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

Cerebral plasticity processes developing from late visual deficit are not fully understood. Insights into these mechanisms could improve the rehabilitation programs, provide the patients with new sensory substitution devices, and even predict the outcome of some vision restoration treatments. A variety of combined approaches should allow to better define these mechanisms. On the one hand, we investigated the functional connectivity (FC) of the brain by a resting-state fMRI analysis, and on the other hand we carried out a behavioral study. The selected subjects (1) had lost the peripheral visual field due to a pigmentary retinopathy and therefore holding a “tunnel vision”, (2) had lost the central visual field i.e. subjects suffering from central scotoma resulting from a Stargardt macular dystrophy, (3) became lately blind, as the result of pigmentary retinopathy terminal stage and (4) potentially visually-restored by a retinal prosthesis.(A) Resting-state functional connectivity studiesStudy 1. In subjects suffering from peripheral or complete visual loss, we studied the FC of visual and language areas. We found an increased FC in Broca’s and specific visually deprived areas in both groups of patients as compared to sighted controls. Therefore, the plasticity between the visual and language systems can develop in the adult brain i.e. long after the end of a developmental sensitive period, following not only total but also partial visual deprivation. These data also contribute to the debate about the development of such plasticity in the late blind. Furthermore, they reshape the conditions of vision and language systems plasticity, which is (1) constrained to visually deafferented regions and (2) possible even in presence of a residual vision.Study 2. In subjects with converse central or peripheral visual field defects, we studied the FC of V1 subregions – onto which the central visual field (cV1) and the peripheral visual field (pV1) are projected, with the rest of the brain. The results showed an increased FC of (1) tunnel vision subjects afferented region (cV1) with regions involved in space, scene processing and multisensory integration and (2) central scotoma subjects afferented region (pV1) with regions involved in face perception. Moreover, an increased FC was observed between deafferented regions and regions involved in high-order functions and top-down mechanisms. These findings suggest that the afferented regions of V1 strengthen the connections with regions involved in deficient visual functions, whereas the sensory-deafferented V1 tunes-up preexisting high-order mechanisms to assist vision. These data bring new information about the plasticity in sub-regions of V1 that develops to process various functions, following partial visual loss.(B) Behavioural study of blind subjects fitted with a retinal prosthesis Study 3. We finally examined the adaptive behavior of subjects suffering from pigmentary retinopathy fitted with a camera-connected retinal prosthesis for 4 years. Such a device can potentially lead to dissociation between eyes and head-mounted camera; this is incompatible with physiological mechanisms of the spatial localization of visualized images, which depend on the gaze direction. This kind of dissociation is expected to alter the visuomotor coordination in subjects fitted with the considered retinal prosthesis device. We observed that misalignments between gaze and head (i.e. camera) positions occur during visual search, and could not be prevented when following vestibulo-ocular reflexes. This misalignment leads to the illusion of a visual target movement, and affects the visuo-motor coordination that was quantified in this study. After 4 years of current use of their device, the subjects develop compensatory strategies that partially solve these issues.Les processus de plasticité cérébrale consécutifs à un déficit visuel survenu tardivement sont encore peu connus. En comprendre les mécanismes est pourtant essentiel à l'optimisation de méthodes de rééducation des sujets atteints, au développement de dispositifs visant à substituer l'information normalement apportée par la modalité déficiente, par celle d'une autre modalité sensorielle, et à la conception de systèmes permettant de restaurer une certaine fonction visuelle. Afin d'étudier ces processus, nous avons choisi d'une part, d'analyser la connectivité fonctionnelle du cerveau à l'état de repos par imagerie par résonance magnétique fonctionnelle (IRMf), et d'autre part de les explorer par une approche comportementale. Les sujets étudiés avaient soit sélectivement perdu (1) la périphérie du champ visuel, à la suite d'une rétinopathie pigmentaire au stade de " vision tunnellaire ", ou (2) le centre du champ visuel, c'est-à-dire souffrant d'un scotome central des suites d'une dégénérescence maculaire de Stargardt soit (3) l'intégralité du champ visuel, au stade terminal d'une rétinopathie pigmentaire et (4) étaient éventuellement porteurs d'un système de prothèse rétinienne. (A) Études de la connectivité fonctionnelle par IRMf de repos Étude 1. Chez des sujets tardivement atteints dans la périphérie ou dans la totalité du champ visuel, nous avons étudié la connectivité fonctionnelle de l'aire de Broca et des aires visuelles. Comparée à celle des sujets sains, la connectivité fonctionnelle de ces patients est accrue entre l’aire de Broca et, dans V1, les parties privées d’afférences visuelles. Ainsi, à la suite d’une privation visuelle totale ou sectorielle, un processus plastique entre les systèmes de la vision et du langage peut se produire chez l’adulte, au-delà donc de la période sensible du développement. Ces données apportent aussi une contribution au débat sur la possibilité d’une telle plasticité chez le sujet devenu tardivement aveugle. Elles permettent, par ailleurs, de définir les conditions qui accompagnent la plasticité des systèmes de la vision et du langage, c’est-à-dire d’une part le confinement de son développement au niveau des régions visuelles désafférentées et d’autre part la possibilité de son développement alors qu’une partie de la vision est encore fonctionnelle. Étude 2. Chez des sujets présentant des atteintes du champ visuel périphérique ou central, nous avons analysé la connectivité fonctionnelle des parties de V1 où se projettent respectivement le champ visuel central (V1 centrale) et le champ visuel périphérique (V1 périphérique) avec les autres régions du cerveau. Comparée à celle des sujets sains, nous avons observé une augmentation de la connectivité fonctionnelle entre (1) la région afférentée des sujets avec vision tunnellaire (V1 centrale) et des régions impliquées dans le traitement des scènes, de l’espace et de l’intégration multisensorielle, et (2) la région afférentée des sujets avec scotome central (V1 périphérique) et des régions notamment impliquées dans la perception des visages. Quant aux régions désafférentées (V1 périphérique pour les sujets avec vision tunnellaire et V1 centrale pour les sujets avec scotome central), nous leur avons trouvé une connectivité fonctionnelle accrue avec des régions impliquées dans des fonctions supérieures et des mécanismes top-down. Il apparaît que les régions encore afférentées de V1 renforcent leurs connexions avec des régions cérébrales dont les fonctions sont altérées par la désafférentation de l’autre partie de V1, alors que les régions visuelles désafférentées modulent des mécanismes de haut-niveau, préexistants, dans la probable intention de soutenir la vision résiduelle de ces sujets. Ces données apportent des informations nouvelles sur l’adaptation plastique des régions de V1 au traitement de diverses fonctions, suite à la perte d’un secteur périmétrique

Exploring the Structural and Functional Organization of the Dorsal Zone of Auditory Cortex in Hearing and Deafness

Recent neuroscientific research has focused on cortical plasticity, which refers to the ability of the cerebral cortex to adapt as a consequence of experience. Over the past decade, an increasing number of studies have convincingly shown that the brain can adapt to the loss or impairment of a sensory system, resulting in the expansion or heightened ability of the remaining senses. A particular region in cat auditory cortex, the dorsal zone (DZ), has been shown to mediate enhanced visual motion detection in deaf animals. The purpose of this thesis is to further our understanding of the structure and function of DZ in both hearing and deaf animals, in order to better understand how the brain compensates following insult or injury to a sensory system, with the ultimate goal of improving the utility of sensory prostheses. First, I demonstrate that the brain connectivity profile of animals with early- and late-onset deafness is similar to that of hearing animals, but the projection strength to visual brain regions involved in motion processing increases as a consequence of deafness. Second, I specifically evaluate the functional impact of the strongest auditory connections to area DZ using reversible deactivation and electrophysiological recordings. I show that projections that ultimately originate in primary auditory cortex (A1) form much of the basis of the response of DZ neurons to auditory stimulation. Third, I show that almost half of the neurons in DZ are influenced by visual or somatosensory information. I further demonstrate that this modulation by other sensory systems can have effects that are opposite in direction during different portions of the auditory response. I also show that techniques that incorporate the responses of multiple neurons, such as multi-unit and local field potential recordings, may vastly overestimate the degree to which multisensory processing occurs in a given brain region. Finally, I confirm that individual neurons in DZ become responsive mainly to visual stimulation following deafness. Together, these results shed light on the function and structural organization of area DZ in both hearing and deaf animals, and will contribute to the development of a comprehensive model of cross-modal plasticity

Medial Geniculate Projections to Auditory and Visual Cortex in Hearing and Deaf Cats

Following early-onset deafness, studies have demonstrated crossmodal plasticity, throughout “deaf” auditory cortex. Crossmodally reorganized auditory cortex shows increased dendritic spine density, which suggests increased numbers of axon terminals. I examined projections from the medial geniculate body (MGB) of hearing and early-deaf cats in order to reveal the distribution of synaptic boutons in the cortex, originating from MGB neurons. Anterograde fluorescent dextran tracers were deposited bilaterally in the MGB in order to label cortical axon terminals. Deafness resulted in axon terminal increases in visual cortex, and conservation of auditory axon terminal distribution. Visual areas PLLS and area 18 received increased projections from deaf MGB. Distributions of thalamocortical axon terminals in crossmodally reorganized deaf auditory areas PAF, DZ and fAES were stable. These findings indicate a need for studies of corticocortical connectivity, to find an anatomical basis for crossmodal reorganization

Simultaneous Assessment of White Matter Changes in Microstructure and Connectedness in the Blind Brain

Magnetic resonance imaging (MRI) of the human brain has provided converging evidence that visual deprivation induces regional changes in white matter (WM) microstructure. It remains unclear how these changes modify network connections between brain regions. Here we used diffusion-weighted MRI to relate differences in microstructure and structural connectedness of WM in individuals with congenital or late-onset blindness relative to normally sighted controls. Diffusion tensor imaging (DTI) provided voxel-specific microstructural features of the tissue, while anatomical connectivity mapping (ACM) assessed the connectedness of each voxel with the rest of the brain. ACM yielded reduced anatomical connectivity in the corpus callosum in individuals with congenital but not late-onset blindness. ACM did not identify any brain region where blindness resulted in increased anatomical connectivity. DTI revealed widespread microstructural differences as indexed by a reduced regional fractional anisotropy (FA). Blind individuals showed lower FA in the primary visual and the ventral visual processing stream relative to sighted controls regardless of the blindness onset. The results show that visual deprivation shapes WM microstructure and anatomical connectivity, but these changes appear to be spatially dissociated as changes emerge in different WM tracts. They also indicate that regional differences in anatomical connectivity depend on the onset of blindness

Neural and behavioral plasticity in olfactory sensory deprivation

The human brain has a remarkable ability to reorganize as a consequence of altered demands. This ability is particularly noticeable when studying the neural effects of complete sensory deprivation. Both structural and functional cerebral reorganization have repeatedly been demonstrated in individuals with sensory deprivation, most evident in cortical regions associated with the processing of the absent sensory modality. Furthermore, sensory deprivation has been linked to altered abilities in remaining sensory modalities, often of a compensatory character. Although anosmia, complete olfactory sensory deprivation, is our most common sensory deprivation, estimated to affect around 5 % of the population, the effects of anosmia on brain and behavior are still poorly understood. The overall aim of this thesis was to investigate how the human brain and behavior are affected by anosmia, with a focus on individuals with congenital (lifelong) sensory deprivation. Specifically, Study I and Study IV assessed potential behavioral and neural multisensory compensatory abilities whereas Study II and Study III assessed potential reorganization beyond the processing of specific stimuli; the latter by determining morphological and resting-state functional connectivity alterations. Integration of information from different sensory modalities leads to a more accurate perception of the world around us, given that our senses provide complementary information. Although an improved ability to extract multisensory information would be of particular relevance to individuals deprived of one sensory modality, multisensory integration has been sparsely studied in relation to sensory deprivation. In Study I, multisensory integration of audio-visual stimuli was assessed in individuals with anosmia using two different experimental tasks. First, individuals with anosmia were better than matched controls in detecting multisensory temporal asynchronies in a simultaneity judgement task. Second, individuals with congenital, but not acquired, anosmia demonstrated indications of an enhanced ability to utilize multisensory information in an object identification task with degraded stimuli. Based on these results, the neural correlates of audio-visual processing and integration were assessed in individuals with congenital anosmia in Study IV. Relative to matched normosmic individuals, individuals with congenital anosmia demonstrated increased activity in established multisensory regions when integrating degraded audio-visual stimuli; however, no compensatory cross-modal processing in olfactory regions was demonstrated. Together, Study I and IV suggest that complete olfactory sensory deprivation is linked to enhanced audio-visual integration performance that might be facilitated by increased processing in multisensory regions. In Study II, whole-brain gray matter morphology was assessed in individuals with congenital anosmia. Both increases and decreases in the orbitofrontal cortex, a region associated with olfaction and sometimes referred to as secondary olfactory cortex, were observed in individuals with congenital anosmia in relation to matched controls. However, in contrast to our expectations, no sensory deprivation-dependent effects were demonstrated in piriform cortex, a region commonly referred to as primary olfactory cortex. Furthermore, Study III revealed an absence of differences in resting-state functional connectivity between individuals withcongenital anosmia and normosmic individuals within the primary olfactory cortex (including piriform cortex) as well as between core olfactory processing regions. In conclusion, the studies presented within this thesis suggest the existence of a potential multisensory compensatory mechanism in individuals with anosmia, but demonstrate a striking lack of morphological and functional alterations in piriform (primary olfactory) cortex. These results demonstrate that complete olfactory deprivation is associated with a distinct neural and behavioral reorganization in some regions but also a clear lack of effects in other regions; the latter underline the clear differences between our senses and suggest that extrapolating from individual senses should be done cautiously

How input modality and visual experience affect the representation of categories in the brain

The general aim of the present dissertation was to participate in the progress of our understanding of how sensory input and sensory experience impact on how the human brain implements categorical knowledge. The goal was twofold: (1) understand whether there are brain regions that encode information about different categories regardless of input modality and sensory experience (study 1); (2) deepen the investigation of the mechanisms that drive cross-modal and intra-modal plasticity following early blindness and the way they express during the processing of different categories presented as real-world sounds (study 2). To address these fundamental questions, we used fMRI to characterize the brain responses to different conceptual categories presented acoustically in sighted and early blind individuals, and visually in a separate sighted group. In study 1, we observed that the right posterior middle temporal gyrus (rpMTG) is the region that most reliably decoded categories and selectively correlated with conceptual models of our stimuli space independently of input modality and visual experience. However, this region maintains separate the representational format from the different modalities, revealing a multimodal rather than an amodal nature. In addition, we observed that VOTC showed distinct functional profiles according to the hemispheric side. The left VOTC showed an involvement in the acoustical categorization processing at the same degree in sighted and in blind individuals. We propose that this involvement might reflect an engagement of the left VOTC in more semantic/linguistic processing of the stimuli potentially supported by its enhanced connection with the language system. However, paralleling our observation in rpMTG, the representations from different modalities are maintained segregated in VOTC, showing little evidence for sensory-abstraction. On the other side, the right VOTC emerged as a sensory-related visual region in sighted with the ability to rewires itself toward acoustical stimulation in case of early visual deprivation. In study 2, we observed opposite effects of early visual deprivation on auditory decoding in occipital and temporal regions. While occipital regions contained more information about sound categories in the blind, the temporal cortex showed higher decoding in the sighted. This unbalance effect was stronger in the right hemisphere where we, also, observed a negative correlation between occipital and temporal decoding of sound categories in EB. These last results suggest that the intramodal and crossmodal reorganizations might be inter-connected. We therefore propose that the extension of non-visual functions in the occipital cortex of EB may trigger a network-level reorganization that reduce the computational load of the regions typically coding for the remaining senses due to the extension of such computation in occipital regions

Molecular Mechanisms Responsible for Functional Cortical Plasticity During Development and after Focal Ischemic Brain Injury

The cerebral cortex is organized into functional representations, or maps, defined by increased activity during specific tasks. In addition, the brain exhibits robust spontaneous activity with spatiotemporal organization that defines the brain’s functional architecture (termed functional connectivity). Task-evoked representations and functional connectivity demonstrate experience-dependent plasticity, and this plasticity may be important in neurological development and disease. An important case of this is in focal ischemic injury, which results in destruction of the involved representations and disruption of functional connectivity relationships. Behavioral recovery correlates with representation remapping and functional connectivity normalization, suggesting functional organization is critical for recovery and a potentially valuable therapeutic target. However, the cellular and molecular mechanisms that drive this systems-level plasticity are unknown, making it difficult to approach therapeutic modulation of functional brain organization. Using cortical neuroimaging in mice, this dissertation explores the role of specific genes in sensory deprivation induced functional brain map plasticity during development and after focal ischemic injury. In the three contained chapters, I demonstrate the following: 1) Arc, an excitatory neuron synaptic-plasticity gene, is required for representation remapping and behavioral recovery after focal cortical ischemia. Further, perilesional sensory deprivation can direct remapping and improve behavioral recovery. 2) Early visual experience modulates functional connectivity within and outside of the visual cortex through an Arc-dependent mechanism. 3) Electrically coupled inhibitory interneuron networks limit spontaneous activity syncrhony between distant cortical regions. This work starts to define the molecular basis for plasticity in functional brain organization and may help develop approaches for therapeutic modulation of functional brain organization