs from a retinotopy experiment conducted in a group of normally sighted. This approach also eludes the problem of differences in accuracy when defining the primary visual cortex across patients and control subjects. Nevertheless, as deafferented primary visual cortex in visual loss suffers from structural alterations, mainly in the form of gray matter thinning, both in central and peripheral visual loss (Boucard et al. 2009;[START_REF] Plank | Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies[END_REF][START_REF] Hernowo | Morphometric analyses of the visual pathways in macular degeneration[END_REF]Prins et al. 2016), the ROIs we employed in the functional connectivity study may not be limited to V1, and overlap to a certain extent with V2. Thus, to define accurately the ROI we employed the term of "early visual cortex".

Increase in functional correlations is usually interpreted as an increase in functional connectivity, but increased BOLD signal can be produced by other mechanisms (i.e. metabolic alterations), as demonstrated by higher resting-state firing in blind animals, enhanced retinotopic resting-state signals in anophtalmic individuals [START_REF] Bock | Resting-State Retinotopic Organization in the Absence of Retinal Input and Visual Experience[END_REF] or abnormally elevated glucose utilization in early but not late blindness (Fox et al. 2005). We proved that the resting-state firing was equivalent in our three populations since control analysis seeding S1 areas revealed similar symmetric patterns between hemisheres in 3.3. Visual loss models all three groups.

Despite plentiful claims to the contrary in the literature, it cannot be excluded that resting-state f MRI reflects non-neural signals such as the blood flow, as the cerebral blood flow show similitudes with the neural eccentric retinotopy (Bock and Fine 2014). Therefore, to reduce the vascular component, we employed a partial correlation method. Unlike simple correlation, partial correlation identify false positives when looks for direct connections [START_REF] Zhang | Intrinsic Functional Relations Between Human Cerebral Cortex and Thalamus[END_REF][START_REF] Margulies | Resting developments: a review of fMRI post-processing methodologies for spontaneous brain activity[END_REF][START_REF] Smith | Network modelling methods for FMRI[END_REF]Calabro and Vaina 2012;Dawson et al. 2013;[START_REF] Pandit | Traumatic brain injury impairs small-world topology[END_REF][START_REF] Dawson | Partial-correlation based retinotopically organized resting-state functional connectivity within and between areas of the visual cortex relects more than cortical distance[END_REF] but can induce false negative correlations (Murphy et al. 2009). Nevertheless, we found across the studied groups similar negative FC patterns compared to simple correlation analysis and identified the false positives. Moreover, we validated the coherence and specificity of the resting-state partial correlation approach through somatosensory seeds.

Visual loss models

To study central and visual loss we employed as models retinal disorders -Stargardt macular dystrophy for central visual loss and retinitis pigmentosa for peripheral visual loss. Both are disorders that results in photoreceptor loss. However, there are some clinical differences that should be discussed.

In Stargardt macular dystrophy, photoreceptor death (both cones and rods) follows the degeneration of the pigmentary epithelium and occurs mainly in areas with high photoreceptor concentration and metabolic activity, namely in the central retina [START_REF] Meunier | Maladie de Stargardt (Stargardt disease)[END_REF], see also Chapter 3.2). In contrast, in retinitis pigmentosa, photoreceptor death starts with rods that further induce cone degeneration and ultimately blindness; it primarily affects peripheral retina, but also involves central retina, especially its rods (Audo et al. 2012, see also Chapter 3.3). This diffuse photoreceptor damage may also induce complex retinal plastic changes in the functional central retina [START_REF] Jones | Retinal remodeling during retinal degeneration[END_REF], see also Chapter 4.1.). Moreover, the loss of peripheral vison represents the loss of the largest part of the visual field. Therefore, in retinitis pigmentosa, the more diffuse photoreceptor damage and the massive visual field loss likely damage numerous parallel information channels originating in wide-field retinal cells [START_REF] Masland | The Neuronal Organization of the Retina[END_REF] (see also Chapter 2). Also, peripheral visual field and the correspondent cortical areas that subseve it seem to be more involved in cross-modal interactions (Falchier et al. 2002;Burton 2003;[START_REF] Zhang | A dynamic fMRI study of illusory double-flash effect on human visual cortex[END_REF]. Theses peculiarities may account for the more complex structural effects observed in the peripheral visual field loss, especially in the case of the early visual cortex.

Part IV

Conclusion and perspectives

The results of the two studies exposed herein shed light on several aspects of the visual plasticity induced by the visual loss. The distinctive design opposing two models of visual loss affecting central or peripheral vision allowed a unique perspective on these processes. In the first study exploring the structural changes induced in the occipital lobe we observed changes in dissonance with the canonic segregation "central vision -ventral stream", "peripheral vision -dorsal stream" as central visual loss induced cortical thinning in areas of dorsal stream, while the peripheral visual loss, in early visual cortex and in both dorsal and ventral stream areas. Only central visual field loss associated changes in cortical entropy, namely an increase in areas involved in object recognition. The increase in cortical entropy, marker of synaptic complexity, suggest adaptive, plastic changes in response to the loss of the central vision and its high spatial resolution. The second study, exploring the functional connectivity of afferented and deafferented parts of early visual cortex in both types of visual field defects shows different patterns of reorganization. Regions of early visual cortex receiving the residual visual input reinforce local connections presumably to enhance the processing of the incoming visual information, while deafferented regions of early visual cortex reinforce long-rage connections presumably to assist high-order functions. Corroborating the structural and functional data it seems that the reduced cortical thickness in associative visual cortex superpose with areas presenting reduced functional connectivity with the peripheral part of early visual cortex in both types of visual field defects, while the increased cortical entropy areas in central field loss superpose with areas presenting increased functional connectivity with isolated afferented peripheral early visual cortex. Therefore, it is possible that alterations in the peripheral field input are more susceptible to induce plastic changes.

The current approaches provided a global picture of the structural and functional changes induced by the central and peripheral visual loss. This mapping represents a crucial point in the study of this type of plasticity. However, the design of the present investigations does not provide the proper tools to intimately explain the observed changes and their actual physiological role. They could be completed by structural approaches measuring the changes outside the occipital lobe, the changes in subcortical structures like the cerebellum, colliculi , thalamus as well as the white matter; global functional approaches like the assessment of the functionality between canonical resting-state networks; other seed-based resting-state approaches testing the functional connectivity between certain nodes involved in specific functions or task-based f MRI.

Partie IV, Overall, the current work shows a most interesting perspective of the plasticity induced by the loss of central and peripheral vision, demonstrating that it is far more complex that the canonical and probably simplistic view (the "two channels" dichotomy central vision -ventral stream/ central vision -parvocellular pathway or peripheral vision -dorsal stream/ peripheral vision -magnocellular pathway) would have let to presume. It paves the road for other approaches that might explain the exact functional role of the plastic changes we mapped and maybe help revising the current, insufficient model of visual information processing (see also Chapter 2).

Overview

Part V

Acommentaryon

The "Visual Shock" of Francis Bacon an essay in neuroesthetics by Zeki, S., andIshizu, T. (2013). Front. Hum. Neurosci. 7:850. doi: 10.3389/fnhum. 2013.00850 We re a d w i t h i n tere s t t h e re m a r k a b l e paper by [START_REF] Zeki | The "Visual Shock" of Francis Bacon: an essay in neuroesthetics[END_REF],o n Francis Bacon's subverted representation of the body. On that occasion, we wish to share the results of an observation we recently made on Bacon's depicted deformities [START_REF] Safran | Francis Bacon's distorted representation of faces presumably reflects occipital dysfunction[END_REF],A R V Op o s t e r , ) that led us to consider Bacon's paintings to be the reflexion of a rare central perception disorder called dysmorphopsia [START_REF] Kölmel | Visual illusions and hallucinations[END_REF]( s e eFigure 1). This conclusion was supported by Bacon's own detailed description of a perceptual phenomenon of dynamic distortion, progressively changing in magnitude and pattern, which he consistently experienced upon steady fixation.

Bacon's comments on his perceptual experience are found in published interviews [START_REF] Russell | Francis Bacon[END_REF][START_REF] Sylvester | Interviews with Francis Bacon[END_REF][START_REF] Clair | Entretien avec Jean Clair[END_REF][START_REF] Peppiatt | L o n d o n :C o n s t a b l e& Robinson Ltd[END_REF]. In his discussions with renown art critic Jean Clair, Bacon reportedly stated: "When I am watching you talking-I don't know what it is -I see a kind of image, which constantly changes: the movement of your mouth, of the head, somehow; it keeps changing all the time. I attempted to trap this thing in the portraits." (Clair et al., 1996, p 29). Another distinguished critic, David Sylvester, further quoted him as saying "[...]i nm yc a s e ,w i t ht h i s disruption all the time of the image-or distortion, or whatever you like to call it-it's an elliptical way of coming to the appearance of that particular body... And it needs a sort of magic to coagulate color and form so that it gets the equivalent of appearance, the appearance that you see at any moment, because so-called appearance is only retrieved for one moment as that appearance. (Sylvester, 1980,pp.116-117). Still according to Sylvester, Bacon also acknowledged "I'm just trying to make images as accurately off my nervous system as I can. I don't even know what half of them mean" (Sylvester, 1980,p.82).

Gross image distortion is a rare clinical manifestation of disordered higher visual function. It presents as episodes of dynamic, ever-changing deformities, ac o n d i t i o nr e f e r r e dt oa sd y s m o r p h o psia [START_REF] Kölmel | Visual illusions and hallucinations[END_REF]o r( c e n t r a l )m e t amorphopsia (ffytche and [START_REF] Howard | The perceptual consequences of visual loss: 'positive' pathologies of vision[END_REF]. Usually, the image initially appears normal but undergoes illusionary transformation if looked at for any length of time. Visages appear distorted, contracted or expanded, often in a dynamic manner [START_REF] Kölmel | Visual illusions and hallucinations[END_REF][START_REF] Howard | The perceptual consequences of visual loss: 'positive' pathologies of vision[END_REF]; image may appear "cut up" and displaced (ffytche and [START_REF] Howard | The perceptual consequences of visual loss: 'positive' pathologies of vision[END_REF]. It was associated with occipito-parietal [START_REF] Trojano | Unilateral left prosopometamorphopsia: a neuropsychological case study[END_REF]andcallosal [START_REF] Cho | Teaching neuroImages: unilateral prosopometamorphopsia as a dominant hemisphere-specific disconnection sign[END_REF] lesions. Dysmorphopsia might represent a variant of the "thin man phenomenon" (Safran et al., 1999), a perceptual distortion phenomenon occurring around focal field defects (Mavrakanas et al., 2009), as suggested by [START_REF] Ganssauge | Facial dysmorphopsia: a notable variant of the "thin man" phenomenon?[END_REF].

Striking similarities to Bacon's portraits are found in drawings produced by a patient with a parasagittal parietooccipital meningioma, and right inferior homonymous defect [START_REF] Mooney | Parasagittal parieto-occipital meningioma. With visual hallucinations[END_REF]. This patient also experienced abnormal percepts featuring persons who demonstrated continuously changing distortions, similar to those described by Bacon. He stated the following: "[...] everything was always moving [...]. The girl would start normal enough but rapidly her lips would get coarser, her mouth more open and her teeth long and pointed. [...] men's faces going through similar contortions, very red and shiny under a fishlike eye, the lower part of the lid dragged down, showing a very bloodshot white" [START_REF] Mooney | Parasagittal parieto-occipital meningioma. With visual hallucinations[END_REF]. Dysmorphic percepts apparently occurred over virtually the whole duration of his painting activities. With one exception, all 131 Bacon portraits assembled in the volume by [START_REF] Kundera | Francis Bacon: Portraits et Autoportraits[END_REF] were produced between 1961 and 1989, and showed consistent abnormalities in face depiction. Similar deformities were noted in other paintings, created from 1959 up to 1991 [START_REF] Peppiatt | L o n d o n :C o n s t a b l e& Robinson Ltd[END_REF]. Previously (1949)(1950)(1951)(1952)(1953)(1954)(1955)(1956)(1957), Bacon depicted distorted faces where salient abnormalities repeatedly consisted of frightening wide open mouth and large, pointed teeth [START_REF] Russell | Francis Bacon[END_REF][START_REF] Sylvester | Interviews with Francis Bacon[END_REF][START_REF] Kundera | Francis Bacon: Portraits et Autoportraits[END_REF]. Remarkably that specific deformity is one of the commonest features reported individual suffering from dysmorphopsia [START_REF] Mooney | Parasagittal parieto-occipital meningioma. With visual hallucinations[END_REF][START_REF] Howard | The perceptual consequences of visual loss: 'positive' pathologies of vision[END_REF]. Over the years, deformities in Bacon's portraits increased in forms and roughness.

The origin of Bacon's visual percepts is unknown. Painter's creativity has been ascribed to catalyzing effects of psychological disturbances generated by unhappy childhood [START_REF] Peppiatt | L o n d o n :C o n s t a b l e& Robinson Ltd[END_REF][START_REF] Zeki | The "Visual Shock" of Francis Bacon: an essay in neuroesthetics[END_REF]. It is conceivable that cerebral injury had been caused during his childhood by violent blows reportedly inflicted by his father [START_REF] Peppiatt | L o n d o n :C o n s t a b l e& Robinson Ltd[END_REF]. Moreover, Bacon suffered from asthma [START_REF] Falliers | Asthma in the life of a modern british painter. Francis bacon (1909-1992[END_REF]. Cerebral hypoxicischemic lesions could have occurred during asthmatic attacks, which were reported to be "so severe that Bacon would lie in bed for days, blue in the face, struggling for each breath" (Peppiatt, 2008,p.11).In addition, since Bacon has been prescribed morphine and stramonium to ease his bronchial spasms [START_REF] Peppiatt | L o n d o n :C o n s t a b l e& Robinson Ltd[END_REF], toxic factors (Ve l l a -B r i n c a t a n d Ma c l e o d , 2 0 0 7 ; [START_REF] Glatstein | Use of physostigmine for hallucinogenic plant poisoning in a teenager: case report and review of the literature[END_REF]m i g h tb ec o n s i dered, although unlikely as not associated with pronounced systemic manifestations; in addition, distorted percepts upon sustained fixation consistently occurred over decades [START_REF] Sylvester | Interviews with Francis Bacon[END_REF].

Influence on Bacon by fellow artists has been suggested [START_REF] Sylvester | Interviews with Francis Bacon[END_REF][START_REF] Peppiatt | L o n d o n :C o n s t a b l e& Robinson Ltd[END_REF]. Bacon was impressed by Picasso's fluidity of lines and inventiveness, which he discovered in 1927 at Rosenberg's Gallery. Bacon considered Picasso as the artist having come closer than anyone to "the core of what feeling is about" (Peppiatt, 2008,p .4 6 ) .A l t h o u g h most of works presented at Rosenberg's gallery were classical in style, and included no cubist compositions, it is conceivable that Bacon saw in some of the forms elaborated by Picasso a resemblance to his own perceptions, as also did other subjects affected by dysmorphopsia [START_REF] Mooney | Parasagittal parieto-occipital meningioma. With visual hallucinations[END_REF][START_REF] Howard | The perceptual consequences of visual loss: 'positive' pathologies of vision[END_REF]. He then felt that there was a way to transpose on canvas the reality-the very one reality that his senses presented him: "[...]It h o u g h ta f t e r w a r d s ,w e l l ,p e rhaps I could draw as well" (Peppiatt, 2008,p.46).

Bacon detailed description of distorted percepts point out the organic element in the grounds of his art. It might contribute to clarify Bacon's "enigma" [START_REF] Peppiatt | L o n d o n :C o n s t a b l e& Robinson Ltd[END_REF], and assist art analysts to revisit foundations of Bacon's major contribution to twentieth century painting. Furthermore, Bacon's observational and artistic talents provide us with invaluable insights into the perceptual phenomena of dysmorphopsia. Purpose of review Synesthesia is an extraordinary perceptual phenomenon, in which individuals experience unusual percepts elicited by the activation of an unrelated sensory modality or by a cognitive process. Emotional reactions are commonly associated. The condition prompted philosophical debates on the nature of perception and impacted the course of art history. It recently generated a considerable interest among neuroscientists, but its clinical significance apparently remains underevaluated. This review focuses on the recent studies regarding variants of color synesthesia, the commonest form of the condition.

Recent findings

Synesthesia is commonly classified as developmental and acquired. Developmental forms predispose to changes in primary sensory processing and cognitive functions, usually with better performances in certain aspects and worse in others, and to heightened creativity. Acquired forms of synesthesia commonly arise from drug ingestion or neurological disorders, including thalamic lesions and sensory deprivation (e.g., blindness). Cerebral exploration using structural and functional imaging has demonstrated distinct patterns in cortical activation and brain connectivity for controls and synesthetes. Artworks of affected painters are most illustrative of the nature of synesthetic experiences.

INTRODUCTION

Synesthesia is an extraordinary perceptual phenomenon, in which the world is experienced in unusual ways. In this condition, a particular stimulation in a given sensory modality (e.g., touch) or cognitive process (e.g., computing) automatically triggers additional experiences in one or several other unstimulated domains (e.g., vision, emotion) [1]. An illustrative presentation of the condition would be that of a given person in whom hearing the sound of a trumpet consistently elicits the vision of brightly colored triangles dancing in front of his eyes, in association with a sensation of pressure on his arms, letting him feel uncomfortable to sit still. Stimuli generating additional unusual experiences are termed 'inducers', whereas internally produced synesthetic percepts are termed 'concurrents' [2]. Synesthetic experiences have had over the centuries far-reaching sociocultural implications. They prompted philosophical debates on the nature of perception, consciousness and even talent and creativity, and significantly impacted the course of art history, notably at the turn of the 20th Century [3][4][5][6]. Moreover, favored by the emergence of sophisticated tools for functional brain exploration, they have generated a considerable interest among neuroscientists [6,7]. Clinical significance of synesthesia, however, is still largely underevaluated.

Although some synesthetic phenomena express the presence of a disease, developmental synesthesia as a rule is considered an individual cognitive This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. variant in the normal population [8]. Unfortunately, the astonishing features of these percepts have too often led the entourage of affected persons, including physicians, to wrongfully consider them as confabulators, drug users, or schizophrenics [7]. In this regard, the following history reported by Vincent Van Gogh is representative. While in 1885 the painter was taking piano lessons, his teacher noticed that he was continually relating the sounds of the piano keys with specific colors; considering then that his pupil was insane, the teacher sent him away [9]. It is therefore understandable that synesthetes (i.e., persons affected by synesthesia) commonly avoid mentioning their percepts and even tend to close on themselves in psychological distress [10][11][12]. For that very reason, scientific studies probably underestimate synesthesia prevalence in the general population.

SYNESTHESIA VARIANTS

Synesthesia is commonly classified as developmental and acquired. Developmental synesthesia appears to be the most frequent type of this condition, with a 4.4% estimated prevalence rate [13]. It can run in families and demonstrate Mendelian transmission [14]. Different forms of synesthesia can be observed in the same person or in the same family [15]. The condition is occasionally associated with autism spectrum disorders, like Asperger syndrome [16].

The following criteria have been proposed to help establishing a diagnosis of developmental synesthesia: induced percepts should be elicited by a specific stimulus, they should be automatically generated, and typically have percept-like qualities [8,17,18]. Usually, pairings of inducers and concurrents are specific (i.e., a particular stimulus consistently triggers the same synesthetic percept). They tend to be stable over time in a given individual, although this has recently been challenged by the finding that synesthetic ability can disappear over time [19 & ]. Acquired forms of synesthesia have also been reported, essentially associated with neurologic disorders or following psychotropic drug ingestion [20][21][22][23]. In contrast to its developmental counterpart, acquired synesthesia does not demonstrate either idiosyncrasy or automaticity or stability [3,24 & ]. So far, over 60 types of synesthetic phenomena have been described. The apparently most common form (with a 64.4% prevalence among synesthetes) is grapheme-color synesthesia, in which achromatic letters or digits automatically trigger an idiosyncratic color perceptual experience (e.g., the letter 'm' induces blue color percepts) [25,26] (Fig. 1 [27]). The second most prevalent form is time unit (e.g., Monday, January)-color synesthesia (22.4%), followed by musical sound-color synesthesia (18.50%) [26,28] (Figs 2 and 3 [29,30]). Inducers and concurrents also include smells, tastes, temperatures, personalities and emotions [26], and can be multiple during a single synesthetic experience. Thus, percepts induced by grapheme-color synesthesia are occasionally accompanied by shape, texture, movement features, and even nonvisual percepts such as smells and tastes, particularly emotions [31,32]. Synesthetic colors generated in grapheme-color synesthesia are determined by systematic rules rather than randomly occurring, and based on the psycholinguistic mechanisms of language processing. The same occurs with both Latin characters and Chinese ideograms [33,34 & ]. An additional type of colored synesthetic experience was recently described and termed 'swimmingstyle color synesthesia'. It is characterized by the generation of specific colored percepts upon conceptual representation of swimming in a particular style (i.e., breast, backstroke, crawl, and butterfly) [35,36]. This phenomenon could be triggered by either presenting a picture of a swimming individual or asking the tested individual to think about a given swimming style. It was speculated that this synesthetic type was caused by overactivity in the mirror neuron system responding to the specific representation [37].

Synesthetic experiences are labeled 'lower' when triggered by elementary perceptual processes (e.g., texture) or 'higher' when involving a higher cognitive process (e.g., semantic, computing) [7,38,39]. Synesthetes who experience the atypical percepts in an internal space ('in the mind's eye', as they sometimes describe it) have been categorized into 'associators', whereas those for whom the additional,

KEY POINTS

Persons presenting with synesthesia commonly avoid mentioning their unusual percepts and even tend to close on themselves in psychological distress.

Developmental synesthesia predisposes to changes in primary sensory processing and cognitive functions, and heightened creativity. www.co-neurology.com atypical percept appears to be 'out there', overlaying the actual, external surrounding, are designated as 'projectors' [40,41].

PAINTERS' COMPREHENSION OF SYNESTHESIA

Painters commonly demonstrate unique skills in the observation of visual phenomena, in which depiction offers an invaluable source of information for neuroscientists investigating visual function in health and disease [42][43][44][45][46]. Regarding our understanding of synesthesia, painters' contribution is particularly precious. Among this population, the prevalence of synesthesia was found higher than in general population; in addition, their percepts are frequently represented in their artworks [47]. Indeed, synesthete prevalence among fine art students was estimated to be 23% [48]. Among art students, prevalence of grapheme-color synesthesia alone was reported to be 7%, compared to 2% in controls [49].

Interestingly, synesthetes' personality profile favors their involvement in creative, artistic activities [50]. Recently evaluated by a structured measure of personality (the 'Big Five Inventory') and by questionnaires assessing empathy, synesthetes exhibited higher levels of 'Openness to Experience', considered to be related to imagination and artistic tendencies, and higher levels of 'Fantasizing', conceptually related to 'Openness' [51 & ]. Moreover, grapheme-color synesthetes show a distinct cognitive style, with a preference for processing information in both verbal and vivid imagery styles [52 & ]. The peculiar world perception decisively impacted the artistic work of numerous 'synesthetic' artists. Thus, Kandinsky's nonfigurative paintings and theory of synesthesia [53], prompted by his experience of extraordinary visions of lines and colors elicited by the sound of musical instruments, paved the way to abstract art and thus marked a turning point in history of art [47]. A recent analysis of Kandinsky's works using the Implicit Association Test found no implicit association between the original color-form combinations, and authors concluded that these are probably not a universal property of the visual system [44].

Most informative indications on the character of percepts commonly observed by synesthetic painters, as well as on the compulsive manner they depict their visions, were provided by Carol Steen, a remarkable synesthetic painter [54]. She emphasized that synesthetes' internal world differs tremendously from what is commonly perceived by others. For instance, colors can be perceived intensely bright, 'similar to sunlight streaming through a stained glass window'. Noteworthy, she felt that the 'overwhelming beauty of what she has seen' powerfully compelled her to capture and reproduce her visions, and that 'urgency to paint needed to be expressed'. To depict the brightness of colors perceived, synesthetic painters reportedly often apply with speed, pure, unmixed oil paint, or watercolor straight from the tube. Faithfully representing their perceptions may require breaking some long-standing rules, a feature that -as underlined by Carol Steen -characterizes modern art. The artist also specified that her visions were never representational nor figurative. This is apparently typical of many synesthetes' experiences, and probably explains why synesthetic artwork commonly looks abstract, even though it is a ' realistic' depiction of the artist's perceptions [54].

EMOTIONAL DIMENSION OF SYNESTHESIA

Emotional reactions play a prominent role in synesthetic processes. They are commonly experienced in such conditions [32,55], acting as either inducer, concurrent, or modulator [32,56]. A conflict between the actual color of a stimulus and synesthetically induced percepts can generate discomfort, whereas 'pleasantness' is experienced when synesthetic and actual stimulus features match. Some synesthetes indicate that all disagreeable events generate same color, specific for the given individual. Saturation of evoked colors is susceptible to be altered by mood [32]. In some personality-color type of synesthesia, viewing known faces elicits emotionally mediated color percepts, presenting either as colored faces or colored auras around heads [1,32,57] (Figs 4 and 5 [58]), conceivably as a result of cross-activation between right, face recognition area and neighboring V4 color cortex [7,59]. In this regard, the following delightful dedication by Julia Simner, a prominent expert in synesthesia, is illustrative: 'For my two children: the blue one (Indigo) and the brown one (Tommy Bruno)' [60]. In the so-called 'ordinal linguistic personification' synesthesia, letters have emotional valences, as well as a sex and personality [61,62]. Sexual arousal also triggers synesthetic experiences in some 2% of individuals [26]. These perceptual phenomena mainly consist of colored shapes, less commonly of flavors, smells, sounds, or temperatures, and are associated with a higher degree of trance and loss of environmental boundaries [63]. Cerebral structures processing emotion are altered in developmental synesthestes. MRI exploration of associator grapheme-color synesthetes recently brought further evidence of structural changes in emotional areas both at cortical and at subcortical levels [64 && ]. Acquired cerebral disorders are also susceptible to cause emotional synesthetic percepts. Thus, a patient who had sustained a posterolateral thalamus hemorrhage [24 & ] experienced blue photisms, intense extracorporeal sensation, and 'orgasmic' ecstasy when hearing brass instruments, or severe disgust sensations when reading words printed in blue characters. Occurrence, expression, and the underlying mechanisms of affectrelated forms of synesthesia have recently been reconsidered [56].

IMPACT OF SYNESTHESIA ON COGNITIVE FUNCTIONS

Synesthetic experiences impact the cognitive functions to a larger extent than believed in the past [65,66 && ,67,68]. Constitutional synesthesia predisposes to better performances in certain aspects and worse in others. Although having better color perception compared with nonsynesthetes [69,70], synesthetes present impaired motion [66

&&

,67] and speech perception [71]. Speech perception deficit could be a consequence of the impaired motion perception, namely the biological movement of lips or of a much wider deficit in multisensory integration [71]. In grapheme-color and tone-color synesthetes, increased gray matter volume in the left posterior fusiform gyrus and decreased gray matter volume of the anterior part of the same gyrus and in the left MT/V5 support these hypotheses [72]. Improved perception can occur within both inducing stimulus and concurrent domains [68]. Memory was also found enhanced when using synesthetic percepts [25,73].

Improved performances depend partly on preconscious mechanisms, operating early in sensory processing [74]. Thus, a recent investigation using pictures containing hidden letters found that grapheme-color projectors recognized the letters faster than nonsynesthetes; interestingly, tested individuals noted that concurrent colors were generated before conscious letter recognition [75 & ]. Grapheme-color synesthesia even allows computing via synesthetically perceived colors [68] and as expected, emotional experience modulates synesthetes' performances [55].

CEREBRAL DISORDERS CAUSING SYNESTHESIA

Acquired forms of synesthesia have been related to a variety of neurological conditions, including migraine [76,77], multiple sclerosis -radiologically isolated syndrome [34 & ], posthypnotic suggestion [78], and drug ingestion [20,79]. In recent years, secondary synesthesia has been reported following thalamic stroke [24 & ,80-83]: two of these affected individuals experienced colored synesthetic percepts [24 & ,83]. Thalamic insult may induce largescale reorganization of the brain, modify the balance between excitatory and inhibitory connections in high-order visual areas, and favor the development of synesthesia [80].

Sensory deprivation favors the occurrence of synesthetic phenomena. With blind people, nonvisual stimuli tend to elicit various percepts in the suppressed sensory modality, including colored photisms [84,85] presumably by cross-modal activation of the deafferented cortex [86]. Soundinduced photisms in visually affected people are a well recognized phenomenon [87]. Six late-blind individuals were recently reported experiencing colored phenomena when hearing or thinking about letters, numbers, and time-related terms [88,89]. In one of these individuals, touching Braille characters induced colored photisms. A patient of ours, blinded by bilateral arteritic anterior ischemic optic neuropathy, reported perceiving colored photisms when brushing his teeth or hearing a hand clap (personal observation). We also recently observed an unusual case of a late-blind individual suffering from retinitis pigmentosa who volunteered consistently 'seeing' his limbs when moving them, a phenomenon presumably related to crossmodal activation of his visual cortex by proprioceptive inputs [90 & ]. Brain lesions disrupting canonical networks and sensory input to associative areas are also susceptible to induce synesthetic-like hallucinatory syndromes. A right monophtalm patient with right parosmia reported intricate visual and olfactory hallucinations following a right occipitotemporal stroke [91]. The patient described seeing people with strong odors. The presumed mechanism of these hallucinations was the desinhibition of the connections from the visual association areas to perirhinal and parahippocampal gyri [92].

ARTIFICIALLY ELICITED SYNESTHESIA

Sensory substitution devices (SSDs) have been developed to provide blind individuals with information on their visual surrounding. They convey visual information through another sensory modality, like audition [93]. Visual-to-auditory SSDs proceed by online translation of camera-captured views into sounds, which represent the visual features of the scene [93,94]. Users of such devices commonly claim to 'see' the objects figured by sounds, and therefore sensory substitution has been considered a kind of synthetic synesthesia [93]. Interestingly, functional magnetic resonance imaging (fMRI) investigations using a visual-to-auditory SSD, both in blindfolded healthy individuals [95] and in congenitally blind individuals [96 & ], showed activation of visual areas. Whether -and to what extent -SSD users also perceive the auditory stimulus as a sound is debated [97,98].

Sensory substitution, however, differs in some respect from the naturally occurring synesthesia. Indeed, intended to reliably figure the visual surrounding, percepts elicited by SSDs are elaborated, whereas regular synesthetic phenomena exhibit essentially idiosyncratic features [8]. Further, in contrast to SSD-provoked synesthetic experiences, in developmental synesthesia, inducers do not conform to sensorimotor contingencies of the concurrent modality [98].

NEURAL FOUNDATIONS OF SYNESTHESIA

Assumptions have been made on the mechanisms underlying synesthesia, including hyperconnectivity between cortical areas [99], reduced level of feedback from inhibitory cerebral structures [2], learned association in early life [100], and a normal perceptual mechanism incompletely suppressed in synesthetes [17]. Neurocognitive models have been elaborated [101][102][103][104][105].

In recent years, brain-imaging studies brought further evidence that synesthetes connect more inside and between sensory regions and less with remote areas, especially the frontal cortex. Indeed, these individuals exhibit increased intranetwork connectivity in medial visual, auditory and intraparietal networks, and internetworks connectivity between the medial and lateral visual networks, the right frontoparietal network and between the lateral visual and auditory networks. In contrast, nonsynesthetes have more intranetwork connections within frontoparietal network [106]. When presented with inducers, synesthetes exhibit a clustering pattern of activated brain areas uniting more visual regions, whereas nonsynesthetes activate particularly frontal and parietal regions [107 && ] (Fig. 6).

Involvement of the bottom-up and top-down mechanisms has further been considered [105,[108][109][110][111]. The bottom-up model stipulates that the concurrent representation is prompted by the inducer representation via over represented and overactive horizontal connections, whereas the top-down model proposes that the inducer stimulates the concurrent percept via an input from a convergent, higher order integrator [2].

Using dynamic causal modeling, Van Leeuwen et al. [106] have shown that projectors exhibited effective connectivity patterns involving a bottomup mechanism, whereas associators used a top-down mechanism. However, a recent electroencephalographic (EEG) study found evidence favoring the top-down disinhibited feedback model as the core of the synesthetic phenomenon [112 && ]. Reduction of long-range couplings in the theta frequency band could facilitate the top-down feedback. An fMRI study demonstrated that, in contrast with projectors, associators' synesthetic experience was related to areas linked to memory processes, including hippocampus and parahippocampal gyrus [113,114].

THALAMUS AND DEVELOPMENTAL SYNESTHESIA

It was suggested that congenital alterations in thalamic circuitry might be responsible for atypical cortical morphology and connections, found with different synesthetic phenotypes [64 && ,115]. Cytoarchitectonic maturation of the primary sensory areas and the development of their specific connections are highly dependent on the thalamic input [116]. Enucleation in prenatal macaque drastically alters the equivalents of V1 and V2 visual cortices, and induces rich noncanonical connections with somatosensory, auditory, and frontal areas [117], resembling transient fetal connections [118]. Thus, the visual cortex ends up treating other types of information. Likewise, congenitally blind humans exhibit occipital cortex activation following auditory or somatosensory stimulation [96 & ]. It is therefore conceivable that in developmental synesthesia, congenitally anomalous sensory input leads to abnormal synaptic pruning and differences in brain connectivity. In grapheme-color synesthetes, low white matter densities in pulvinar, medial and lateral ventral posterior nuclei, and low fractional anisotropy in medial dorsal and ventral anterior nuclei suggest a constitutional disconnection and hypoconnection between thalamus and cerebral cortex [64 && ]. The concerned white matter tracts project to the left prefrontal cortex and bilateral temporal and posterior parietal cortex, regions that in synesthetes are distinct both in structure and function. Secondary synesthesia after thalamic stroke also support the involvement of thalamic output in synesthetic phenomena [24 & ,80-83].

CONCLUSION

Over the last few years, substantial advances have been made in the understanding of synesthesia, and hence more globally in the comprehension of perception and consciousness. Fortunately, awareness of this condition in the societal environment also significantly improved, finally allowing synesthetes to feel relieved by the so badly needed recognition of their particular situation. In a near future, in addition to the expected deepening of the explorations undertaken, elaborating a more comprehensive definition of synesthesia would be welcomed. Currently used criteria are rather restrictive for a condition that is quite polymorphic in nature. This process, however, is customary in the history of medicine, which consists of initially establishing a restricted definition to encapsulate the core of the condition and then broadening it, taking into account the numerous subtle presentations encountered.

Impact of thrombolysis in acute ischaemic stroke without occlusion:

an observational comparative study

Introduction

The efficacy of intravenous recombinant tissue plasminogen activator (IV-rtPA) in the setting of acute ischaemic stroke (AIS) was demonstrated in trials where intracranial arterial status was not studied [1]. As the rationale for IV-rtPA benefit is based on intracranial artery recanalization, the absence of arterial occlusion documented on vascular imaging in AIS patients raises the question of their eligibility for reperfusion therapy [2]. The benefit/risk balance is a significant issue in the daily practice of physicians managing AIS patients. Indeed, 30% of AIS patients treated with rtPA have no occlusion at admission e-mail: b.lapergue@hopital-foch.org). [2,3], and any benefit of fibrinolysis is hampered by a 10-fold increase in haemorrhagic transformation, with devastating consequences (7.7% of symptomatic intracerebral haemorrhage) [1]. Two recent studies on the impact of thrombolysis in cerebral infarction without occlusion showed opposing results [4,5]. Here, our aim was to assess the outcome of AIS patients without arterial occlusion with respect to IV-rtPA use.

Methods

Study design and data sources

A collaborative retrospective analysis was performed of observational data from five European university hospitals to assess the impact of IV-rtPA use in AIS patients without visible arterial occlusion. In all centres, data were prospectively collected using a structured questionnaire and approved by local institutional review boards. There were four participating centres in France (Bordeaux, Foch, Dijon and Nantes University Hospitals) and one in Switzerland (Lausanne University Hospital). In Lausanne University Hospital, data were extracted from the Acute Stroke Registry and Analysis of Lausanne (ASTRAL), which is a published ongoing prospective registry of AIS patients admitted within 24 h of symptom onset [6]. A subset of 236 included patients from the ASTRAL registry has been used in a previous publication testing the influence of arterial occlusion on favourable outcome after IV-rtPA use [5] but without focusing on lacunar subgroups. In this centre, all patients eligible for IV-rtPA treatment, as assessed by a vascular neurologist within 4.5 h (3 h before August 2008), received conventional IV-rtPA treatment. In Foch University Hospital, data were extracted from an unpublished ongoing prospective registry of AIS patients admitted within 6 h of symptom onset. In this centre, all patients eligible for IV-rtPA treatment, as assessed by a vascular neurologist within 4.5 h, received conventional IV-rtPA treatment when arterial occlusion was documented by angiography; in cases of no documented occlusion, patients received appropriate antithrombotic medication. In the remaining three participating centres, data were extracted from a local registry of consecutive patients having undergone conventional IV-rtPA treatment [7].

The study was considered and approved as observational by the internal review board (Comit e de protection des personnes, CPP Ile de France VIII, 10 July 2013). Patient databases were approved by the locally competent ethics committees and the 'Comit e consultatif sur le traitement de l'information en mati ere de recherche dans le domaine de sant e' of the individual participating centres.

Data collection

Patients were eligible for inclusion in this study if they (i) were admitted to hospital within 4.5 h, (ii) had no arterial occlusion documented by magnetic resonance angiography (MRA) or computed tomography angiography (CTA) at admission, (iii) had an admission National Institutes of Health Stroke Scale (NIHSS) score >4, (iv) had a pre-stroke modified Rankin Scale (mRS) <3 and (v) had available information on mRS at 3 months.

No arterial occlusion was documented on CT or MR angiograms at presentation, before IV-rtPA therapy. This variable was prospectively collected after adjudication by a senior neuroradiologist and a vascular neurologist in each case.

Data from individual patients were extracted from the observational data sources using a standardized form with predefined variables and were compiled at the coordinating centre (Foch University Hospital, Suresnes, France). The following variables were collected: age, sex, time between symptom onset (or from when the patient was last seen in a normal condition) and admission, medical history including main vascular risk factors (hypertension, diabetes mellitus, current smoking, prior stroke history) and antithrombotic treatment, clinical measures at admission (systolic and diastolic blood pressure, glucose level, heart rate, NIHSS score, pre-stroke mRS), NIHSS at 24 h, functional outcome assessed by the mRS at 3 months, symptomatic intracerebral haemorrhage (defined as a haemorrhage on the follow-up CT/MRI scan associated with an increase of ≥4 points in NIHSS score) [8] and lacunar stroke aetiology according to the TOAST classification. The mRS at 3 months was recorded either at the outpatient stroke clinic visit in an unblinded manner or by a structured telephone interview by mRS-certified medical personnel in a manner blinded to treatment type and recanalization [9].

Outcome definitions

The primary study outcome was excellent, defined by a 90-day mRS of 0-1. Secondary outcomes included a favourable outcome (defined as a 90-day mRS of 0-2), early neurological improvement (ENI) (defined as an NIHSS score of 0-1 at 24 h or a decrease of ≥4 points in NIHSS score at 24 h), 90-day all-cause mortality and symptomatic intracerebral haemorrhage.

Statistical analysis

Quantitative variables are expressed as means (standard deviation) in the case of normal distribution or medians (interquartile range, IQR) otherwise. Categorical variables are expressed as percentages (count). Normality of distributions was assessed using histograms and the ShapiroÀWilk test. Bivariate comparisons between IV-rtPA-treated and non-IV-rtPA-treated patients were made using chi-squared tests for qualitative variables (Fisher's exact test was used when the expected cell frequency was <5) and Student's t test for continuous variables (Mann-Whitney U test was used for non-Gaussian distributions). Comparisons in efficacy outcomes (excellent outcome, favourable outcome and ENI) were further adjusted for baseline between-group differences (at P < 0.10 in bivariate analyses) using logistic regression models. Unadjusted and adjusted odds ratios (ORs) for reaching each outcome were calculated using non-IV-rtPA-treated patients as the control group. Our first analyses covered the whole study group. Further analyses were stratified according to lacunar stroke aetiology; heterogeneity in IV-rtPA treatment effects across non-lacunar and lacunar subgroups were tested by formal interaction tests.

Two sensitivity analyses were performed. As a first sensitivity analysis, the main analysis was repeated after excluding the patients with a pre-stroke mRS ≥1. A secondary sensitivity analysis was performed using a propensity score adjustment approach [10]. A propensity score was calculated using a non-parsimonious multivariable logistic regression model, with IV-rtPA use as the dependent variable and all of the characteristics listed in Table 1 as covariates [10].

Finally, a meta-analysis was performed pooling the two existing previous studies [4,5] with our study results (after excluding the 236 overlapping participants in the Medlin et al. [5] publication). From the two previous studies the fully adjusted effect size [OR associated with IV use with its 95% confidence interval (CI)] for favourable outcome (available in both studies) was extracted. The adjusted effect sizes were combined using the inverse variance weighted fixedeffects model; heterogeneity between studies was quantified by calculation of the I 2 statistic.

Statistical testing was done at the two-tailed a level of 0.05. Data were analysed using the SAS software version 9.3 (SAS Institute, Cary, NC, USA).

Results

A total of 488 patients without arterial occlusion documented by angiography admitted from five European university hospitals were included in the present study; amongst them, 300 received IV-rtPA and 188 did not. The baseline characteristics of patients are shown in Table 1. IV-rtPA-treated patients less frequently had antithrombotic medications, prior stroke history, prestroke mRS ≥1, lacunar stroke aetiology, had lower Excellent outcome (our primary outcome) was achieved in 50% (n = 242) of patients overall, with no significant difference between the two groups (P = 0.82). A similar result was found when considering favourable outcome, whereas IV-rtPA-treated patients had significantly better ENI than non-IV-rtPA-treated patients (Figs 1 andS1). After adjustment for baseline between-group differences, the increased probability of ENI for IV-rtPA-treated patients remained significant, with an adjusted OR of 1.99 (95% CI 1.29-3.07, P = 0.002).

When the analysis was stratified according to lacunar and non-lacunar stroke aetiology, a significant heterogeneity was found in the IV-rtPA effect size for ENI (Fig. 1). The adjusted OR of ENI for IV-rtPAtreated relative to non-IV-rtPA-treated patients was 0.53 (95% CI 0.16-1.75, P = 0.30) in lacunar stroke patients and 2.52 (95% CI 1.56-4.09, P < 0.001) in non-lacunar stroke patients. Although the heterogeneity test did not reach the significance level for functional outcome, a detrimental effect of IV-rtPA was found in lacunar stroke patients only, whereas a trend towards a higher rate of favourable outcome in IV-rtPA-treated patients was found in non-lacunar stroke patients only.

Both sensitivity analyses (Fig. S2) yielded similar results.

Twenty-three deaths occurred in each group, with a non-significant between-group difference (8% in the IV-rtPA-treated group versus 12% in the non-IV-rtPA group; P = 0.09). Symptomatic intracerebral haemorrhage occurred in 6% of IV-rtPA-treated patients (n = 18) and in 3% of controls (P = 0.18). Death and symptomatic intracerebral haemorrhage occurred more frequently in non-lacunar stroke patients; only three deaths and two cases of symptomatic intracerebral haemorrhage occurred in lacunar stroke patients.

Finally, in a meta-analysis combining the three existing studies (including our result after excluding overlapping patients), the impact of IV use on favourable outcome was not significant; the combined adjusted OR was 1.43 (95% CI 0.51-3.99; P = 0.50; I 2 = 20%) (Fig. 2).

Discussion

Our study suggests that AIS patients without visible arterial occlusion treated with IV-rtPA may have a no better outcome at three months than those untreated. However, they have better early neurological improvement without evidence of safety concerns. Acute ischaemic stroke patients without arterial occlusion are commonly admitted to stroke centres, and such a situation may result from either a spontaneous recanalization before vascular imaging in 17% [3] or a lacunar infarction in up to 30% of patients [2]. Our results are consistent with the hypothesis that IV-rtPA may not benefit AIS patients without arterial occlusion as suggested by previous reported studies [5,11,12]. The issue of IV-rtPA benefit according to the occlusion status in AIS was first debated after post hoc subgroup analysis from the NINDS trial [13]. Recently, Medlin et al. [5] reported, in 272 AIS patients with no/minimal arterial occlusion, no improved outcome in IV-rtPA-treated patients compared to those who did not undergo thrombolysis (adjusted OR 0.76; 95% CI 0.21-2.74).

Interestingly, Lahoti et al. [4] reported opposite findings with a benefit of IV-rtPA amongst 256 stroke patients without arterial occlusion. In the latter study, high ORs for favourable outcome (3.42, 95% CI 2.05-7.03) [4] were observed, which contrasts with the non-significant OR observed in our study (1.25, or the OR from Medlin et al. [5] (0.71, 95% CI 0.21-2.74). It cannot be excluded that these discrepancies may be explained by differences in the patients' baseline characteristics. Besides, Lahoti et al.'s study did not adjust for confounding factors, such as pre Rankin score, onset to admission time, which may have potentially affected their results [4]. Nevertheless, in meta-analysis combining these results, the combined adjusted OR for favourable outcome was not significant (pooled OR 1.43; 95% CI 0.51-3.99) (Fig. 2).

In the present study, the effect of IV-rtPA also differed according to stroke aetiology. Indeed, although there was no significant benefit of IV-rtPA on the overall sample of 488 patients whatever the outcomes (Fig. 1), adjusted OR of ENI for IV-rtPA-treated patients was 2.52 (95% CI 1.56-4.09, P < 0.001) in non-lacunar stroke patients but not for those with lacunar stroke, in a stratified analysis.

A trend for the benefit of IV-rtPA on favourable outcome was seen only for non-lacunar stroke (adjusted OR 1.51; 95% CI 0.88-2.58). Lahoti et al. [4] found the same result when they stratified according to lacunar and non-lacunar stroke aetiology. IV-rtPA increased the rates of excellent or favourable outcome in the nonlacunar group but not in the lacunar group [4].

Several hypotheses may explain the difference of IV-rtPA according to lacunar or non-lacunar stroke patients. It could be speculated that cardioembolic stroke or extra/intra-cranial atherosclerosis stroke (i.e. non-lacunar stroke patients) may be more sensitive to IV-rtPA than lacunar stroke. Although the lacunar group sample was limited (n = 83), a detrimental effect of IV-rtPA was found on excellent outcome (adjusted OR 0.29; 95% CI 0.10-0.88). The detrimental effect of IV-rtPA found in lacunar stroke patients was not associated with an increased risk of intracerebral haemorrhage, despite the presence of small vessel disease usually associated with such AIS. It can be hypothesized that high blood pressure management may play a role in this detrimental effect in lacunar stroke, as suggested in a post hoc analysis of the SCAST trial [14]. rtPA-treated stroke patients require a lower blood pressure target such as systolic blood pressure <185 mmHg and diastolic blood pressure <110 mmHg. This lower blood pressure target may impact lacunar versus non-lacunar stroke differently. This point must be evaluated in further prospective trials. However, the debated definition of lacunar stroke as suggested elsewhere [15], together with the small sample size of lacunar patients in our study, make it difficult to draw any definite conclusion from these findings. These differences between lacunar and nonlacunar subgroups should be interpreted with extreme caution since only a small number of patients with lacunar strokes were included in our cohort.

The increased probability of early improvement for IV-rtPA-treated patients was driven by non-lacunar stroke patients. Amongst non-lacunar stroke patients, the discrepancy between a significantly improved ENI and the lack of benefit on an excellent outcome at 3 months may be explained by the fact that patients without occlusion have spontaneously a better 3 month prognosis (rate of favourable outcome 68.1%; Fig. S1).

None of the previous rtPA trials in AIS routinely assessed or controlled for arterial pathology. However, recent data were published from the International Stroke Trial (IST-3) [16]. Amongst 3035 patients enrolled in IST-3, 342 were classified as lacunar arterial cerebral infarction (LACI, subtype defined by the Oxfordshire Community Stroke Project classification, thus without occlusion). Amongst lacunar patients, the adjusted OR of the effect of rtPA on functional outcome at 6 months was 1.17 (0.70-1.94). Besides, in the LACI subgroup of IST-3, eight (5%) patients suffered from symptomatic intracerebral haemorrhage versus none in the control group. These results confirm the trend observed in our study of the absence of beneficial effect of rtPA on the mRS and a non-significant increase of symptomatic intracerebral haemorrhage (rtPA-treated group, 6% vs. 3%).

But, the test of heterogeneity was not significant (P = 0.867) suggesting that the global beneficial effect (adjusted ordinal analysis of Oxford Handicap score) of rtPA in IST-3 may be applicable to lacunar patients.

In our study, MRA or CTA were used according to local protocols. Furthermore, the presence of a small distal occlusion cannot be ruled out in some cases, especially with CTA. Indeed, the sensitivity of CTA and MRA for detecting distal branch occlusions is limited [17].

The present study has several limitations. First, our findings are derived from observational non-randomized analyses which are subject to well-known limitations. The first is the potential for confounding factors by measured or unmeasured variables, which cannot be ruled out. However, the findings were consistent after several methods of adjustment and sensitivity analyses (Fig. S2).

Secondly, the analysis of IV-rtPA effect amongst a stroke population with no occlusion and good outcome exposes a risk of lack of power. However, our study included the largest reported series of stroke patients without arterial occlusion studied in the acute phase of ischaemic stroke (n = 488). A post hoc power analysis was performed using the observed excellent outcome rate (60%). With 80% power, an OR of 2.3 could be detected with our study sample. For these reasons, the present findings can be considered as hypothesis-generating.

Although IV-rtPA-treated patients without visible occlusion did not have a better outcome at 3 months than without rtPA, a better ENI is shown in non-lacunar patients. Taking this into account could reduce cost by shortening the duration of hospitalization and decreasing the length of rehabilitation.

Besides, our observations support that there are no safety concerns in using IV-rtPA in patients without occlusion and that IV-rtPA may have some beneficial effects (faster recovery, a trend towards fewer deaths).

Further randomized controlled trials, analysis of prospective registry data and cost/effectiveness study analysis are warranted to address the level of efficacy of IV thrombolysis treatment in AIS without occlusion. Our conclusion is that only a randomized controlled trial would provide a definitive answer about the impact of rtPA in acute stroke patients without occlusion. Until then, these patients should be treated by rtPA as recommended.

patients with a pre-stroke Rankin ≥1. (B) Sensitivity analysis after adjusting for propensity score † .

Chapter 3

Annexe VI: "Increased functional connectivity between language and visually deprived areas in late and partial blindness" Introduction Functional magnetic resonance imaging studies have shown that the relationship between the language and visual areas varies depending on the presence or absence of visual function. For instance, during an abstract word recall task, sighted individuals exhibited strong visual area deactivation alongside activation of language specific regions [START_REF] Azulay | Negative BOLD in sensory cortices during verbal memory: a component in generating internal representations[END_REF]. In congenitally blind subjects, however, most groups have reported strong activation of the early visual cortex in addition to the classical language areas (e.g. Broca's area) during both verbal memory [START_REF] Amedi | Early "visual" cortex activation correlates with superior verbal memory performance in the blind[END_REF][START_REF] Azulay | Negative BOLD in sensory cortices during verbal memory: a component in generating internal representations[END_REF] and language-related verb generation tasks [START_REF] Amedi | Early "visual" cortex activation correlates with superior verbal memory performance in the blind[END_REF]Burton et al., 2002a[START_REF] Burton | Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people[END_REF]. Activations of visual areas also play a functional role in both semantic memory and generation tasks, in that blind individuals showing strong recruitment of V1 also demonstrated superior performance in such processes [START_REF] Amedi | Early "visual" cortex activation correlates with superior verbal memory performance in the blind[END_REF][START_REF] Raz | V1 activation in congenitally blind humans is associated with episodic retrieval[END_REF]. Furthermore, languagerelated early visual cortex activity was shown to make a key contribution to this task in congenitally blind but not in sighted individuals. This is one of the very few examples of a causal relationship indicative of cross-modal plasticity in the blind [START_REF] Amedi | Transcranial magnetic stimulation of the occipital pole interferes with verbal processing in blind subjects[END_REF]. Bedny et al.'s recent study using a variety of well-controlled language tasks showed that activity in the visual (essentially left) areas actually reflected complex language processing in the congenitally blind. They suggested that there was a critical period for this recruitment, as no such activation was found in the late blind (Bedny et al., 2011(Bedny et al., , 2012)).

Anatomically, the semantic processing of the occipital cortex is likely supported by the inferior frontal-occipital fasciculus (IFOF), namely its superficial layer and the posterior component of the deep layer [START_REF] Sarubbo | Frontal terminations for the inferior fronto-occipital fascicle: anatomical dissection, DTI study and functional considerations on a multi-component bundle[END_REF]. Congenitally but not late blind individuals exhibit altered IFOF, decreased structural global connectivity efficiency and increased local connectivity efficiency both in occipital and frontal lobes [START_REF] Li | Age of onset of blindness affects brain anatomical networks constructed using diffusion tensor tractography[END_REF]Shu et al., 2009;Reislev et al., 2016). These structural changes, together with the above mentioned functional and behavioral data point to early absence of visual input altering brain structure to serve specific tuned-up non-visual functions of occipital cortex. Do only congenitally blind individuals develop this type of early visual cortex recruitment for language and memory? Or can it also occur in the late blind? This issue goes beyond the field of blindness to the wider question of whether this processing can only occur during critical or sensitive periods in childhood or whether some traces and mechanisms for this ability are present even in the adult brain [START_REF] Bavelier | Cross-modal plasticity: where and how?[END_REF]Bedny et al., 2012;Sadato et al., 2002). This has implications for rehabilitation, especially in the context of stroke since the loss of a specialized area requires another area to take over the missing function (Pascual-Leone et al., 2005). It also remains unclear whether visual deprivation needs to be complete for such plasticity to emerge or whether some changes can start even in the presence of residual vision (Cunningham et al., 2015). Finally, little is known about the largescale anatomical and functional changes that might support such radical brain plasticity.

The current literature provides somewhat conflicting observations on these questions. Burton et al. (2002aBurton et al. ( , 2002b) ) found that when listening to words, both congenitally and late blind subjects exhibited bilateral activation of the visual cortex regions in addition to language and auditory areas (Burton et al., 2002a). By contrast, Bedny et al. (2012) found that only the congenitally blindand not the late blindshowed an increased response in V1 to heard sentences as compared to backwards speech. They concluded that recruitment of the visual cortex for language processing depends critically on the age of blindness onset (Bedny et al., 2012). Thus, even in very recent research it remains unclear whether visual cortex activation by language is affected by previous visual experience in the blind. The picture in the effect of partial blindness on adult brain plasticity and visual input is even more limited and debated.

The analysis of resting-state functional connectivity constitutes a rich, efficient approach to studying brain function, brain large-scale connectivity and brain plasticity [START_REF] Fox | Clinical applications of resting state functional connectivity[END_REF][START_REF] Guerra-Carrillo | Resting-state fMRI: a window into human brain plasticity[END_REF][START_REF] Smith | Correspondence of the brain's functional architecture during activation and rest[END_REF] as illustrated in the human connectome project [START_REF] Hodge | ConnectomeDB-sharing human brain connectivity data[END_REF]. These temporal correlations were shown to echo the co-activation between brain regions found in task-based fMRI studies (Buckner et al., 2013;Dosenbach et al., 2007). Of course like any method, rs-fMRI also has some limitations, which are discussed in depth in the discussion (see Limitations and methodological considerations section). Nevertheless, rs-fMRI is sensitive enough to detect interactions between specific language regions such as Broca's area and the visual cortex. Several teams found specific increased functional connectivity between the inferior frontal triangular gyrus (part of BA 44,45,47) including Broca's area and several occipital visual areas in the congenitally blind as compared to sighted subjects (Liu et al., 2007;[START_REF] Heine | Prevalence of increases in functional connectivity in visual, somatosensory and language areas in congenital blindness[END_REF]. Striem-Amit et al. (2015) recently studied the same type of population and found that central V1 was more tightly connected to language areas whereas peripheral V1 was linked to spatial attention and control networks in the congenitally blind as compared to a sighted group (Striem-Amit et al., 2015). Butt et al. (2013) also analyzed the brain resting-state in a heterogeneous population of blind subjects, and suggested that long-range FC between Broca's area and V1 could be explained by age at blindness onset; however, variability in visual conditions (e.g. age onset of vision loss, cause of the disease, visual field location of the scotoma before blindness) combined with the limited number of subjects in each condition constrained data interpretation (Butt et al., 2013). The type of condition has also been considered by other authors (Bedny et al., 2012;[START_REF] Watkins | Language networks in anophthalmia: maintained hierarchy of processing in "visual" cortex[END_REF], who have argued that retina versus optic nerve disorders or gradual versus sudden loss of vision may differentially affect the reorganization of the visual cortex.

Hence, analyzing the functional resting-state connectivity in visually affected individuals categorized into clinically well-defined homogeneous groups in terms of the etiology of blindness might provide valuable indications whether partial or total late deprivation of vision affects the functional links between Broca's area and the visual cortex. The current work was conducted with clinically homogeneous groups of subjects suffering from retinitis pigmentosa, a retinal degenerative condition that causes particularly structured defects initially involving the visual field periphery (and sparing the central "tunnel vision" area), and eventually leading to complete blindness.

Beyond its theoretical contribution, this study has important clinical implications. Late blind patients suffering from RP are the group most expected to benefit from visual restoration such as retinal prosthesis [START_REF] Ayton | First-in-human trial of a novel suprachoroidal retinal prosthesis[END_REF][START_REF] Stingl | Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS[END_REF][START_REF] Weiland | Retinal prosthesis[END_REF]. The existence of cross-modality plasticity mechanisms in RP subjects has only been investigated in a few studies (Cunningham et al., 2015;Masuda et al., 2010) using other methodologies that the ones employed here. Given that there is some evidence of maladaptive cross-modal plasticity in deaf patients following cochlear implantation [START_REF] Lee | Crossmodal plasticity and cochlear implants[END_REF]Striem-Amit et al., 2011a), there is a crucial need to better understand the reorganization following progressive RP visual loss to overcome this potential issue in the context of sight restoration.

The present study thus used brain resting-state to characterize the functional connectivity between Broca's area and sub-regions of the visual cortex in: (1) individuals suffering from RP who still retain central "tunnel vision"-the RP tunnel vision group; and (2) individuals with more severe RP so that now there is not even tunnel vision, and visual loss covers the entire visual field, leading to blindness (please note that such patients might still occasionally have faint light perception but zero form vision, as in advanced disease most individuals report some visual fluctuation, described as "good days and bad days" (see [START_REF] Heckenlively | Good days, bad days[END_REF]) -the RP blind group (3) sighted individuals -the sighted control group. The following specific questions were explored:

(1) What is the pattern of functional connectivity between Broca's area and visual areas in the sighted? Does this pattern show negative FC as might be predicted based on the deactivation (negative BOLD) in V1 to language and memory tasks [START_REF] Azulay | Negative BOLD in sensory cortices during verbal memory: a component in generating internal representations[END_REF])? (2) Do Broca's and visual areas exhibit a different pattern of functional connectivity in the RP blind (e.g. reversal to positive FC)? (3) What is the functional connectivity of these same regions for RP tunnel vision subjects? Is a complete lack of visual input necessary for the development of such changes? (4) Does this pattern vary according to the topography of the visual retinotopic areas; e.g. does the peripheral visual cortex show a different pattern of connectivity than the foveal across groups, as might be predicted by the fact that at the tunnel vision stage, the disease affects more peripheral than central areas of the visual field?

Materials and methods

Subjects and ethics

The sample was made up of 35 subjects divided into 3 groups. Subjects were matched for age, and no subject had any reported neurological or psychiatric antecedents (Table 1). The Ethics Committee (Comité de protection des personnes, Ile de France V, and Agence Nationale de Sécurité du Médicament et des Produits de Santé) approved the experimental protocol (number 12873), and all subjects gave their written informed consent (according to the Declaration of Helsinki) before participating.

Functional imaging

fMRI was conducted on a whole-body 3T clinical imager (Sigma Horizon) by using an 8-channel head coil. In each scanning sequence, 32 contiguous axial T2*-weighted gradient-echo echo-planar images (TE/TR, 93/3000 ms; FOV, 240 × 240 mm; matrix, 64 × 64; voxel size, 3.75 × 3.75 × 4 mm; thickness, 4 mm; interslice spacing, 0 mm; NEX, 1) were recorded to encompass the entire brain. 180 volumes were acquired including 4 "dummy" volumes obtained at the start of the session. The scan duration was 9.25 min for the echo planar imaging sequence. Off-line, T2*-weighted images were co-registered and overlaid on the corresponding anatomic T1-weighted gradient-echo images (TE/TR/flip angle, 3.9/9.5 ms/20°; FOV, 25.6 × 25.6 mm; matrix, 512 × 512; source voxel size, 1.2 × 0.5 × 0.5 × mm converted to 1 × 1 × 1 × mm; thickness, 1.2 × mm; interslice spacing, 1.2 × mm). During the scan, subjects were supine in the magnetic resonance imaging scanner and wore earplugs to compensate for the noisy environment. Subjects were instructed to keep their eyes closed. No explicit task was required. fMRI preprocessing fMRI data were preprocessed using the BrainVoyager QX 2.8 software package (Brain Innovation, Maastricht, Netherlands) and complementary software written in MATLAB R2009a (MathWorks, USA). Preprocessing of functional scans included: slice-time correction, 3D motion correction (no head motion exceeded 2 mm in any direction; which means movements are maximum in the order of magnitude of one functional voxel only as voxels size was: 3.75 × 3.75 × 4 mm) in order to control and remove artifacts, band-pass filtering between 0.01 and 0.1 Hz to regress non-relevant frequencies (e.g. breathing, pulse), voxel-to-voxel linear regression (Cole et al., 2010) of spurious signal from the white matter and ventricles regions anatomically defined for each subject, normalization in the Talairach coordinate system in the volume (Talairach and Tournoux, 1988), and spatial smoothing with a Gaussian filter kernel of 6 mm full-width-at-half-maximum. We did not include global signal removing because of the potential introduction of false negative correlations (see Murphy et al., 2009). For the between groups comparison we tested and found no significant difference (or even a trend) in the extent (mm) of head movement between the three groups (ANOVAs: p N 0.05 for each direction: X, Y, Z, translations, X, Y, Z, rotations; see Supplementary Table. S1). These data were confirmed by repeating the GLM analysis (see Seed ROI definition and analysis section) including the head movement predictors (control analysis; see Supplementary Fig. S1). Including these movement predictors in the GLM did not change the main results.

Seed ROI definition and analysis

For each subject, a seed region-of-interest (ROI) consisting of a 5 mmradius sphere was located in Broca's area (BA45, pars triangularis; Talairach coordinates: -39, 17, 11; see (Burton et al., 2002a;[START_REF] Sarubbo | Frontal terminations for the inferior fronto-occipital fascicle: anatomical dissection, DTI study and functional considerations on a multi-component bundle[END_REF]) which served to extract the blood-oxygen leveldependent time-course of this region [START_REF] Burton | Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people[END_REF]. The average time-course for each subject was calculated, z-transformed and used as individual predictors in a group random-effect analysis based on the general linear model (GLM) (see Fig. 1; Friston et al., 1999). To establish a contrast among groups, a between-subject random effect ANOVA was performed with a significance level of p b 0.05, corrected for multiple comparisons using cluster-size thresholding [START_REF] Forman | Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold[END_REF][START_REF] Goebel | Analysis of functional image analysis contest (FIAC) data with brainvoyager QX: from single-subject to cortically aligned group general linear model analysis and self-organizing group independent component analysis[END_REF]Striem-Amit et al., 2015) implemented in BrainVoyager using the Monte Carlo simulation approach (see Figs. 2 and3). This method takes the data contiguity of neighboring voxels directly into account and corrects for the false-positive rate of continuous clusters (a set-level statistical inference correction; corrected to p b 0.05).

External functional localizers

External functional localizers were used to define the seed ROI from visual localizers (left hemisphere foveal V1, peripheral V1). Each of these localizers was extracted from a group of sighted controls and analyzed in normalized Talairach space using a random effect GLM, which enabled generalization of the findings to the population (see details below; Friston et al., 1999).

To define the primary visual cortex seeds, 13 control subjects were scanned in a standard phase-encoded retinotopic mapping procedure, with ring (eccentricity mapping) and wedge (polar mapping) stimuli to establish the visual retinotopic mapping [START_REF] Engel | fMRI of human visual cortex[END_REF]Sereno et al., 1995;Striem-Amit et al., 2015;Wandell et al., 2007;[START_REF] Wandell | Imaging retinotopic maps in the human brain[END_REF] delivered during the two separate experiments. The stimuli were projected via an LCD screen positioned over the subject's forehead and watched through a tilted mirror. In Experiment 1 an annulus was projected, expanding from 0°to 34°of the subject's visual field in 30 s, repeated 10 times. Experiment 2 included a wedge with a polar angle of 22.5°that rotated around the fixation point, and completed a cycle in 30 s repeated 20 times. Both the annulus in Experiment 1 and the wedge in Experiment 2 contained a flickering (6 Hz) radial checkerboard pattern with respect to standard retinotopic procedures [START_REF] Engel | fMRI of human visual cortex[END_REF] for the mapping of field maps. In both cases, there was a 30 s mute period before and after the visual stream for baseline. Group phase analysis was conducted on the two experiments as done in other studies from our group (Hertz and Amedi, 2010;Striem-Amit et al., 2011b) resulting in group maps of eccentricity and angle mapping. Angle mapping was then used to define the borders of V1, and the two maps were used to segregate it according to eccentricity (center or periphery of the visual field), laterality (left or right parts of the visual field).

The external functional definition of the early visual cortex was further used to calculate the within-subject correlation between Broca's area and left posterior or anterior calcarine sulcus and cuneus (localizers for the left fovea and the periphery of V1 respectively). Individual average time-courses from ROIs were sampled from each participant. The Pearson correlation coefficient between the time-courses of the two ROIs (within each subject) was calculated (see Fig. 4). ANOVA and Sheffe post-hoc analyses were also performed to test for differences between the groups (p b 0.05). Then, non-parametric Wilcoxon rank sum tests were run on the same data to control for the effect of Braille reading skills in segregated populations of RP blind subjects (see Supplementary Table S2).

To evaluate the effect of age, blindness duration and Braille reading skills (see Supplementary Table S2) on the FC between Broca's area and the extrastriate areas of RP blind subjects, 5 mm-radius spheres were defined according to the most significant foci exhibiting positive FC at the within-group level (i.e. left inferior occipital gyrus, -24 -89 -18; left middle occipital gyrus -26 -89 4; left fusiform gyrus -24 -62 -7; left parahippocampal gyrus -24 -39 -8; see Fig. 3). Then, non-parametric Wilcoxon rank sum and Pearson tests were performed on the correlation coefficients of Broca's area and each of these extrastriate regions in segregated populations of the RP blind subjects (Braille reader vs. non-Braille readers; see Supplementary Table S2).

To summarize, the resting-state data were analyzed by several complementary methods and levels. First, ROI-based seed functional connectivity analysis was performed on the rs-fMRI data to investigate the functional connectivity between the seeded Broca's area and the rest of the brain within each group (see Fig. 1). Next, ANOVAs and post-hoc tests were carried out to compare functional maps between groups (see Figs. 234; Table 2). FC coefficients between specific ROIs such as Broca's area and the anterior and posterior regions of the calcarine sulcus were also calculated for each group (see Fig. 4). ANOVAs and post-hoc tests were then performed on the mean z-score correlation coefficients to compare the groups. Finally, non-parametric Wilcoxon rank sum tests and Pearson tests were performed on the level of correlation of Broca's area and both the striate and extrastriate visual areas to control for the effects of age, duration of blindness and Braille reading skills in RP blind subjects (see Supplementary Table S2).

Results

In all groups, the data showed that Broca's area was functionally connected to the anterior cingulate, left supramarginal gyrus (Wernicke's area), the precentral gyrus (e.g. primary motor area), and the subcortical (e.g. bilateral insula, thalamus), auditory (e.g. A1) and frontoparietal regions (see Fig. 1).

In the sighted control within-group analysis, there was strong negative FC between Broca's area and early and high order visual areas as well as the medial part of the superior frontal gyrus. These included the major ventral and dorsal visual areas along the calcarine sulcus (corresponding to Brodmann Area 17/Visual area V1 -Primary visual cortex), cuneus, inferior occipital, lingual, parahippocampal, retrosplenial, fusiform, and inferior temporal gyri (see Fig. 1A).

The RP tunnel vision within-group analysis revealed almost no negative FC between Broca's area and the calcarine sulcus and cuneus but still preserved negative FC with the inferior occipital, lingual, parahippocampal, restrosplenial, fusiform, and inferior temporal gyri (see Fig. 1B).

The RP blind group showed a complete reversal of the level of FC between Broca's area and the early visual cortex. The data showed positive FC between Broca's area and the calcarine sulcus/cuneus, but almost all the negative FC with other visual areas was lost (see Fig. 1C).

In the RP blind subjects compared to the sighted controls, betweengroup analyses revealed a significantly increased level of FC between Broca's area and parts of the calcarine sulcus, cuneus, lingual, left fusiform, left inferior occipital, left parahippocampal, left inferior temporal and medial part of the superior frontal gyri (see Figs. 2A and3A; for Talairach coordinates of all the peaks for these contrasts see Table 2).

Increased FC between Broca's area and the anterior calcarine sulcus/ cuneus as well as the medial part of the superior frontal gyrus was found for the RP tunnel vision subjects compared to the sighted controls (see Fig. 2B; for Talairach coordinates of all the peaks for these contrasts see Table 2).

Compared to the RP tunnel vision subjects, the RP blind subjects showed increased FC between Broca's area and specific extrastriate areas such as the left middle occipital, inferior occipital and parahippocampal gyri (see Fig. 3B, Table 2).

In terms of correlation coefficients between ROIs, there was a group main effect for both the left anterior (ANOVA: F(2,32) = 13.6 p b 0.0001) and posterior (ANOVA: F(2,32) = 5.78 p b 0.01) calcarine sulcus and Broca's area (see Fig. 4). Post-hoc tests showed (1) a Fig. 2. Between-groups analysis of functional connectivity seeded from Broca's area (focus on calcarine sulcus/cuneus differences). The maps are shown in fMRI full-slice view (neurological convention) for (A) RP blind subjects or (B) RP tunnel vision subjects compared to the sighted control subjects. Colors depict the magnitude of the difference between groups of the FC of Broca's area localizer and the rest of the brain: yellow-orange for increased FC (away from zero) and green-blue for decreased FC (toward zero). X, Y, Z are Talairach coordinates. (A) Increased functional connectivity was found in RP blind subjects compared to sighted control subjects between Broca's area and the calcarine sulcus (Brodmann area 17) delineated in white as well as the cuneus, lingual, fusiform, inferior occipital, parahippocampal and medial part of the superior frontal gyri. (B) Increased functional connectivity was found in RP tunnel vision subjects compared to the sighted control subjects between Broca's area and the anterior calcarine sulcus/Cuneus (Brodmann areas [17][18] and the medial part of the superior frontal gyrus. As between-groups differences could result from positive or (and) negative functional connectivity at the group level, we show the within-group maps for selected regions with a blow-up at the bottom of each figure. Yellow-orange and green-blue represent positive and negative functional connectivity respectively with Broca's area for each group. S: sighted controls. TV: RP tunnel vision. FB: RP blind. Fig. 3. Between-groups analysis of functional connectivity seeded from Broca's area (focus on extrastriate area differences). The maps are shown in fMRI full-slice view (neurological convention) for RP blind subjects compared to (A) sighted control subjects or (B) RP tunnel vision subjects. Colors depict the magnitude of the difference between groups of the FC of Broca's area localizer and the rest of the brain: yellow-orange for increased FC (away from zero) and green-blue for decreased FC (toward zero). X, Y, Z are Talairach coordinates. (A) Increased functional connectivity was found in RP blind compared to the sighted control subjects between Broca's area and the left fusiform (FFG), parahippocampal (ParaH), inferior (IOG) and middle (MOG) occipital gyri (delineated in black). (B) Increased functional connectivity was found in RP blind subjects compared to RP tunnel vision subjects between Broca's area and the parahippocampal, inferior and middle occipital gyri (delineated in black). As between-groups differences could result from positive or (and) negative functional connectivity at the group level, we show the within-group maps for selected regions with a blow-up at the bottom of each figure. Yellow-orange and green-blue represent positive and negative functional connectivity respectively with Broca's area for each group. S: sighted controls. TV: RP tunnel vision. FB: RP blind.

Discussion

In this rs-fMRI study, we explored the FC between Broca's area (BA45, pars triangularis of the inferior frontal gyrus) and visual areas in sighted subjects as well as in two groups of subjects suffering from late onset retinitis pigmentosa (RP), one with tunnel vision (partial blind) and the other RP blind (covering the entire visual field). These groups exhibited negative, null and positive FC patterns respectively (see Fig. 1). Furthermore, in comparison to the sighted controls, both groups of RP subjects presented increased FC between Broca's area and regions of the calcarine sulcus and cuneus that are specifically deprived according to the evolution of their condition (i.e. the anterior part (peripheral V1) for the RP tunnel vision subjects, and both anterior and posterior part of V1 for the RP blind subjects; see Figs. 2 and4, Table 2). Finally, compared to both the sighted control and the RP tunnel vision subjects, the RP blind showed increased FC between Broca's area and specific extrastriate areas including the left parahippocampal, fusiform, inferior and middle occipital gyri (see Fig. 3, Table 2).

Negative functional connectivity between Broca's area and visual areas in the sighted control group Several studies support the claim that negative correlations reflect a true reduction in neuronal processing [START_REF] Behzadi | A component based noise correction method (CompCor) for BOLD and perfusion based fMRI[END_REF][START_REF] Chai | Selective development of anticorrelated networks in the intrinsic functional organization of the human brain[END_REF]Fox et al., 2005;[START_REF] Guerra-Carrillo | Resting-state fMRI: a window into human brain plasticity[END_REF][START_REF] Logothetis | How not to study spontaneous activity[END_REF][START_REF] Shmuel | Sustained negative BOLD, blood flow and oxygen consumption response and its coupling to the positive response in the human brain[END_REF][START_REF] Shmuel | Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1[END_REF][START_REF] Shulman | Common blood flow changes across visual tasks: II. Decreases in cerebral cortex[END_REF]Zeharia et al., 2012).

In the current study, Broca's area in the sighted control group exhibited strong negative FC with the entire calcarine sulcus/cuneus (i.e. V1) and both the ventral and dorsal extrastriate visual areas. This is in agreement with a fMRI study which reported that in a verbal memory retrieval task, sighted subjects showed activation of classical language areas (including Broca's area) coupled with strong deactivation of visual areas including V1 calcarine sulcus and cuneus [START_REF] Azulay | Negative BOLD in sensory cortices during verbal memory: a component in generating internal representations[END_REF]. These study argued that a balance between activation and deactivation is required to filter out irrelevant information and enable an attentional focus on internal representations. This may imply that the negative FC we observed between language/control at rest (i.e. the intrinsic system) and visual (i.e. the extrinsic system) networks could reflect a functional competition that prevents visual inputs from disturbing language processing (for reviews of extrinsic and intrinsic systems see (Fox et al., 2005;[START_REF] Golland | Extrinsic and intrinsic systems in the posterior cortex of the human brain revealed during natural sensory stimulation[END_REF][START_REF] Golland | Data-driven clustering reveals a fundamental subdivision of the human cortex into two global systems[END_REF]). Broca's area in the sighted control group also showed negative FC with the medial part of the superior frontal gyrus. We assume based on its anatomical location (talairach coordinates: -1, 47, -4; see Fox et al., 2005), that it is part of the defaultmode network. In healthy subjects, default-mode network regions are well known to be deactivated in a set of functional tasks (e.g. language), and activated in rest conditions, and would contribute to the emergence of spontaneous inner-oriented thoughts (Greicius et al., 2003;[START_REF] Raichle | A default mode of brain function[END_REF].

Differences in Broca's area functional connectivity to the calcarine sulcus/ cuneus in the three groups

The results help clarify whether the pattern of connectivity can help to support language recruitment in visual areas in subjects with late visual deficits or partial visual deficits like tunnel vision. Burton et al. argued that recruitment can occur in both early and late blind subjects, and that it may be related to the learning of Braille reading (Burton et al., 2002a). More recently, Bedny et al. (2012) only found languagerelated activation of V1 in early but not in late blind participants (Bedny et al., 2012). They argued that the V1 activation observed in the late blind in previous studies reflects attention or preparation mechanisms and concluded that the recruitment of the visual cortex for language processing depends on the age of blindness onset (Bedny et al., 2012).

In the current study, the RP blind group exhibited positive Broca's area FC with parts of the calcarine sulcus/cuneus and increased FC of the same regions compared to the sighted controls (see Figs. 1C-2A), which completely reversed the picture of resting state functional connectivity found in the sighted. In the RP blind subjects, the entire visual field is lost, which is probably why the FC to Broca's area stretched from the anterior to the posterior deprived regions of the calcarine sulcus/ cuneus (corresponding to early visual areas). However, no evidence for a FC difference was found between Broca's area and regions implicated in attentional mechanisms between groups. In contrast to the hypothesis put forward by Bedny et al. (2012), we suggest that our results might support the recruitment of the early visual areas by the language system, even in blind subjects with previous visual experience, or at least, that the basis for such recruitment emerges from the restingstate functional connectivity pattern. On the other hand, our data do not support the notion that this recruitment is tightly linked to the acquisition of Braille reading skills (Burton et al., 2002a(Burton et al., , 2002b;;Cunningham et al., 2015) since we did not find significant differences between Braille and non-Braille readers within the RP blind group (see Supplementary Table S2). Thus, the functional relevance of this connectivity still remains unclear. We also evaluated the effect of age and blindness duration, and found no correlation with the FC between Broca and V1. Overall, these data suggest that there is no critical age for developing functional connectivity between Broca's area and early visual areas or for the complete reversal of their sign from negative FC in the sighted to positive in RP complete late blindness.

The data for the RP tunnel vision subjects were generally consistent with what was found for the RP blind in the sense that they support the hypothesis that recruitment for language processing is specific to visually deprived regions. They also demonstrate that these processes cannot only occur in the blind but also in subjects with residual visual function.

The RP tunnel vision subjects showed a slight negative FC of Broca's area with the calcarine sulcus/cuneus (Brodmann area 17; see Fig. 1). However, when compared to the sighted subjects, the RP tunnel vision subjects presented increased FC between Broca's area and specific visually deprived regions (i.e., the anterior but not the posterior part of the calcarine sulcus/cuneus; see Figs. 2 and4).

In sighted individuals, the anterior and posterior parts of the calcarine sulcus/cuneus code for peripheral and foveal representations of the visual field respectively (Sereno et al., 1995). In the RP tunnel vision subjects, however, the peripheral representation of the visual field is lost whereas the foveal field is preserved [START_REF] Kalloniatis | Retinitis pigmentosa: understanding the clinical presentation, mechanisms and treatment options[END_REF]. Based on the inter-modality competition hypothesis [START_REF] Azulay | Negative BOLD in sensory cortices during verbal memory: a component in generating internal representations[END_REF], and given the intra-group null FC for the tunnel vision group, in conjunction with their increased FC compared to the sighted, Table 2 Peaks of functional connectivity differences between groups (seed region-of-interest: Broca's area). Peaks X, Y, Z: Talairach coordinates. P values corrected for multiple comparisons. LH: Left hemisphere. RH: Right hemisphere. BA: Brodmann areas.

we suggest that the language network develops functional connectivity with the sensory deprived early visual cortex and that this connectivity is limited by the remaining foveal vision input. Furthermore, the selective changes observed in the anterior V1 may be related to function reallocation facilitated by the putative cross-modal abilities of this area [START_REF] Eckert | A cross-modal system linking primary auditory and visual cortices: evidence from intrinsic fMRI connectivity analysis[END_REF]Falchier et al., 2002;[START_REF] Wandell | Plasticity and stability of visual field maps in adult primary visual cortex[END_REF]. It would be worthwhile comparing RP tunnel vision subjects with other clinical conditions in which patients present with central vision loss (e.g. age-related macular degeneration, Stargardt disease) to test whether the posterior/foveal regions of V1 are also functionally connected to the language network. Thus overall, these findings suggest that (1) dramatic changes occur in functional connectivity between the language and early visual areas of the adult brain that change the sign of the FC from negative to positive; (2) these changes occur even in a partial visual defect condition, though to a lesser extent; and (3) these changes presumably depend on the topography of the functionally deprived areas.

Differences in Broca's area functional connectivity to extrastriate areas in the three groups RP blind subjects also exhibited increased FC between Broca's area and a set of extrastriate regions as compared to both RP tunnel vision and sighted subjects (see Fig. 3, Table 2) but not with the lateral occipital regions. Most of these regions have been identified in verb generation tasks on the late blind (Burton et al., 2002a[START_REF] Burton | Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people[END_REF]. It was suggested that multisensory regions transfer language functions to tactile or auditory stimuli. Our results challenge this explanation for two main reasons: (1) we did not find any significant functional connectivity changes between Broca's area and these regions in Braille as compared to non-Braille readers (see Supplementary Table S2); (2) we did not find any significant difference in functional connectivity between the auditory and extrastriate visual areas across groups, as would be expected according to the auditory cross-modality hypothesis (Burton et al., 2002a).

These extrastriate visual areas have also been identified in verbal and semantic retrieval task studies in the congenitally blind [START_REF] Amedi | Early "visual" cortex activation correlates with superior verbal memory performance in the blind[END_REF][START_REF] Azulay | Negative BOLD in sensory cortices during verbal memory: a component in generating internal representations[END_REF][START_REF] Noppeney | Effects of visual deprivation on the organization of the semantic system[END_REF][START_REF] Raz | V1 activation in congenitally blind humans is associated with episodic retrieval[END_REF]. Hence increased FC between Broca's area and these extrastriate regions may reflect the lifting of inhibition of the visual association cortex to process verbal memory and semantic information. Nevertheless, the specific differences between the functional connectivity of these regions in RP blind compared to the RP tunnel vision subjects support the idea that complete vision loss is required for such changes to occur.

Preserved functional connectivity between Broca's area and the rest of the brain in the three groups In all three groups, we identified regions that are regularly activated in functional language tasks and also belong to several intrinsically connected networks such as the language network [START_REF] Bookheimer | Functional MRI of language: new approaches to understanding the cortical organization of semantic processing[END_REF][START_REF] Hagoort | On Broca, brain, and binding: a new framework[END_REF][START_REF] Hampson | Detection of functional connectivity using temporal correlations in MR images[END_REF][START_REF] Johnson | The role of the human thalamus in language and memory: evidence from electrophysiological studies[END_REF][START_REF] Price | The anatomy of language: a review of 100 fMRI studies published in[END_REF][START_REF] Yetkin | A comparison of functional MR activation patterns during silent and audible language tasks[END_REF] and the executive control network [START_REF] Doucet | Brain activity at rest: a multiscale hierarchical functional organization[END_REF]Spreng et al., 2010;[START_REF] Sundermann | Functional connectivity profile of the human inferior frontal junction: involvement in a cognitive control network[END_REF]Vincent et al., 2008). These findings suggest that functional connectivity is useful in delineating networks for a given function, including language, and may imply that beyond the changes between Broca's and visual areas, the rest of the network is well preserved in cases of visual deprivation.

No sensitive period for the development of cross-modal plasticity at least as reflected by the rs-fMRI data The massive changes observed in functional connectivity between language and visual areas in the late blind support the notion that some level of reorganization even in the calcarine sulcus/V1 can occur in the adult brain. This change in connectivity was gradual and quite dramatic in term of the distance between these areas and the different functions they support. The fact that the tunnel vision subjects exhibited an intermediate pattern reinforces this idea and further suggests that it occurs not only after complete visual deprivation, but also in the context of partial visual loss. These observations strengthen arguments from the field of stroke rehabilitation where musical stimulation [START_REF] Särkämö | Music listening enhances cognitive recovery and mood after middle cerebral artery stroke[END_REF] as well as noninvasive stimulation devices [START_REF] Pino | Modulation of brain plasticity in stroke: a novel model for neurorehabilitation[END_REF] enhanced recovery in aphasia, probably by influencing the way information is processed in alternative networks. Taken together, these data imply that following input loss or damage to a certain network, the adult brain preserves the ability to functionally connect with other networks and to potentially optimize their performance. Nevertheless, the challenge of selecting the appropriate way to harness this functional connectivity for optimal behavioral recovery in such clinical conditions as stroke or visual restoration via retinalprosthesesisstilltobeaddressed. It is also not clear whether these changes are compensatory in nature or whether they simply underlie connections in the adult brain and furnish the 'raw material' for task-related compensatory plasticity.

Limitations and methodological considerations

Rs-fMRI is an invaluable sensitive tool to detect changes in brain connectivity [START_REF] Fox | Clinical applications of resting state functional connectivity[END_REF][START_REF] Guerra-Carrillo | Resting-state fMRI: a window into human brain plasticity[END_REF][START_REF] Smith | Correspondence of the brain's functional architecture during activation and rest[END_REF]. However, it should be mentioned that this method is subject to reliability problems induced by movement (a main confound) but also by mind wandering, or wakefulness state (Caceres et al., 2009;Tagliazucchi et al., 2012;van Dijk et al., 2012). This is why we took extra measures in order to control for head movement and verify that there was no significant difference in head movements between the groups. In our study, this method allowed us to delineate regions that are classically activated in functional language tasks and also belong to the intrinsic language network [START_REF] Bookheimer | Functional MRI of language: new approaches to understanding the cortical organization of semantic processing[END_REF][START_REF] Hagoort | On Broca, brain, and binding: a new framework[END_REF][START_REF] Hampson | Detection of functional connectivity using temporal correlations in MR images[END_REF][START_REF] Johnson | The role of the human thalamus in language and memory: evidence from electrophysiological studies[END_REF][START_REF] Price | The anatomy of language: a review of 100 fMRI studies published in[END_REF][START_REF] Yetkin | A comparison of functional MR activation patterns during silent and audible language tasks[END_REF] supporting that our analysis is valid. Moreover, it allowed the identification of specific functional connectivity between Broca's area and V1. This result points toward probable plastic changes induced by visual loss. However, our approach does not allow a direct inference about the role of the increased FC between Broca's area and V1. Other approaches, such as language task-based fMRI (Burton et al., 2002a[START_REF] Burton | Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people[END_REF]Bedny et al., 2011Bedny et al., , 2012) ) or transcranial magnetic resonance [START_REF] Amedi | Early "visual" cortex activation correlates with superior verbal memory performance in the blind[END_REF] could provide complementary data to accurately establish the origin and the influence of this connectivity on processes that involve Broca's area. It should be noted that the limited availability of such relatively rare homogenous blind and tunnel vision subjects prevented us from extending the protocol to include these behavioral tasks or other interesting experiments such as retinotopy, at least not in this point of time. For instance, a retinotopy experiment in RP tunnel vision subjects would allow us to design seeds of different portions of V1 (i.e. underlying the projections of normal central and deprived peripheral visual field) and give an insight on the cross-modal FC changes occurring in their brain.

We should also specify that information on disease onset is lacking and therefore was not used as a covariate in our analysis. Indeed, in clinical practice, it is very hard to define the onset of RP because of fading and filling-in processes that could hide scotoma for years after the disease onset (see Pessoa and De Weerd, 2003).

As previously described in the discussion, several studies support that negative FC reflect a physiological neuronal processing [START_REF] Behzadi | A component based noise correction method (CompCor) for BOLD and perfusion based fMRI[END_REF][START_REF] Chai | Selective development of anticorrelated networks in the intrinsic functional organization of the human brain[END_REF]Fox et al., 2005;[START_REF] Guerra-Carrillo | Resting-state fMRI: a window into human brain plasticity[END_REF][START_REF] Logothetis | How not to study spontaneous activity[END_REF][START_REF] Shmuel | Sustained negative BOLD, blood flow and oxygen consumption response and its coupling to the positive response in the human brain[END_REF][START_REF] Shmuel | Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1[END_REF][START_REF] Shulman | Common blood flow changes across visual tasks: II. Decreases in cerebral cortex[END_REF]Zeharia et al., 2012) and may even have a role in cases of mental disorders [START_REF] Whitfield-Gabrieli | Default mode network activity and connectivity in psychopathology[END_REF]. Nevertheless, the interpretation of the negative correlation is subject to debate (Buckner et al., 2013). Indeed, several noise removal methods such as global signal regressions are believed to introduce false negative Murphy et al., 2009). These preprocessing methods were not used in our study, which give us some confidence in the data interpretation. Additionally, note that we did not record breathing or pulse during the scan but that their frequencies were regressed out by the bandpass filtering preprocessing step.

Conclusion

The findings presented here showed increased functional connectivity between language and visual areas, which strengthened with the progression of RP from tunnel vision to complete blindness. The data suggest that the changes observed between the language and the visual areas depend on the topography of the functionally deprived regions. These results contribute to the debate on claims concerning a sensitive period for the development of cross-modal mechanisms between language and visual areas, at least in the context of large-scale functional connectivity patterns between areas.

Future studies could address (1) the functional recruitment of foveal V1 for language processing in central visual deficits (e.g. in age macular degeneration and Stargardt disease), ( 2) the behavioral counterparts of the functional connectivity changes observed in the present study, and their applicability to visual restoration (e.g. using retinal prosthesis) and substitution (e.g. using sensory substitution devices) processes (3) the functional connectivity changes of different regions (as seed) of V1 and the rest of the brain across populations.

Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.neuroimage.2016.04.056.

  primaire recevant les projections de la partie centrale » et périphérique champ visuel 10 CHAPTER 0. [RÉSUMÉ]

Synoptique 12 CONTENTS 3 . 2 . 3 2 1

 123231 Cerebral plasticity and MRI . . . . . . . . . . . . . . . . . . . . . . 3.2.4 Cerebral plasticity in early blindness . . . . . . . . . . . . . . . . . 3.2.5 Cerebral plasticity in late blindness . . . . . . . . . . . . . . . . . . 3.2.6 Plasticity in partial visual loss . . . . . . . . . . . . . . . . . . . . . 3.2.7 Visual input and peculiar perceptive phenomena . . . . . . . . . . . Functional changes: "Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss"* Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 MRI protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Visual loss models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 3 -

 3 Figure 3 -The evolutionary origin of retinal neuronal cells in human retina.Data from molecular comparative cell biology points that photoreceptors (rods and cones) evolved from a common ciliary photoreceptor precursor while horizontal, amacrine and ganglion cells evolved from a common rhabdomeric photoreceptor precursor. The origin of bipolar cells is uncertain, but it might also be derived from a ciliary precursor (modified from Arendt 2003; Lamb 2013).

Figure 5 -

 5 Figure 5 -Various eyes designs. A. The compound eye of the dragonfly. 1.Macroscopic view -note the smaller and more densely packed omatidia ("little eyes") placed frontally and offering a better spatial acuity. 2 Microscopic view -the corneal lens has been lost. Note the cristaline cone (CC) that focuses the light, the iris pigment (IPC) that prevent light from spilling across adjacent cells, the rhabdomeric photoreceptor cells (RC) and the rhabdom (Rh), formed by the microvilli of several adjacent receptor cells and acting like a fiber optic cable. B. Bony fish eye. 1. Macroscopic view -note the spheric lens, the falciform process providing nutrition to the inner retina, the choroidal gland providing nutrition to the outer retina and the scleral ossicles that evolved to strengthen the eye wall. 2. Microscopic view -note the thin retina and the choroid gland. C. Reptilian eye. 1. Macroscopic view -note the different shape of the lens and the conus (red arrow) a structure derived from the hyaloid artery that is responsible for the nutrition of the inner retina. 2. Microscopic view -note the cartilaginous coup (yellow arrow), the thicker retina and the optic nerve (ON). D. Avian eye. 1. Macroscopic view -note the flattened shape and the pectin a vascular structure similar to the reptilian conus and responsible for eye's thermoregulation and the nutrition of the inner retina. 2. Microscopic view -note the thick steep fovea that allow for a supplementary "telescopic" magnification of the image. E. Monotreme eye. 1. Macroscopic view -note the presence of a cartilaginous cup in the sclera (like in the reptilian eye) and the thick choroid. The eye is spherical; the current flattened image is a preparation artifact. 2 Microscopic view -note the thick choroid; Ph -photoreceptors, Gang -ganglion cells. Interestingly, cones in monotremes are bothsimple and double with some double cones presenting, as in reptiles, eye droplets that contribute in discrimination and spatial tuning (not shown). F. Human eye. 1. Macro schematics of the human eye. 2. Microscopic view of the fovea -the depression and the lateral displacement of the neural cells allows a direct exposure of photoreceptors and the avoidance of light scattering. G. Human eye fundus and macular reflexes. 1. The exterior annular reflex demarcates the ridge of the pit; the central reflex -a reflected telescope-like image of the incident light, due to the concave shape of the fovea. 2. Loss of ganglion cells axons in optic nerve atrophy flattens the ridge of the macula inducing the disappearance of the central reflex and the distortion of the annular reflex. (modified from[START_REF] Safran | Macular reflexes in optic atrophy[END_REF][START_REF] Schwab | Evolutions's Witness[END_REF]

Figure 6 -

 6 Figure 6 -Visual information from the visual input to the emergence of visual percepts(from Nassi and Callaway 2009)

Figure 7 -

 7 Figure 7 -Central nervous system evolution. A. Comparison between different metazoan nervous systems and body plans. B. Different scenarios for the evolution of nervous system in bilaterians. C. Conservation of brain divisions in vertebrates. aobaccessory olfactory bulb , cb -cerebellum, ch, cerebral hemispheres, m -medula oblongata, ob -olfactory bulb, ot -optic tectum, p -pituitary gland (modified from Hollandet al. 2013 and Northcutt, 2002).

Figure 8 -

 8 Figure 8 -Cones and rods retinal distribution in humans. I. Note the variable distribution in L, M and S cones in two different individuals. II. A. Cone densities over the entire retina. Detail -foveal cones densities. B. Rod densities over the entire retina.Detail -central slope of rod ring and the foveal rod-free zone. C. Rods : cones ratio in the retina[START_REF] Curcio | Human photoreceptor topography[END_REF]. D. The classical diagram of Osterberg with cone and rods distribution over the horizontal meridian (1 -fovea centralis, 2-optic disk, 3 -ora serrata) (modified from[START_REF] Dacey | Parallel Pathways for Spectral Coding in Primate Retina[END_REF][START_REF] Curcio | Human photoreceptor topography[END_REF][START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF].

Figure 9 -

 9 Figure 9 -Cone circuitry. Midget pathways for fovea and peripheral retina (parvocellular); S-cones pathways (koniocellular) and parasol pathway (magnocellular). Hhorizontal cell; DB -diffuse bipolar cell (modified from Dacey 2000).

Figure 11 -

 11 Figure 11 -Retinocortical connections potentially involved in blindsight.Thick, gray arrow depicts the lemnothalamic pathway that projects to V1. Red arrows mark projections originating in superior colliculus and reaching the dorsal cortical stream through a thalamic relay in the pulvinar. Green arrows indicate projection from specific pulvinar subnuclei to areas of the ventral cortical stream. Blue arrow marks the projections from koniocellular layers of lateral geniculate nucleus to middle temporal area. Color codes in lateral geniculate and superior colliculs: yellow -magnocellular, blue -koniocellular, pink -parvocellular channels. In pulvinar the segregation of the channels in unclear and depicted in blue-yellow and pink-yellow gradients. LGN -lateral geniculate nucleus; MT -middle temporal; Plcl -pulvinar inferior centro-lateral; Plcm -pulvinar inferior centromedial; Plm -pulvinar inferior medial; Plp -pulvinar inferior posterior; PLdm -pulvinar lateral dorso-medial; PLvl -pulvinar lateral ventro-lateral; PM -pulvinar medial; TEtemporal inferior rostral; TEO -temporal inferior posterior (from Tamietto and Morrone 2016).

Figure 13 -

 13 Figure 13 -Afferences and efferences of the superior colliculus. A. Collicular retinotopy of the left hemifield in macaque monkey. Color code: grey -ipsilateral connections; red contralateral connections. Note the bilateral projections of the hemifield with predominance of contralateral connections. B. The afferent connections of the superior colliculus. Afferences to the superficial layers are depicded on the left half of the brainstem diagram; afferences to intermediate layers are depicted in the intermediate layers. Red arrows mark inhibitory connections. C. The efferent connections of the superior colliculus. Color code: grey arrows -efferent connections from the superficial layers; red arrows -efferent connections from the intermediate layers. D. Detail with the superficial (grey), intermediate (red) and profound layers of the superior colliculus. CN -cerebellar nuclei; EBC -excitatory burst cells; FF -frontal eye field; Hor -horizontal meridian; IBC -inhibitory burst cells; Ice -external nucleus of the inferior colliculus; ILK -intralaminar thalamic nuclei; Int Cajal -interstitial nucleus of Cajal; LGB -lateral geniculate body; MAOc -caudal part of medial accessory olive; MD -mediodorsal thalamic nucleus; Mon -monocular periphery projection (only contralateral projections); MST -medial superior temporal visual area; MT middle temporal visual area; nu.ped.pont -nucleus pedunculopontinus; NOT -nucleus of the optic tract; parabig -parabigeminal nucleus; NRTP -nucleus reticularis tegmenti pontis; parabig -parabigeminal nucleus; PF -parietal eye field; prep. hyp. -prepositus hypoglossi; pretect -pretectum; RI -nucleus raphe interpositus; riMLF -rostral interstitial nucleus of the medial longitudinal fasciculus; s.alb.int, s.gris.int -intermediate gray layers; s.gris.sup -superficial gray layer; s. prof -deep layers; SCi -intermediate layers; SCs -superficial layers; SF -supplementary frontal eye field; s.ret.mes -reticular formation of the mesencephalon; staderini -nucleus intercalatus of Staderini; tr.opt -optic tract; V princeps -principal trigeminal sensory nucleus; V spin -trigeminal spinal nucleus; V -trigeminal nerve. V1/ V2 -early visual cortex (from Nieuwenhuys et al. 2008)

Figure 14 -

 14 Figure 14 -Ventral and dorsal visual streams. A, B. Boundaries and retinotopical organization of visual areas. A -lateral view; B -medial view. C -Diagram of the visual field. Dotted line codes the vertical meridian and the dashed line the horizontal meridian. Note correspondent retinotopic representation of meridians in A. D. Diagram of the dorsal and ventral visual streams.Color code: red -dorsal stream; gray -ventral stream; black -V1; dark gray -V2. E. Diagram of the origin of dorsal and ventral streams. Both ventral and dorsal stream originate in V1 or V2. Magnocellular (black, M, m), parvocellular (red, P,p) and koniocellular (red contour, K, k ) pathways originate in the correspondent layers of the lateral geniculate body (LGB). Main direct and indirect projections of M pathway end up in V1 layers 4C and 4B. From 4B M pathway projects onto the thick stripes of V2 and onto middle temporal area (MT) of the dorsal stream. M, P and K pathways combine in the and interblobs of V1's layer 2/3. Thus, local projections (i) and remote projections of layer 2/3 via the thin and thick layers of V2 into dorsal and ventral stream carry mixed M, P and K signals. The intrinsic connections are shown for one ocular dominance column (odc). Meynert cells, involved in motion detection and located in small clusters in the V1's L5/L6 layers boundary, in the region containing the representation of the far periphery projects both to superior colliculus and MT area. K pathway also send direct projections to MT area. AIP-anterior parietal area; FFA -fusiform face area; inf.par.lob -inferior parietal lobule; LIP -lateral intraparietal area; LO -lateral occipital area; MST -medial superior temporal visual area; MIP -medial intraparietal area; PEip intraparietal part of area PE; STP -superior temporal polysensory area; sup.par.lob-superior parietal lobule; TE -inferior temporal area; V1-V6A, V8 -visual areas; VIP -visual intraparietal area (from[START_REF] Nieuwenhuys | Visual system. In Hum. cent. nerv. syst. (Forth[END_REF].

Figure 18 -

 18 Figure 18 -Diagram depicting the three stages of retinal degeneration and consecutive retinal reorganization. (a) normal lamination and connectivity of retinal cells. (b) Stage 1 -photoreceptor stress; outer segments shortening; rod, cone and horizontal cells neurite projections to the inner retina; dendrite retraction in rod and cone bipolar cells; early stage of Müller cells hypertrophy. (c) Stage 2 -complete photoreceptor loss and elaboration of Müller cells seal between retina and choroid. (d) Early stage 3 -complex neurites extensions evolved in complex tangles called microneurinomas and formed by GABAergic and glycinergic amacrine cells, bipolar and ganglion cells. Microneurinomas exhibit active synapses corruptive of normal signalling. (e) Late stage 3 -final stage exhibiting degeneration and death of various retinal cells; note the bidirectional cell migration from inner nuclear and ganglion cell layers. Color code: yellow -Müller cells; orange -normal photoreceptors; light orange -degenerated photoreceptors (b); light blue -cone bipolar cells; dark blue -rod bipolar cells; dark green -horizontal; light green glycinergic amacrine cells; red -GABAergic amacrine cells; violet ganglion cells (from Jones and Marc 2005)

Figure 19 -

 19 Figure 19 -Anatomical and functional plasticity in early blind. I. Long-range projections. II. Inter-hemispheric connections. Colour code: orange -increase in anatomical connectivity; teal -decrease in anatomical connectivity; red -increase in functional correlations; blue -decrease in functional correlations. Method abbreviations (yellow): AD -axial diffusivity; FA -fractional anisotropy; RD -radial diffusivity; WMV -white matter volume. Regions abbreviations (white): AT -anterior temporal cortex; CST -corticospinal tract; FG -fusiform gyrus; IFG -inferior frontal gyrus; IOG -inferior occipital gyrus; IPC -intraparietal cortex; IPS -intraparietal sulcus; LGN -lateral geniculate nucleus; LING -lingual gyrus; LO -lateral occipital area; MD -medial dorsal nucleus; MFG -middle frontral gyrus; MOG -middle occipital gyrus; MT -middle temporal area; MTG -middle temporal gyrus; PCL -paracentral lobule; PreCG -precentral gyrus; PoCGpostcentral gyrus; PR -perirhinal cortex; ROL -rolandic cortex; SFG -superior frontal gyrus; SMA -supplementary motor area; SO -superior occipital cortex; SPC -superior parietal cortex; STG -superior temporal gyrus; V1 -Brodmann area 17; V2 -Brodmann area 18; V3 -Brodmann area 19; VL -thalamic ventral lateral nucleus (Bock and Fine 2014).

  al., 2000; Malikovic et al., 2007; Rottschy et al., 2007; Mohlberg et al., 2012; Kujovic et al., 2013; Caspers et al., 2013; Lorenz et al., 2015; Rosenke et al., 2017). CoTks and rs-CoEn extracted from each of these regions were used to perform group comparisons.

1 Sorbonne

 1 Universités, UPMC Université Paris 06, UMR S968, Institut de la Vision, Paris, F-75012, France. 2 INSERM, U968, Institut de la Vision, Paris, F-75012, France. 3 CNRS, UMR 7210, Institut de la Vision, Paris, F-75012, France. 4 Centre d'investigation clinique, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DGOS CIC 1423, Paris, F-75012, France.

Figure 1 .

 1 Figure 1. Intra-group analysis of functional connectivity seeded from the central EVC (peripheral EVC regressed). he maps are shown in mesh for the (A) aferented central EVC (normal vision); * the dotted line on the medial aspect of the brain represents the seed region (central EVC) (B) isolately aferented central EVC (retinitis pigmentosa tunnel vision) (C) deaferented central EVC (Stargardt macular dystrophy). Yelloworange depicts areas of higher positive functional connectivity for each group, and green-blue higher negative functional connectivity. LH: let hemisphere, RH: right hemisphere. Ant. hal.: anterior thalamus; Cing. S: cingulate sulcus; Cn: cuneus; Fus. G: fusiform gyrus; IFG: inferior frontal gyrus; Ins.: Insula; IOG: inferior occipital gyrus; IPL: inferior parietal lobule; IPS: intraparietal sulcus; ITG; inferior temporal gyrus; Ling. G: lingual gyrus; MFG: middle frontal gyrus; MOG: middle occipital gyrus; ParaH. G: parahippocampal gyrus; Pcn: precuneus; Post.hal.: posterior thalamus; PrCG: precentral gyrus; PoCS: postcentral sulcus; SFG: superior frontal gyrus; SPL: superior parietal lobule.

Figure 2 .

 2 Figure 2. Intra-group analysis of functional connectivity seeded from the peripheral EVC (central EVC regressed). he maps are shown in mesh for the (A) aferented peripheral EVC (normal vision); * the dotted line on the median aspect of the brain represents the seed region (peripheral EVC) (B) isolated aferented peripheral EVC (Stargardt macular dystrophy) (C) deaferented peripheral EVC (retinitis pigmentosa tunnel vision). Yellow-orange depicts areas of higher positive functional connectivity for each group, and green-blue higher negative functional connectivity. LH: let hemisphere, RH: right hemisphere. aCC: anterior cingulate cortex; CS: central sulcus; Cn: cuneus; Fus. G: fusiform gyrus; IFG: inferior frontal gyrus; IFS: inferior frontal sulcus; Ins.: insula; IOG: inferior occipital gyrus; IPL: inferior parietal lobule; IPS: intraparietal sulcus; ITG: inferior temporal gyrus; ITS: inferior temporal sulcus; Ling. G: lingual gyrus; LOC: lateral occipital complex; MFG: middle frontal gyrus; MOG: middle occipital gyrus; Pcn: precuneus; PrCS: precentral sulcus; Post.hal.: posterior thalamus; PrCG: precentral gyrus; PoCS: postcentral sulcus; SFG: superior frontal gyrus; SFS: superior frontal sulcus; SOG: superior occipital gyrus; SPL: superior parietal lobule STG: superior temporal gyrus; STS: superior temporal sulcus; V5/hMT+ : V5/human MT+ .

Figure 3 .

 3 Figure 3. Between-group analysis of functional connectivity seeded from the central EVC (peripheral EVC regressed). he maps are shown in mesh for (A) retinitis pigmentosa tunnel vision vs. normal vision (B) Stargardt macular dystrophy vs. normal vision (C) Stargardt macular dystrophy vs. retinitis pigmentosa tunnel vision (yellow-orange depicts areas of higher positive/lower negative functional connectivity with the central EVC for the irst group compared to the second, and green-blue the opposite comparison; LH: let hemisphere, RH: right hemisphere). aCC: anterior cingulated cortex; aMTG: anterior middle temporal gyrus; Cn: cuneus; Fus. G: fusiform gyrus; SPL: superior parietal lobule; IPL: inferior parietal lobule; IOG: inferior occipital gyrus; MOG: middle occipital gyrus; MTG: middle temporal gyrus; Pcn: precuneus; PoCG: postcentral gyrus POS: parieto-occipital sulcus; STG: superior temporal gyrus; SMG: supramarginal gyrus.

Figure 4 .

 4 Figure 4. Between-group analysis of functional connectivity seeded from the peripheral EVC (central EVC regressed). he maps are shown in mesh for (A) retinitis pigmentosa tunnel vision vs. normal vision (B) Stargardt macular dystrophy vs. normal vision (C) Stargardt macular dystrophy vs. retinitis pigmentosa tunnel vision (yellow-orange depicts areas of higher positive/lower negative functional connectivity with central EVC for the irst group compared to the second, and green-blue the opposite comparison; x, y, z are Talairach coordinates; LH: let hemisphere, RH: right hemisphere). aCC: anterior cingulate cortex; aMFG: anterior middle frontal gyrus; aMTG: anterior middle temporal gyrus; Cn: cuneus; CS: central sulcus; Fus. G: fusiform gyrus; Ling. G: lingual gyrus; LOC: lateral occipital complex; IOG: inferior occipital gyrus; ITG: inferior temporal gyrus; IPL: inferior parietal lobule; MFG: middle frontal gyrus; MOG: middle occipital gyrus; MTG: middle temporal gyrus; ParaH G: parahippocampal gyrus; Pcn: precuneus; pMFG: posterior middle frontal gyrus; PoCG: postcentral gyrus; POS: parieto-occipital sulcus; SFG: superior frontal gyrus; SMG: supramarginal gyrus; SOG: superior occipital gyrus; SPL: superior parietal lobule; STG: superior temporal gyrus; STS: superior temporal sulcus.

Figure 5 .

 5 Figure 5. Intra-group analysis of functional connectivity seeded from the let hemisphere S1 lip area (S1 foot area regressed). he maps are shown in mesh for the (A) aferented peripheral EVC (normal vision) (B) isolated aferented peripheral EVC (Stargardt macular dystrophy) (C) deaferented peripheral EVC (retinitis pigmentosa tunnel vision). Yellow-orange depicts areas of higher positive connectivity for each group, and green-blue higher negative connectivity. LH: let hemisphere, RH: right hemisphere. Cn: cuneus; Fus. G: fusiform gyrus; IFG: inferior frontal gyrus; Ins.: Insula; IOG: inferior occipital gyrus; IPL: inferior parietal lobule; IPS: intraparietal sulcus; STG: superior tempral gyrus; ITG: inferior temporal gyrus; Ling. G: lingual gyrus; IFG: inferior frontal gyrus; MOG: middle occipital gyrus; Pcn: precuneus; PrCG: precentral gyrus; PoCG: postcentral gyrus; MTG: middle temporal gyrus; LOC: lateral occipital complex; aCC: anterior cinulate cortex; pCC: posterior cingulate cortex; SFG/SFS: superior frontal gyrus/sulcus.

Figure 6 .

 6 Figure 6. Intra-group analysis of functional connectivity seeded from the let hemisphere S1 foot area (S1 lip area regressed). he maps are shown in mesh for the (A) aferented peripheral EVC (normal vision) (B) isolated aferented peripheral EVC (Stargardt macular dystrophy) (C) deaferented peripheral EVC (retinitis pigmentosa tunnel vision). Yellow-orange depicts areas of higher positive connectivity for each group, and green-blue higher negative connectivity. LH: let hemisphere, RH: right hemisphere. EVC: early visual cortex; Cn: cuneus; RTC: retrosplenial cortex; Fus. G: fusiform gyrus; IFG: inferior frontal gyrus; Ins.: Insula; IOG: inferior occipital gyrus; SPL: superior parietal lobule; IPS: intraparietal sulcus; Ling. G: lingual gyrus; IFG: inferior frontal gyrus; MOG: middle occipital gyrus; SOG: superior occipital gyrus; LS: lateral sulcus; STG: superior temporal gyrus; Pcn: precuneus; PrCG: precentral gyrus; PoCG: postcentral gyrus; MTG: middle temporal gyrus; LOC: lateral occipital complex; aCC: anterior cinulate cortex; pCC: posterior cingulate cortex. CS: central sulcus.

Figure 7 .

 7 Figure 7. Between-group analysis of functional connectivity seeded from the let hemisphere S1 lip area (S1 foot area regressed). he maps are shown in mesh for (A) retinitis pigmentosa tunnel vision vs. normal vision (B) Stargardt macular dystrophy vs. normal vision (C) Stargardt macular dystrophy vs. retinitis pigmentosa tunnel vision (yellow-orange depicts areas of higher positive/lower negative functional connectivity with S1 lip area for the irst group compared to the second, and green-blue the opposite comparison; LH: let hemisphere, RH: right hemisphere). SPL: superior parietal lobule; STG: superior temporal gyrus; MTG: middle temporal gyrus; EVC: early visual cortex; IFS: inferior frontal sulcus; IPS: intraparietal sulcus; CG: central gyrus.

Figure 8 .

 8 Figure 8. Between-group analysis of functional connectivity seeded from the let hemisphere S1 foot area (S1 lip area regressed). he maps are shown in mesh for (A) retinitis pigmentosa tunnel vision vs. normal vision (B) Stargardt macular dystrophy vs. normal vision (C) Stargardt macular dystrophy vs. retinitis pigmentosa tunnel vision (yellow-orange depicts areas of higher positive/lower negative functional connectivity with S1 foot area for the irst group compared to the second, and green-blue the opposite comparison; LH: let hemisphere, RH: right hemisphere). SPL: superior parietal lobule; PoCG: post central gyrus; STG: superior temporal gyrus; Fus. G: fusiform gyrus; Ling. G: lingual gyrus; MOG: middle occipital gyrus; EVC: early visual cortex; Cn: Cuneus.

Figure 9 .

 9 Figure 9. Summary of the main results of the FC analysis seeding peripheral and central EVC. he main FC results are shown for the comparison between (A). retinitis pigmentosa tunnel vision or (B). Stargardt macular dystrophy and normal vision. Small circles indicate regions of the EVC coding for the central projection of the retina, large circles indicate regions of the EVC coding for the peripheral projection of the retina. Green depicts aferented areas of the EVC. Black depicts deaferented areas of the EVC. Red arrows indicate positive FC between areas at the intra-group level and blue arrows negative FC between areas at the intra-group level. he arrow thickness indicates the level of FC at the intra-group level. Stars indicate statistical signiicance at p < 0.05 for the FC between groups. LH: let hemisphere, RH: right hemisphere. MFG: middle frontal gyrus; STG/ STS: Superior temporal gyrus/sulcus; Cn: cuneus; Fus. G: fusiform gyrus; Ling. G: lingual gyrus; LOC: lateral occipital complex; IOG: inferior occipital gyrus; ITG: inferior temporal gyrus; IPL: inferior parietal lobule; MFG: middle frontal gyrus; MOG: middle occipital gyrus; ParaH G: parahippocampal gyrus; Pcn: precuneus; POS: parieto-occipital sulcus; SOG: superior occipital gyrus.

Figure S5 .

 S5 Figure S5. Intra-group analysis of functional connectivity seeded from I. The central and II. The peripheral EVC (without regression). The maps are shown in mesh. Yellow-orange depicts areas of higher positive functional connectivity for each group, and green-blue higher negative functional connectivity. I. The rs-FC seeded from the central EVC: (A) the afferented central EVC (normal vision) (B) the isolated afferented central EVC (retinitis pigmentosa tunnel vision) (C) the deafferented central EVC (Stargardt macular dystrophy) II. The rs-FC seeded from the peripheral EVC:(A) the afferented central EVC (normal vision) (B) the isolated afferented central EVC (retinitis pigmentosa tunnel vision) (C) deafferented central EVC (Stargardt macular dystrophy). Yelloworange depicts areas of higher positive functional connectivity for each group, and green-blue higher negative functional connectivity. Dashed lines: probable false positive correlations; solid lines: the likely origin of the positive correlations. Red lines: areas that differ with vs. without the partial correlation method in normal vision. Green lines: areas that differ with vs. without the partial correlation method in Stargardt macular dystrophy. Blue lines: areas that differ with vs. without the partial correlation method in retinitis pigmentosa tunnel vision (see also Figure1). Cn: cuneus; IOG: inferior occipital gyrus; IPL: inferior parietal lobule; MTS: middle temporal sulcus; MOG: middle occipital gyrus. pMTG: posterior middle temporal gyrus. aMTG: anterior middle temporal gyrus.

Figure S6 .

 S6 Figure S6. Between-group analysis of functional connectivity seeded from I. The central and II. The peripheral EVC (without regression). The maps are shown in mesh. Yellow-orange depicts areas of higher positive/lower negative functional connectivity with I. The central EVC or II. The peripheral EVC for the first group compared to the second, and green-blue the opposite comparison. I. Seeded from the central EVC: (A) retinitis pigmentosa tunnel vision vs. normal vision (B) Stargardt macular dystrophy vs. normal vision (C) Stargardt macular dystrophy vs. retinitis pigmentosa tunnel vision. II. seeded from the peripheral EVC: (A) retinitis pigmentosa tunnel vision vs. normal vision (B) Stargardt macular dystrophy vs. normal vision (C) Stargardt macular dystrophy vs. retinitis pigmentosa tunnel vision. Green arrowheads show lack of differences in rs-FC compared to the partial correlation analysis.

Figure S7 .

 S7 Figure S7. Correlation between functional and anatomical localizers at the individual level. Two individual subjects were randomly selected from each group. For each individual subject, Pearson correlation tests (R) were run to test for time courses correlation between seed regions defined based on external functional localizers and seed regions defined based on anatomical localizers (as defined by 7-mm spheres on A. posterior or B. anterior portions of the calcarine sulcus). Yellow depicts areas defined by the functional localizers whereas blue depicts areas defined by the anatomical localizers on the f MRI slices from each individual. S: sighted control subjects, RPTV: subjects with retinitis pigmentosa tunnel vision, SMD: subjects with Stargardt macular dystrophy.

Figure 22 -

 22 Figure 22 -Comparative display of structural and functional connectivity data in central visual loss (Stargardt macular dystrophy) vs normally sighted.Regions are indicated through arrowheads filled with colors that correspond to the associated cytoarchytectonic area. Arrow border is colored magenta for the correspondence decreased CoTks -decreased functional connectivity and red for the correspondence decreased CoTks -decreased functional connectivity

FIGURE 1 |

 1 FIGURE 1 | Francis Bacon-Self-portrait 1971. Centre Georges Pompidou, Paris, France. © The Estate of Francis Bacon/All rights reserved/ADAGP, Paris 2014.

  synesthesia. Insight into perception, emotion, and consciousness Avinoam B. Safran a,b and Nicolae Sanda a,c

a

  Sorbonne Universite ´s, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, INSERM, U968, CNRS, UMR_7210, Paris, France, b Department of Clinical Neurosciences, Geneva University School of Medicine, Geneva, Switzerland and c Neurology Department, Ho ˆpital Foch, Suresnes, Paris, France Correspondence to Avinoam B. Safran, MD, 17 rue Moreau, Paris, F-75012, France. E-mail: avinoam.safran@unige.ch Curr Opin Neurol 2015, 28:36-44 DOI:10.1097/WCO.0000000000000169

  Affected individuals demonstrate distinct patterns in cerebral activation and connectivity, compared with nonsynesthetes.Acquired forms of synesthesia are commonly related to drug ingestion or neurological conditions.Color synesthesia Safran and Sanda 1350-7540 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

FIGURE 1 .

 1 FIGURE 1. Visual segregation test demonstrating improved digit identification performances by grapheme-color synesthetes.(a) Pattern presented to the tested individuals and (b) same pattern as perceived by a grapheme-color synesthete. To identify digits '2', a person with regular visual perception must perfom a systematic search; in contrast, for a grapheme-color synesthete, who links a specific color with a given number, digits '2' instantly pop-out. Adapted with permission[27].

FIGURE 4 .

 4 FIGURE 4. 'I and the Village' 1911, by Marc Chagall. Museum of Modern Art, New York, USA. Reproduced with permission, ß Adagp, Paris 2014. Over decades, Chagall repeatedly depicted using intense green or blue colors, the faces of central characters in his paintings[58]. This most probably reflected a variant of personality-color synesthesia.

FIGURE 5 .

 5 FIGURE 5. 'Half-Past Three' ('The Poet') 1911, by Marc Chagall. Philadelphia Museum of Art, The Louise and Walter Arensberg Collection, Philadelphia, PA, USA. Reproduced with permission, ß Adagp, Paris 2014. For comments, see the legend of Fig. 4.

N

  . Ajili a , J. P. Decroix a , C. Preda b , J. Labreuche c , D. Lopez a , Y. Bejot d , P. Michel e , M. S evin-Allouet f , I. Sibon g , S. Vergnet g , A. Wang a , N. Sanda a , M. Mazighi h , F. Bourdain a and B. Lapergue a

  Correspondence: B. Lapergue, Division of Neurology, Stroke Centre, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Suresnes, France (tel.: +33 1 46 25 73 43; fax: +33 1 46 25 27 24;

  blood pressure values and a lower time from symptom onset to admission than non-IV-rtPA-treated patients (all P < 0.05). However, IV-rtPA-treated patients had one point difference in baseline NIHSS than non-IV-rtPA-treated patients [median (IQR): 8(6)(7)(8)(9)(10)(11)(12) vs. 7 (6-10), P < 0.001]. Amongst 488 patients without occlusion included in the study, 188 were not treated by IV-rtPA. The details are 50 (27%) because of local protocol of treatment indicating no fibrinolysis in the case of no documented arterial occlusion; 19 (10%) were on oral anticoagulants and 119 (63%) were assessed after the time window for rtPA treatment of 3 h until the ECASS-III trial publication in 2008 or after 4.5 h after 2008.

Figure 1

 1 Figure1Clinical efficacy outcomes in IV-rtPA-treated and control groups, overall and according to lacunar stroke subtype. *Adjusted for antithrombotic therapy, prior stroke history, admission systolic blood pressure, diastolic blood pressure, National Institutes of Health Stroke Scale, pre-stroke Rankin ≥1, lacunar stroke aetiology and time to admission from symptom onset. P values for heterogeneity between lacunar and non-lacunar stroke (P het) are reported. CI, confidence interval; IV, intravenous; OR, odds ratio; rtPA, recombinant tissue plasminogen activator.

Figure 2

 2 Figure 2 Meta-analysis pooling the available adjusted odds ratios (ORs) of favourable outcome. *This paper; calculated after excluding the 236 overlapping participants in the Medlin et al. publication.

Fig. 1 .

 1 Fig.1. Within-group analysis of functional connectivity seeded from Broca's area. The maps are shown in fMRI full-slice view (neurological convention) for (A) Sighted controls, (B) RP tunnel vision, (C) RP blind subjects. Colors depict the magnitude of the FC of Broca's area localizer and the rest of the brain: yellow-orange for positive FC and green-blue for negative FC. X, Y, Z are in Talairach coordinates. In all groups, the inferior frontal Broca's area is functionally connected to the anterior cingulate, left supramarginal gyrus (e.g. Wernicke's area), subcortical regions (e.g. bilateral insula, thalamus), superior temporal auditory regions and bilateral fronto-parietal regions. (A) The sighted control subjects show a strong negative FC of Broca's area with major ventral and dorsal visual areas (i.e. along the calcarine sulcus/lingual, cuneus, inferior occipital, middle occipital, parahippocampal, restrosplenial, fusiform, and inferior temporal gyri) and medial part of the superior frontal gyrus. (B) RP tunnel vision subjects show almost no negative FC of Broca's area with calcarine sulcus/cuneus but still preserve a negative FC with the inferior occipital, middle occipital, lingual, parahippocampal, restrosplenial, fusiform, and inferior temporal gyri. (C) RP blind subjects show positive FC of Broca's area with the calcarine sulcus/cuneus and lose almost all negative functional connectivity with the other extrastriate visual areas.

7 N.

 7 Sabbah et al. / NeuroImage xxx (2016) xxx-xxx Please cite this article as: Sabbah, N., et al., Increased functional connectivity between language and visually deprived areas in late and partial blindness, NeuroImage (2016), http://dx.doi.org/10.1016/j.neuroimage.2016.04.056 statistically significant difference for both the anterior and posterior regions of the calcarine sulcus and Broca's area between the RP blind and the sighted control subjects (p b 0.01; see Fig. 4A-B), and (2) a statistically significant difference solely for the anterior regions of the calcarine sulcus and Broca's area in the RP tunnel vision subjects and the sighted controls (p b 0.05; see Fig.4A).In the RP blind subjects, Pearson tests revealed no effect for age or blindness duration on the FC between Broca's area and the anterior calcarine sulcus/cuneus (age: R(9) = 0.32 p N 0.05; blindness duration: R(9) = 0.24 p N 0.05), posterior calcarine sulcus/cuneus (age: R(9) = 0.49 p N 0.05; blindness duration: R(9) = -0.14 p N 0.05), left inferior occipital gyrus (age: R(9) = -0.024 p N 0.05; blindness duration: R(9) = 0.18 p N 0.05), left fusiform gyrus (age: R(9) = 0.51 p N 0.05; blindness duration: R(9) = 0.094 p N 0.05), and left parahippocampal gyrus (age: R(9) = 0.23 p N 0.05; blindness duration: R(9) = -0.12 p N 0.05).

Fig. 4 .

 4 Fig. 4. Correlations between Broca's area and specific parts of the calcarine sulcus across populations (RP blind, RP tunnel vision, sighted control subjects). Correlations (R 2 Pearson test; mean z-score) of Broca's area with (A) left anterior or (B) left posterior calcarine sulcus was calculated for each group. Bars indicate between-subject standard error. (A) There was a group main effect for the correlation between the left anterior calcarine sulcus and Broca's area (ANOVA: F(2,32) = 13.59 p b 0.0001). Post-hoc tests (Scheffe) revealed significant differences between the RP blind and sighted control subjects' correlation coefficients (** p b 0.01), and between RP tunnel vision and sighted control subjects (* p b 0.05). (B) There was a main effect for the correlation between the groups for the left posterior calcarine sulcus and Broca's area (ANOVA: F(2,32) = 5.78 p b 0.01). Post-hoc tests (Scheffe) only revealed significant differences between the RP blind and the sighted control correlation coefficients (** p b 0.01). For each group, mean R 2 coefficients before Z transformation are mentioned.

sustain this concept. Figure 12 -Lemnothalamic pathway I. 3D

  ventral view of the retinogeniculocortical projections. II. Diagram of the retinogeniculocortical, extrageniculate and extrastriate visual pathways corresponding to A and depicting projections of the upper right visual field. In the cassette, detail from the lateral geniculate nucleus. III.

	Projections of the
	right visual field. A. On the left temporal and right nasal retina. B. V1 projections. Note
	the ocular dominance columns in the left primary visual cortex. Red codes contralateral
	projections, black codes ipsilateral projections; color intensity codes eccentricity: pale -far,
	monocular periphery (only contralateral projection); intermediate intensity -intermediate,
	binocular periphery; high intensity -central visual field (macular vision). Abreviations:
	M -magnocellular, P -parvocellular, K -koniocellular., MT -medial temporal;.Hor -
	horizontal meridian; Mon -monocular visual field, Vert -vertical meridian, * -blind spot
	projection (from Nieuwenhuys et al. 2008)

  Bonferroni corrected for multiple comparisons) are summarized in Table1and in the following paragraphs.

	= 3.882, p=
	0.03, hOc2 [F (2, 35) = 4.05, p= 0.026], hOc3d [F (2, 35) = 7.09; p= 0.003], hOc4d [F (2, 35) = 3.633; p= 0.037],
	hOc4v [F (2, 35) = 5.013; p= 0.012]. Left hemispheric regions did not differ significantly from right
	hemisphere regions [occipital LH, F (2, 35) = 2.873, p= 0.07; occipital RH, F (2, 35) = 2.716; p= 0.08]. Post-
	hoc independent-sample t-tests (

Table 2 . Cytoarchitectonic areas showing significant differences in resting-state cortical entropy. NS

 2 normally sighted; cVfL -central visual field loss (SMD); pVfL -peripheral visual field loss (RPTV).The significant differences are in BOLD.

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  , puisqu'elle démontre que la réorganisation concerne également le cortex afférenté et le cortex déafférénte, que leur réorganisation est différente, et qu'elle accompagne vraisemblablement des fonctions différentes.

	www.nature.com/scientificreports
	Résumé
	Scientific RepoRts | 7:43223 | DOI: 10.1038/srep43223	1

Table 1 . Subjects' clinical data

 1 the maximum head movement49 between the three groups (SMD: 0.29 ± 0.27 mm; RPTV: 0.16 ± 0.08 mm; sighted controls: 0.19 ± 0.18 mm; ANOVA F (2, 35) = 1.5; p = 0.23). We also performed a GLM analysis including the head movement predictors (control analysis; see Supplementary FiguresS1, S2, S3 and S4). Including movement predictors in the GLM did not change the main results.

					Age disease onset	Visual deicit
	Subject	Sex	Age	Cause of disease	(irst symptoms)	duration
	SMD1	F	39	Stargardt macular dystrophy	17	22
	SMD2	M	27	Stargardt macular dystrophy	23	4
	SMD3	F	47	Stargardt macular dystrophy	18	29
	SMD4	M	32	Stargardt macular dystrophy	15	17
	SMD5	M	18	Stargardt macular dystrophy	12	6
	SMD6	F	56	Stargardt macular dystrophy	24	32
	SMD7	F	25	Stargardt macular dystrophy	13	12
	SMD8	M	39	Stargardt macular dystrophy	10	29
	SMD9	F	40	Stargardt macular dystrophy	16	24
	SMD10	M	41	Stargardt macular dystrophy	23	18
	SMD11	M	39	Stargardt macular dystrophy	7	32
	SMD12	F	58	Stargardt macular dystrophy	17	41
	RPTV1	F	43	Retinitis pigmentosa	28	15
	RPTV2	H	54	Retinitis pigmentosa	21	33
	RPTV3	H	62	Retinitis pigmentosa	39	23
	RPTV4	F	37	Retinitis pigmentosa	20	17
	RPTV5	F	28	Retinitis pigmentosa	16	12
	RPTV6	H	60	Retinitis pigmentosa	4	56
	RPTV7	F	61	Retinitis pigmentosa	15	46
	RPTV8	H	59	Retinitis pigmentosa	6	53
	RPTV9	H	27	Retinitis pigmentosa	4	23
	RPTV10	H	29	Retinitis pigmentosa	10	19
	RPTV11	F	23	Retinitis pigmentosa	3	20
	RPTV12	F	18	Retinitis pigmentosa	1	17
	S1	H	31	-	-	-
	S2	F	28	-	-	-
	S3	F	40	-	-	-
	S4	H	59	-	-	-
	S5	H	58	-	-	-
	S6	F	42	-	-	-
	S7	F	54	-	-	-
	S8	F	36	-	-	-
	S9	H	56	-	-	-
	S10	F	54	-	-	-
	S11	H	57	-	-	-
	S12	H	18	-	--	-
	S13	F	24	-	-	-
	S14	H	26	-	-	-

. SMD: subjects with Stargardt macular dystrophy, RPTV: subjects with retinitis pigmentosa tunnel vision. S: sighted control subjects. Age disease onset: subjects' age when they experienced the irst symptoms of the disease. Visual deicit duration: age minus age at disease o ns et . in

ROI: Central EVC (regressed peripheral EVC) Contrast Peaks Brodmann area Peak X Peak Y Peak Z t value p value Retinitis pigmentosa tunnel vision > Normal vision

	LH Middle/Superior occipital gyrus	BA 17/18	-23	-92	0	3,40	0,002
	LH Superior temporal gyrus	BA 22	-55	-11	-3	3,31	0,002
	LH Superior temporal gyrus	BA 41	-37	-29	3	4,36	0,000
	Normal vision > retinitis pigmentosa tunnel vision
	LH Anterior cingulate gyrus	BA 32	-7	34	9	3,34	0,002
	RH Anterior cingulate gyrus	BA 32	8	34	9	2,97	0,005
	RH Anterior middle temporal gyrus	BA 38	41	-2	-21	3,19	0,003
	RH Anterior inferior temporal gyrus	BA 38	35	3	-30	3,53	0,001
	RH Orbital gyrus	BA 11	23	40	6	3,24	0,003
	Stargardt macular dystrophy > Normal vision
	LH Inferior parietal lobule	BA 39	-40	-49	30	3,43	0,002
	LH Parieto-occipital sulcus/Cuneus	BA 19	-7	-71	24	3,19	0,003
	RH Cuneus	BA 19	8	-69	27	3,68	0,001
	RH Parieto-occipital sulcus/ Precuneus	BA 7/BA 19	8	-65	28	3,62	0,001
	Normal vision > Stargardt macular dystrophy
	LH Orbital gyri	BA 47	-25	39	1	2,79	0,008
	RH Superior temporal sulcus	BA 21	50	-17	-9	3,86	0,000
	RH Middle temporal gyrus	BA 38	50	-8	-15	3,27	0,002
	RH Obital gyri	BA 47	20	40	0	4,57	0,000
	Stargardt macular dystrophy > retinitis pigmentosa tunnel vision
	LH Superior occipital gyrus	BA 18	-22	-89	27	3,68	0,001
	LH Parieto-occipital sulcus	BA 19	-7	-68	30	2,51	0,017
	RH Inferior parietal lobule	BA 19	47	-56	30	3,00	0,005
	RH Parieto-occipital sulcus/Cuneus	BA 19	5	-77	30	3,19	0,003
	RH Precuneus	BA 7	8	-70	34	2,85	0,007
	retinitis pigmentosa tunnel vision > Stargardt macular dystrophy
	LH Fusiform gyrus/Collateral sulcus	BA 37	-28	-56	-12	3,25	0,003
	LH Inferior occipital gyrus	BA 18	-40	-80	-12	3,39	0,002
	LH Supramarginal gyrus	BA 40	-49	-20	18	3,85	0,000
	ROI: Peripheral EVC (regressed central EVC)
	retinitis pigmentosa tunnel vision > Normal vision
	RH Inferior parietal lobule	BA 39	56	-50	36	3,61	0,001
	RH Posterior middle frontal gyrus	BA 6	44	1	42	4,48	0,000
	RH Anterior middle frontal gyrus	BA 44	35	28	33	3,01	0,005
	RH Superior frontal gyrus (BA 9)	BA 9	11	31	48	3,48	0,001
	Normal vision > retinitis pigmentosa tunnel vision
	LH Middle occipital gyrus	BA 18	-28	-89	-6	3,75	0,001
	LH Superior occipital gyrus	BA 18	-25	-89	3	3,05	0,004
	LH Middle temporal gyrus	BA 21	-55	-17	0	3,91	0,000
	LH Post central gyrus	BA 2	-13	-38	51	4,20	0,000
	RH Inferior occipital gyrus	BA 18	33	-86	-18	3,04	0,004
	RH Middle occipital gyrus	BA 18	26	-80	3	4,24	0,000
	RH Superior occipital gyrus	BA 18/19	20	-80	21	3,19	0,003
	RH medial central sulcus/medial post and precentral gyri	-	8	-41	59	3,26	0,002
	Stargardt macular dystrophy > Normal vision
	LH Lingual gyrus	BA 19	-22	-65	-9	2,91	0,006
	RH Lingual gyrus	BA 19	17	-50	-6	3,26	0,002
	RH Fusiform gyrus	BA 20	47	-38	-15	4,54	0,000
	RH parahippocampal gyrus	BA 35	35	-31	-21	3,10	0,004
	RH Inferior temporal gyrus	BA 20	55	-42	-11	2,53	0,016
	RH Inferior occipital gyrus	BA 18	44	-68	-12	3,04	0,004
	RH Inferior temporal gyrus	BA 20	53	-47	-9	3,57	0,001
	RH Inferior temporal sulcus	BA 19	35	-68	6	3,42	0,002
	RH Orbital gyrus	BA 11	14	40	-3	3,49	0,001

ROI: Peripheral EVC (regressed central EVC) Constrast peaks Brodmann area Peak X Peak Y Peak Z t value p value Normal vision > Stargardt macular dystrophy

	LH Anterior cingulate gyrus	BA 24	-10	22	30	3,03	0,005
	LH Cuneus	BA 18	-7	-71	27	3,26	0,002
	RH Cuneus/Parieto-occipital sulcus	BA 18	8	-65	27	4,05	0,000
	RH Pre-cuneus	BA 7	8	-65	27	4,05	0,000
	Stargardt macular dystrophy > retinitis pigmentosa tunnel vision
	LH Lingual gyrus/Collateral sulcus	BA 19	-25	-62	-15	4,34	0,000
	LH Fusiform gyrus	BA 19	-33	-68	-15	3,79	0,001
	LH Inferior occipital gyrus	BA 18	-43	-80	-18	5,34	0,000
	LH Middle occipital gyrus	BA 19/19	-35	-86	-3	3,50	0,001
	LH Central sulcus (dorsal)	BA 1/BA 4	-10	-35	57	3,21	0,003
	LH Medial precentral gyrus	BA 4	0	-32	59	3,47	0,001
	RH Lingual gyrus/Collateral sulcus	BA 19	23	-53	-6	3,81	0,001
	RH Inferior occipital gyrus	BA 19	33	-65	-17	3,19	0,003
	RH Fusiform gyrus	BA 37	38	-47	-18	4,25	0,000
	RH Parahippocampal gyrus	BA 35	26	-29	-21	3,76	0,001
	RH Inferior temporal gyrus (posterior)	BA 20	46	-50	-15	2,86	0,007
	RH Inferior occipital gyrus	BA 18/19	38	-68	-15	4,59	0,000
	RH Middle occipital gyrus	BA 18	32	-71	6	4,59	0,000
	RH Superior occipital gyrus	BA 18	26	-80	16	4,07	0,000
	RH Middle occipital gyrus/Middle temporal gyrus	BA 19	41	-63	6	4,04	0,000
	RH Superior temporal gyrus/ Superior temporal sulcus	BA 21/22	50	-14	-6	3,80	0,001
	RH Superior parietal lobule/Post central sulcus	BA 5	26	-38	45	3,61	0,001
	RH Post central gyrus/Central sulcus	BA 2	29	-30	54	3,03	0,005
	RH Precentral gyrus	BA 4	20	-17	54	3,09	0,004
	retinitis pigmentosa tunnel vision > Stargardt macular dystrophy
	LH Cuneus	BA 19	-7	-71	27	-3,77	0,001
	LH Anterior cingulate	BA 32	-4	22	24	-3,42	0,002
	LH Middle frontal gyrus	BA 46	-28	40	21	-3,76	0,001
	RH Inferior parietal lobule	BA 39	50	-59	30	-2,78	0,009
	RH Middle frontal gyrus	BA 9	35	25	36	-4,46	0,000
	RH Superior frontal gyrus	BA 9	14	31	45	-2,67	0,011
	RH Cuneus	BA 19	11	-71	27	-3,63	0,001

T ab le 2. Peaks of functional connectivity diferences between groups

. ROI: region-of-interest. Peaks x, y, z: Talairach coordinates. P values corrected for multiple comparisons. LH: Let hemisphere. RH: Right hemisphere. BA: Brodmann areas.

  To identify digits '2', a person with regular visual perception must perfom a systematic search; in contrast, for a grapheme-color synesthete, who links a specific color with a given number, digits '2' instantly pop-out. Adapted with permission[27].

	FIGURE 2. 'Vision' 1996, by Carol Steen, private
	collection, represents a synesthetic visual experience elicited	FIGURE 3. 'Kondo's Trumpet' 2010, by Carol Steen, private
	in this synesthetic painter by a needle puncture during an	collection, depicts the synesthetic visual experience elicited by
	acupuncture session [29]. Reproduced with permission.	the timbre of that trumpet [30]. Reproduced with permission.

Table 1

 1 Baseline

	characteristics in control and IV-rtPA-treated groups	Variable	Control group	IV-rtPA-treated group	P
		Number of patients	188	300
		Age, years, mean AE SD	69.5 AE 14.0	67.6 AE 14.3	0.16
		Men	128 (68.1)	195 (65.0)	0.48
		Medical history
		Hypertension	114 (60.6)	164 (54.7)	0.19
		Diabetes	32 (17.0)	46 (15.3)	0.62
		Hypercholesterolaemia	70 (37.2)	95 (34.7)	0.57
		Current smoking	52 (28.9)	74 (24.8)	0.32
		Antithrombotic therapy	84 (44.7)	102 (34.0)	0.018
		Prior stroke history	37 (19.7)	37 (12.4)	0.029
		Clinical measures
		Blood glucose, mg/dl, median (IQR)	117 (101-142)	114 (100-137)	0.60
		Heart rate, beats/min, mean AE SD	82 AE 18	82 AE 16	0.84
		Systolic BP, mmHg, mean AE SD	162 AE 30	157 AE 26	0.086
		Diastolic BP, mmHg, mean AE SD	90 AE 18	85 AE 16	0.003
		NIHSS score, median (IQR)	7 (6-10)	8 (6-12)	<0.001
		Pre-stroke Rankin ≥1	76 (40.4)	60 (20.0)	<0.001
		Lacunar stroke	45 (24.2)	38 (12.8)	0.001
		Time to admission, min, mean AE SD	131 AE 76	108 AE 63	<0.001
		BP, blood pressure; IQR, interquartile range; IV, intravenous; NIHSS, National Institutes of
		Health Stroke Scale; rtPA, recombinant tissue plasminogen activator. Values are expressed as
		numbers (percentages) unless otherwise indicated.
	© 2016 EAN

Table 1

 1 Subjects' clinical data. B: RP blind subjects, TV: RP tunnel vision subjects. S: sighted control subjects. N: Normal visual field, i.e. 130°-140°in horizontal diameter. Blindness duration: number of years since the subjects lost any form vision in all parts of their visual field but might still keep some bare light perception. BLP: Bare light perception. NLP: No light perception.

	Subject Sex Age Cause of	Light	Left eye visual	Right eye visual	Left eye visual field	Right eye visual field	Blindness	Handedness Braille
			blindness	perception	acuity (logmar)	acuity (logmar)	diameter (°)	diameter (°)	duration
									(years)
	B1	F	Retinitis pigmentosa NLP	None	None	0	0	8	R	Yes
	B2	F	Retinitis pigmentosa BLP	None	None	0	0	17	R	Yes
	B3	F	Retinitis pigmentosa BLP	None	None	0	0	10	R	Yes
	B4	H	Retinitis pigmentosa BLP	None	None	0	0	19	R	Yes
	B5	H	Retinitis pigmentosa BLP	None	None	0	0	14	R	No
	B6	H	Retinitis pigmentosa BLP	None	None	0	0	7	R	Yes
	B7	H	Retinitis pigmentosa BLP	None	None	0	0	4	R	No
	B8	F	Retinitis pigmentosa BLP	None	None	0	0	15	R	Yes
	B9	F	Retinitis pigmentosa BLP	None	None	0	0	12	R	No
	B10	H	Retinitis pigmentosa BLP	None	None	0	0	6	R	No
	B11	F	Retinitis pigmentosa BLP	None	None	0	0	6	R	No
	TV1	H	Retinitis pigmentosa -	0	0.15	15

  10 N. Sabbah et al. / NeuroImage xxx (2016) xxx-xxx

Please cite this article as: Sabbah, N., et al., Increased functional connectivity between language and visually deprived areas in late and partial blindness, NeuroImage (2016), http://dx.doi.org/10.1016/j.neuroimage.2016.04.056 correlations (see

2.1. Retinal processing

Partie I, Chapter 2 -Visual processing

2.2. Cerebral visual processing

3.2. Plasticity induced by visual loss

Partie I, Chapter 3 -Visual loss

Table3. Clinical data about vision loss onset and evolution. Note that determining the real onset of retinitis pigmentosa is very challenging. Individuals become aware about the visual field defect relatively late in the disease due to fading and filling-in processes. Therefore, the recorded onset age should be regarded with caution for certain subjects.

*An early version of this research was presented in "Réorganisation cérébrale consécutive à la perte tardive d'une partie ou de la totalité du champ visuel et à la restitution sensorielle : approche comportementale et par IRM fonctionnelle.", Norman Sabbah, Neurosciences [q-bio.NC]. Université Pierre et Marie Curie -Paris VI, 2015. Français. <NNT : 2015PA066532>. <tel-01318951>

Partie II, Chapter 2 -Functional changes: "Reorganization of early visual cortex functional connectivity following selective peripheral and central visual loss"*

Scientific RepoRts | 7:43223 | DOI: 10.1038/srep43223

Partie III, Chapter 1 -Synthesis of the principal results

Partie III, Chapter 3 -Limitations

www.co-neurology.com Volume 28 Number 1 February 2015

Color synesthesia Safran and Sanda 1350-7540 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.www.co-neurology.com

1350-7540 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.www.co-neurology.com

© 2016 EAN

N. Sabbah et al. / NeuroImage xxx (2016) xxx-xxx Please cite this article as: Sabbah, N., et al., Increased functional connectivity between language and visually deprived areas in late and partial blindness, NeuroImage (2016), http://dx.doi.org/10.1016/j.neuroimage.2016.04.056

Please cite this article as: Sabbah, N., et al., Increased functional connectivity between language and visually deprived areas in late and partial blindness, NeuroImage (2016), http://dx.doi.org/10.1016/j.neuroimage.2016.04.056

N. Sabbah et al. / NeuroImage xxx (2016) xxx-xxx Please cite this article as: Sabbah, N., et al., Increased functional connectivity between language and visually deprived areas in late and partial blindness, NeuroImage (2016), http://dx.doi.org/10.1016/j.neuroimage.2016.04.056

Remerciements

Je souhaiterais tout d'abord remercier le Pr Avinoam SAFRAN, à qui je ne dois non seulement son soutien crucial dans la réalisation de cette thèse mais également de m'avoir

Acknowledgments

We would like to thank the team of the "Centre d'investigation clinique" of the "Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts", particularly Saddek Mohand-Saïd MD and Céline Devisme PhD for their invaluable help in patients' recruitment and the members of "Forschungszentrum Jülich GmbH" for providing us with the cytoarchitectonic maps of the occipital lobe.

Acknowledgements

We thank Zohar Tal and Noa Zeharia for providing the external functional localizers as well as Sami Abboud, Ella Striem-Amit, Céline Devisme, and Anne-Fleur Barfuss who provided valuable input and assistance on this work. his work was supported by the French State program "Investissements d' Avenir" managed by the Agence Nationale de la Recherche [LABEX LIFESENSES: ANR-10-LABX-65] and Groupe Optic 2000.

Acknowledgements

The authors thank Katia Marazova, MD, PhD, for editorial assistance.

Financial support and sponsorship

Funding: This study was supported in part by grants from LABEX and Humanis.

Acknowledgements

We thank Mary Osborne-Pellegrin for help in editing the final draft of the manuscript.

Acknowledgments

We thank Sami Abboud, Shachar Maidenbaum, Ella Striem-Amit, Ilan Goldberg, Céline Devisme and Anne-Fleur Barfuss who provided valuable input and help on this work.

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Additional information

Funding: The research leading to these results received funding from the programs: "Jeune Chercheuses et Jeunes Chercheurs" ANR-13-JSV4-0001-01, "Investissements d'avenir" ANR-10-IAIHU-06, "LABEX" and "Humanis". Competing financial interests: There is no conflict of interest to declare for any author excepting José-Alain Sahel, consultant for Pixium Vision, GenSight Biologics, Sanofi-Fovea, and Genesignal. However, this had no influence on the results or discussion reported in this paper.

Appendix 1

Supplementary table Table 1. Regression analysis showing the significant effects of age and visual defect duration on CoTks and CoEn.

Author Contributions

Additional Information

Supplementary information accompanies this paper at http://www.nature.com/srep Competing inancial interests: here is no conlict of interest to declare for any author except Pr. José-Alain Sahel, consultant for Pixium Vision, GenSight Biologics, Sanoi-Fovea, and Genesignal. However, it has no inluence on the results or discussion reported in this paper.

How to cite this article:

Supplementary material

Comment to supplementary Figures S1, S2, S3, S4:

The maps are quite similar to the ones presented in main Figures 1 to 4 using the motion correction implemented during the preprocessing stages.

Supplementary material

Part III

General discussion

Part VI

Annexes

Chapter 3

Annexe I: "Increased optic nerve radiosensitivity following optic neuritis"

Chapter 3

Annexe II: "A neurological disorder presumably underlies painter Francis Bacon distorted world depiction"

Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Chapter 3

Annexe IV: "Color synesthesia.

Insight into perception, emotion and consciousness"

Conflicts of interest

There are no conflicts of interest. Chapter 3

Annexe V: "Impact of thrombolysis in acute stroke without occlusion: an observational comparative study"

Disclosure of conflicts of interest

The authors declare no financial or other conflicts of interest.

Supporting Information

Additional Supporting Information may be found in the online version of this article: