Insights from darkness

A. M. Green, C. E. Chapman, J. F. Kalaska and F. Lepore (Eds.) Progress in Brain Research, Vol. 192 ISSN: 0079-6123 Copyright Ó 2011 Elsevier B.V. All rights reserved.

CHAPTER 2

Insights from darkness: what the study of blindness has taught us about brain structure and function Ron Kupers{,* and Maurice Ptito{ {

Institute of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark { Chaire de recherche Harland Sanders en Sciences de la vision, École d'Optométrie, Université de Montréal, Montréal, Québec, Canada

Abstract: Vision plays a central role in how we represent and interact with the world around us. Roughly, one-third of the cortical surface in primates is involved in visual processes. The loss of vision, either at birth or later in life, must therefore have profound consequences on brain organization and on the way the world is perceived and acted upon. In this chapter, we formulate a number of critical questions. Do blind individuals indeed develop supra-normal capacities for the remaining senses in order to compensate for their loss of vision? Do brains from sighted and blind individuals differ, and how? How does the brain of someone who has never had any visual perception form an image of the external world? We discuss findings from animal research as well from recent psychophysical and functional brain imaging studies in sighted and blind individuals that shed some new light on the answers to these questions. Keywords: cross-modal plasticity; visual cortex; sensory substitution; supramodal cortical organization; qualia; brain rewiring. incapacitating events that can befall a person. The importance that vision plays in everyday life is We see with our brains not eyes. —Paul Bach-y-Rita already reflected at the level of the cortical organization. Indeed, roughly one-third of the cortical surface in primates is involved in visual Introduction functions. This raises the question of what happens to this cortex when vision is lacking from Since we are living in a world in which vision birth or when vision is lost at a later stage in plays a very important role, the loss of vision, development. For a long time, it was believed either from birth or later in life, is one of the most that the visually deprived cortex would remain devoid of any particular functional role. However, a wealth of studies in animals *Corresponding author. (reviewed in Ptito and Desgent, 2006), followed Tel.: þ45-3545-6890; Fax: þ45-3545-8949 by studies in humans (reviewed in Merabet and E-mail: [email protected] DOI: 10.1016/B978-0-444-53355-5.00002-6

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Pascual-Leone, 2010; Pietrini et al., 2009), have shown in an unequivocal way that the visually deprived cortex not only reorganizes structurally but also becomes functionally involved in a multitude of nonvisual tasks. Whereas the first studies focused on its acquired role in nonvisual forms of sensory processing, in particular, tactile and auditory functions, more recent studies revealed a broader picture showing that the visually deprived occipital cortex is also involved in various cognitive processes (Amedi et al., 2003; Bonino et al., 2008; Cattaneo et al., 2008; Kupers et al., 2007, 2010; Raz et al., 2005; Stevens et al., 2007). This raises a number of interesting questions. First, how does nonvisual information reach the visual cortex? Is this accomplished through the formation of new anatomical connections or by a strengthening or unmasking of existing pathways in the sighted person's brain? Thanks to modern MRI-based brain imaging techniques, we are starting to understand the reorganization of the connectivity in the blind person's brain. At the functional level, does the fact that blind subjects have extra cortical territory available to process nonvisual information make them more proficient in nonvisual tasks? A final and crucial question is what can we offer to blind people to (partially) restore their lack of visual input? Throughout history, many attempts have been undertaken to develop substitutes for vision. The best known example is undoubtedly Braille reading, which replaces the visual input of letters by embossed arrays of dots which are sensed by the tactile system and translated into meaningful words. Although Braille reading meant an important leap forward in the quality of life of blind persons, its limitations are apparent. In the past decades, many efforts have therefore been undertaken to develop devices that convey “visual” information from objects that are placed outside the immediate egocentric space of the blind individual. The legacy of Professor Paul Bach-y-Rita needs to be acknowledged here. He was one of the pioneers in sensory substitution and in the

field of neuroscience that later became known as cross-modal plasticity. His pioneering work on sensory substitution systems (Bach-y-Rita, 1967; Bach-y-Rita et al., 1969), although met at the beginning with much skepticism, has paved the way for a generation of new sensory substitution devices of which the tongue display unit (TDU) and the vOICe system are the best known examples (reviewed in Bubic et al., 2010).

Visual deprivation models in animals The cerebral cortex has a remarkable capacity for plasticity resulting in anatomical reorganization and behavioral recovery, both in animals (Kaas, 2002) and humans (Pascual-Leone et al., 2005). Bilateral enucleation in hamsters (Izraeli et al., 2002), congenital blindness in mice (Chabot et al., 2007, 2008), and naturally very low vision as in the blind mole rat (Bronchti et al., 2002; Doron and Wollberg, 1994) yield the formation of new ectopic projections from the inferior colliculus to the lateral geniculate nucleus, the primary visual relay in the thalamus. These new aberrant projections are probably responsible for the auditory evoked activity in the visual cortex, as measured in electrophysiological recordings. Rebillard et al. (1977) were the first to report that the primary auditory cortex is driven by visual stimuli in congenitally deaf cats. Conversely, studies on the microphthalmic mole rat (Spalax ehrenbergi) showed that auditory stimulation can drive cells in the primary visual cortex (Bronchti et al., 2002). Cells in the primary visual cortex of visually deprived cats, rats, or mice can also be triggered by somatosensory or auditory inputs, suggesting cross-modal reorganization (Toldi et al., 1994). The same has been shown in nonhuman primates. For instance, neurons in visual cortical areas respond to somatic inputs following early visual deprivation in monkeys (Hyvarinen et al., 1991). This is in sharp contrast with results in normal-seeing animals, in which area 19 neurons respond exclusively to visual

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inputs. Peripheral inputs play a pivotal role in the organization of the neocortex, as cortical territories usually involved in visual processing are invaded by the auditory and somatosensory systems. It seems therefore that the visual cortex is capable of rewiring in order to accommodate these nonvisual inputs. However, in the case of early (perinatal) brain damage, abnormal neuronal connectivity patterns can be produced and an alternative approach to study cross-modal plasticity resides in the tampering with “blueprints” during prenatal development. Relevant to this approach are the numerous studies on “rewiring” in hamsters (Ptito and Desgent, 2006) and ferrets (reviewed in Lyckman and Sur, 2002). The “rewired” hamster brain Early brain damage results in abnormal neuronal connectivity patterns. By destroying central retinal targets, it must therefore be possible to induce the formation of new and permanent retinofugal projections into nonvisual thalamic sites such as the auditory nucleus (Frost and Metin, 1985; Ptito et al., 2001; Fig. 1a). These surgically induced retinal projections are retinotopically organized and make functional synapses (Metin and Frost, 1989). Neurons in the somatosensory cortex of animals with ectopic retinal projections have visual response properties similar to those of neurons in the primary visual cortex of normal animals (Metin and Frost, 1989). Ferrets with retinofugal projections to the auditory thalamus but no visual cortex appear to perceive light stimuli as visual (Von Melchner, et al., 2000). The question concerning the parallelism between a different brain organization (produced by lesions) and behavioral recovery is still debated although recent experiments both in rewired ferrets and hamsters seem to indicate a large degree of recovery in visual functions (reviewed in Ptito et al., 2001). For example, responses to visual stimuli have been observed in the auditory cortex of hamsters with robust

and permanent projections to the auditory thalamic nucleus (medial geniculate nucleus) but which are lacking a visual cortex. Single neurons in the auditory cortex of these animals respond to visual stimuli and some of them respond equally well to visual as to auditory stimuli (Ptito et al., 2001). Moreover, cells responding to visual stimuli show orientation selectivity, and motion and direction sensitivity. These receptive field properties compare favorably well with those obtained from cells in the visual cortex of normal hamsters. At the behavioral level, rewired hamsters can learn visual discrimination tasks as well as normal animals and a lesion of the auditory cortex abolishes this function (Fig. 1b; Frost et al., 2000). In fact, rewired hamsters with auditory cortex lesions exhibit cortical blindness similar to nonrewired hamsters with visual cortex lesions. This cross-modal processing of sensory information in the cortex is not fully understood. Recent work carried out in our laboratory has led to the suggestion that the observed changes may be due to modifications in GABAergic interneurons that express calcium-binding proteins (CaBPs) like parvalbumin (PV) and calbindin (CB; Desgent et al., 2010). In deaf and cross-modal rewired ferrets, for example, qualitative changes were observed in the morphology and proportion of interneurons containing PV and CB (Pallas, 2001, 2002). Since the laminar distribution of these proteins is significantly different in the primary visual and auditory cortices of normal hamsters (Desgent et al., 2005), the induction of aberrant connectivity to these cortices should also be evident at the neurochemical level. Indeed, hamsters enucleated at birth show significant changes in the distribution of CaBPs within their visual cortex. Compared to intact hamsters, the density of PV-immunoreactive neurons is higher in layer IV and lower in layer V, whereas the density of CB-immunoreactive cells is significantly lower in layer V of V1 in enucleated animals. These results suggest that the affected primary visual cortex may adopt chemical features of the auditory cortex through cross-modal rewiring.

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Fig. 1. Anatomical rewiring and behavioral outcome following loss of visual input at birth. (a) Aberrant ectopic projections from the retina to the medial geniculate nucleus (MG) following neonatal lesions of the superior colliculus in hamsters (after Ptito et al., 2001). (b) Performance of rewired hamsters (right panel) in a visual pattern discrimination task compared to controls (left panel). Note that the performance of rewired hamsters following the additional lesion of the auditory cortex is similar to that of controls with a lesion of the primary visual cortex (illustrated by the asterisk; after Frost et al., 2000) Abbreviations: AC = auditory cortex; VC = visual cortex.

Anatomy of the blind human brain How does absence of vision from birth affect the macrostructural organization of the human brain and through which pathways can nonvisual information be funneled to the occipital cortex in the visually deprived brain? In recent years, MRI-based brain imaging techniques such as voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) have been successfully applied for the in vivo investigation of alterations in gray matter (GM) and white matter (WM) in the blind human brain. The results of these studies seem to concur that there is significant

GM atrophy of all structures of the visual pathways, including the lateral geniculate and posterior pulvinar nuclei, the striate and extrastriate visual areas, and the inferior temporal gyrus and lateral orbital cortex, regions that are part of the ventral visual stream which is involved in object recognition (Noppeney et al., 2005; Pan et al., 2007; Ptito et al., 2008b; Shimony et al., 2006; Fig. 2a). These changes can be massive, with volume reductions ranging from 25% in the primary visual cortex up to 20% in extrastriate visual areas (Ptito et al., 2008b). Volume reductions also occur in nonvisual areas such as the hippocampus (Chebat et al., 2007; Fortin et al., 2008). Besides the volume

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Fig. 2. The congenitally blind brain. (a) Axial brain slices showing regional reductions in gray matter (red) and white matter (blue) in congenitally blind compared to matched sighted control subjects. Note that all components of the visual system in the blind are reduced in volume (after Ptito et al., 2008b). (b) Differences in cortical thickness between congenitally blind and sighted control subjects. Despite a reduction in volume of the occipital cortex, blind subjects show an increase in thickness of the cuneus (unpublished data from our lab). (c) Glucose metabolism at rest in a normal sighted control (upper row) and a congenitally blind subject (lower row). Increases in glucose metabolism in the occipital cortex in the blind are shown on sagittal sections (unpublished data from our lab).

reductions in GM, congenitally blind subjects show increases in cortical thickness in the cuneus (Fig. 2b) which are likely due to a reduction in cortical pruning in early maturation stages of the cortex as a consequence of the loss of visual input. Changes in WM include atrophy of the optic tracts and optic chiasm, the optic radiations, the splenium of the corpus callosum (Noppeney et al., 2005; Pan et al., 2007; Ptito et al., 2008a,b; Shimony et al., 2006), and the inferior longitudinal fasciculus (ILF; Ptito et al., 2008b), a pathway connecting the occipital cortex with the temporal lobe. Lesions of the ILF may induce visual agnosia, prosopagnosia, and disturbances in visual recent memory. No studies found direct evidence for the establishment of new pathways, although volume increases in the occipitofrontal fasciculus, the superior longitudinal fasciculus,

and the genu of the corpus callosum have been reported (Ptito et al., 2008a,b). There is also indirect evidence for an increased functional connectivity between parietal and visual areas in the blind (Kupers et al., 2006; Ptito et al., 2005; Wittenberg et al., 2004). Taken together, since no de novo tracts have been demonstrated in congenitally blind subjects, the data suggest that cross-modal functionality of the visual cortex in early blindness is primarily mediated by preserved or strengthened corticocortical connections. Finally, there are also important metabolic changes in the congenitally blind person's brain. Using PET-FDG, we showed that glucose metabolism at rest is increased by around 15% in striate and extrastriate cortex of blind subjects. Figure 2c shows FDG uptake at rest in a congenitally blind and a blindfolded control subject.

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Cross-modal plasticity: substituting vision with touch There are two major classes of sensory substitution devices for blindness, based upon either tactile or auditory input. These are referred to as respectively tactile-to-vision sensory substitution (TVSS) and auditory-to-vision sensory substitution (AVSS) devices. The best known examples of the latter category are the PVSA (prosthesis substituting vision with audition) system developed by Veraart and colleagues (Capelle et al., 1998) and the vOICe system (Meijer, 1992). Both systems translate visual images taken by a video camera into auditory soundscapes. Bright pixels sound loud and pixels in the upper field of view get a higher pitch. Subjects need training to be able to interpret the resulting soundscapes correctly. A discussion of the latter category is beyond the scope of this chapter and we refer the interested reader to a recent review (Ward and Meijer, 2010). Already in the 1960s, Bach-y-Rita (1967) developed the first TVSS device. The system consisted of a video camera, a computer, and 400 small pneumatic stimulators which were mounted in the back of a dental chair. The blind subject, seated with his back against the stimulators, used a video camera to scan an object that was placed in front of him/her and the visual input was translated into vibrotactile stimulation that was delivered to his back. With training, blind subjects could recognize increasingly more complex shapes, detect movement, and certain visual features such as shades and depth. This system was later replaced by the TDU, named after the fact that the tongue became the substrate for stimulation (Bach-y-Rita and Kercel, 2003). This has lead to a system that is much smaller and became portable, allowing it to be used also outside the laboratory in real-life situations. We have used the TDU in a series of behavioral and brain imaging studies. In a first study, we trained a group of congenitally blind and blindfolded sighted control subjects to use the

TDU in an orientation discrimination task (Ptito et al., 2005). We scanned subjects before and after a 1-week training period. Both groups learned the task equally well, although the blind tended to be faster than the sighted participants. As expected, the brain imaging results before training did not show activations in visual cortical areas in either group. In sharp contrast, after training, blind but not blindfolded sighted control subjects activated large parts of their visual cortex (Fig. 3a). Interestingly, the activated clusters in the occipital and occipitoparietal areas showed a strong resemblance with the areas reported to be activated when sighted subjects do a visual orientation task. These results are in line and extend earlier results showing occipital cortical activation in blind subjects during Braille reading (Burton et al., 2002, 2004; Cohen et al., 1999).

A dorsal and a ventral visual stream: also in the absence of vision? The visual system is classically subdivided into a dorsal “where” and a ventral “what” pathway (Ungerleider and Mishkin, 1982). After having shown that the visual cortex in the blind can be recruited by an orientation task, we next addressed the question whether the basic architecture of a dorsal and ventral pathway is preserved in subjects lacking vision from birth. To that end, we did a series of experiments with the TDU, in which we used tasks tailored to activate either the dorsal or the ventral visual pathway. In the first study, congenitally blind and sighted participants used the TDU to detect the motion direction of a random dot pattern (Matteau et al., 2010). Stimuli were moving in a coherent manner (left, right), randomly, or remained static. The fMRI data showed that following training, blind subjects activated large parts of the dorsal extrastriate visual pathway. Both groups activated the motion-sensitive hMTþ complex, although at different anatomical locations (Fig. 3b). The observation that the

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Fig. 3. Cross-modal activation of the occipital cortex in congenitally blind subjects. (a) Brain activation pattern showing that trained blind (upper row) but not sighted controls (lower row) activate their visual cortex in an orientation discrimination task with the TDU. The values below refer to the z-coordinate of the slices as defined in Montreal Neurological Institute (MNI) space (after Ptito et al., 2005). (b) fMRI data showing activations of area hMTþ in blind (upper row) and sighted control (lower row) subjects for the contrasts “coherent motion versus rest,” “incoherent motion versus rest,” and “coherent þ incoherent motion versus rest.” The numbers next to the slices refer to the positioning of the slice in the z-direction in MNI space (after Matteau et al., 2010). (c) Blind subjects showed significantly stronger BOLD responses in the occipital cortex compared to sighted controls in an odor detection task (after Kupers et al., 2011). (d). Cortical flatmap representation of fMRI data showing activation of the occipital cortex and right parahippocampus in blind subjects performing a spatial navigation task with the TDU (upper row). When sighted subjects performed the same navigation task visually (lower row), they activated a highly similar network (after Kupers et al., 2010).

hMTþ complex can be activated by tactile motion in congenitally blind subjects demonstrates that its recruitment is not mediated by visual-based mental imagery and that visual experience is not

necessary for the development of this cortical system. The fact that area hMTþ was activated at different anatomical locations in sighted and congenitally blind individuals, however, suggests that

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lack of vision leads to functional rearrangements of this supramodal area. Indeed, results from an earlier brain imaging study showed that visual experience plays a critical role in the functional segregation of hMTþ into a more anterior part that is involved in the representation of both optic and tactile motion and a more posterior part that is uniquely involved in the representation of optic flow (Ricciardi et al., 2007). In the case that hMTþ develops in the absence of visual experience, the entire structure becomes involved in tactile motion representation. This suggests that competitive interactions between visual and tactile inputs in normal development lead to a functional specialization in hMTþ that does not develop without visual input. In a subsequent study, we trained blind and blindfolded sighted subjects to use the TDU in a shape recognition task. Participants were presented four different shapes (a triangle, rectangle, square, and the letter E) and they had to indicate which of the four shapes had been presented. In line with our hypothesis, the fMRI data showed that during nonhaptic shape recognition, blind subjects activated large portions of the ventral visual stream, including the cuneus, inferotemporal (IT) cortex, lateral occipital tactile vision area (LOtv), and fusiform gyrus (Matteau et al., 2008). Control subjects activated area LOtv and precuneus but not cuneus, IT, and fusiform gyrus. These results indicate that congenitally blind subjects recruit key regions in the ventral visual pathway during nonhaptic tactile shape discrimination. The activation of LOtv by nonhaptic tactile shape processing in blind and sighted subjects adds further support to the notion that this area subserves an abstract or meta-modal representation of shape (Amedi et al., 2001, 2002; Pietrini et al., 2004). The above results lead us to the following conclusions. First, the segregation of the efferent projections of the primary visual cortex into a dorsal and ventral visual stream is preserved in individuals blind from birth. Second, cortical “visual” association areas are capable of processing and interpreting

information carried by nonvisual sensory modalities. This is not merely the consequence of brain reorganization following congenital blindness, as this ability also exists in sighted subjects. Third, the differences in the extent and magnitude of the activated areas in blind and sighted subjects are likely due to the effects of rearrangements that follow the lack of sight. The supramodal nature of this functional cortical organization explains how individuals who never had any visual experience are able to acquire normal knowledge about objects and their position in space and form mental representations of and interact effectively with the external world.

There is more than touch to activate the occipital cortex in the blind The studies we have been discussing so far mainly concern the somatosensory system. However, there is ample evidence that other sensory inputs also activate the visual cortex. For instance, studies in the auditory domain have demonstrated that congenitally blind subjects have superior auditory capacities (Lessard et al., 1998; Röder et al., 1999) and that this is related to activation of their visual cortex by auditory stimuli (Gougoux et al., 2005). Not much is known about the other remaining senses. We recently started investigating olfactory processing in the blind. The few published studies in this field have reported highly contradictory results, some finding no performance differences between congenitally blind and sighted subjects, whereas others concluded that the blind have a better developed sense of smell. We studied odor detection threshold, odor discrimination, and odor identification in congenitally blind subjects and a group of matched sighted subjects. We also assessed self-reported odor awareness—that is, consciousness of olfactory sensations—by means of the Odor Awareness Scale (OAS). The OAS questionnaire measures to which degree participants notice, pay attention to, or attach importance to smells

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(Smeets et al., 2008). Our results showed that blind subjects have a lower odor detection threshold compared to sighted subjects (Kupers et al., 2011). However, we found no differences in odor discrimination or identification. Interestingly, blind subjects scored higher on the OAS, indicating an increased awareness for smells. Among the OAS items that were rated significantly higher by blind subjects, most were related to fragrances or to the smell of people. This suggests that in the absence of vision, more attention is directed toward other people's smell, which can provide information about a person's identity. Next, we conducted an event-related fMRI study in which congenitally blind and sighted controls performed an odor detection task (BeaulieuLefebvre et al., 2010). Blind participants showed significantly stronger blood oxygenation leveldependent (BOLD) responses in primary (right amygdala) and higher order (right orbitofrontal and bilateral hippocampus) olfactory cortex and occipital cortex during odor detection (Fig. 3c). These data provide the first demonstration that the visual cortex of the blind can also be recruited by odorants, thus adding new evidence to its multimodal function. The increased BOLD responses in higher order olfactory cortex and visual cortex may provide a neurobiological substrate for the increased odor awareness in blind subjects. There is strong evidence that congenitally blind subjects also recruit their visual cortex in a variety of cognitive tasks such as lexical and phonological processing, episodic memory, and visuospatial imagery (Amedi et al., 2003; Cattaneo et al., 2008; Raz et al., 2005; Röder et al., 2002; Stevens et al., 2007). We investigated the possible role of the occipital cortex in the congenitally blind in repetition priming which is a nonconscious (implicit) form of learning (Kupers et al., 2007). Repetition priming involves a change in the ability to identify an object or generate a word as a consequence of a specific prior encounter with it. At the behavioral level, it manifests itself by an increase in accuracy or speed of task

performance following earlier encounter(s) with the task or stimulus (Schacter et al., 2007). We asked a group of congenitally blind subjects to read a list of Braille words in a language (Finnish) unknown to them. Participants read the list three times in a row, as fast and as accurately as possible. The improvement in performance between the first and the third reading provides an index of the magnitude of the repetition priming effect. Next, participants read a new list of words immediately following a 15-min period of repetitive transcranial magnetic stimulation (rTMS) over the mid-occipital cortex or over a control region. The data showed that the repetition priming effect was largely abolished when rTMS was applied over the occipital cortex but not when applied over a control area. Participants also made significantly more reading errors following mid-occipital rTMS. These data further highlight the role of the occipital cortex in the blind in higher cognitive functions.

A journey through the dark: navigation in the absence of vision Vision is undoubtedly an important facilitator of navigation. The access to visual information explains why sighted individuals can easily select a navigational path through a hallway scattered with obstacles. Avoiding obstacles and creating a cognitive map of the environment is obviously more difficult in the absence of vision and remains one of the greatest navigational challenges faced by blind individuals. Notwithstanding, congenitally blind subjects are able to generate spatial representations, probably through tactile, auditory, and olfactory cues, as well as motion-related cues arising from the vestibular and proprioceptive systems, and they preserve the ability to recognize a traveled route and to represent spatial information mentally (Passini et al., 1990; Thinus-Blanc and Gaunet, 1997).

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One area for which the TDU could be particularly useful in the daily life of the blind is therefore spatial navigation. We tested the potential of the TDU in a series of behavioral and brain imaging studies. In a first study, we trained a group of blind and blindfolded sighted control subjects to use the TDU in a life-size obstacle course (Chebat et al., 2011). The obstacle course was composed of two hallways in which obstacles of different sizes and shapes were placed. Although both groups learned to detect and avoid the obstacles, blind subjects performed significantly better than the sighted. These data underscore the potential of the TDU as a navigational aid in people lacking vision from birth. This brings us to the question concerning the cortical network that is recruited for navigation in the blind. The neural correlates of navigation in congenital blindness have remained largely elusive, mainly because of the difficulty in testing navigational skills of blind subjects in a functional brain imaging study. We circumvented this difficulty by using the TDU (Kupers et al., 2010). During 4 consecutive days, congenitally blind and blindfolded sighted participants were trained in a route navigation and a route recognition task. In the route navigation task, they learned to navigate through two virtual routes that were presented via the TDU, by using the arrow keys of a keyboard. In the route recognition task, the computer program guided the participants automatically through the routes and they then had to indicate which route had been presented. Both groups learned the navigation tasks with the blind slightly outperforming the sighted controls. Following behavioral training, subjects repeated the route recognition task inside the MRI scanner. The fMRI data revealed that during route recognition, blind subjects showed increased BOLD responses in large parts of the visual cortex, the right parahippocampus, posterior parietal cortex, precuneus, and dorsolateral prefrontal cortex (Fig. 3d). These data are in sharp contrast with those of the blindfolded sighted controls who did not show task-dependent BOLD signal increases

in the parahippocampus or in any region of the visual cortex. In a second fMRI experiment, we demonstrated that the areas activated by the blind participants are the same as those activated by sighted subjects when they did the same navigational task under full vision. These data suggest cross-modal plasticity in spatial coding. They also suggest that visual experience is not necessary for the development of a spatial navigation network in the brain, as visual association cortical areas are capable of processing and interpreting spatial information carried by nonvisual sensory modalities.

Subjective experience associated with activation of the visual cortex In the preceding sections, we provided evidence that the occipital cortex in the congenitally blind is recruited by a wide variety of different sensory stimuli and cognitive tasks. It is generally accepted that cortical activity in a certain area produces a subjective sensation within the same domain. Thus, electrical stimulation experiments by Penfield showed that when stimulating the somatosensory cortex, tactile sensations referred to a particular body area are induced. Moreover, the body is somatotopically mapped: inputs from neighboring body parts are encoded in adjacent parts within the primary somatosensory cortex (Penfield and Boldrey, 1937). Transcranial magnetic stimulation (TMS) is a technique that allows stimulation of the cortex in a noninvasive manner (Cowey and Walsh, 2001). A large number of studies have shown that TMS applied over the occipital cortex in normal sighted subjects produces transient perceptions of light, called phosphenes (Kammer et al., 2005). In view of the above finding of cross-modal responses in the occipital cortex of the blind, the question is now which type of sensations will be induced by TMS of the occipital cortex in these subjects. In a first study, we used the TDU to examine the subjective character of experience associated with

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the activation of occipital cortex before and after the establishment of cross-modal plasticity (Kupers et al., 2006). More specifically, we wanted to test the possibility that stimulation of the occipital cortex can induce subjective sensations associated with the new (tactile) input. Before training, TMS of the occipital cortex elicited phosphenes in the control subjects but not in the congenitally blind. In sharp contrast, following a 1-week training with the TDU, occipital TMS evoked “tactile sensations” on the tongue in the blind subjects (Fig. 4a). These were described as short-lasting tingling sensations, varying in intensity, extent, and topography depending on the precise occipital stimulation site. We found a positive correlation between the amount of occipital cortex activated in a

PET study with the TDU and the number of occipital sites from which TMS-induced tactile sensations could be induced. None of the trained sighted participants reported TMS-induced tactile sensations on the tongue. If tactile sensations referred to the tongue can be induced by stimulating the occipital cortex in blind subjects trained with the TDU, TMS should also be able to induce tactile sensations referred to the fingertips in proficient blind Braille readers. We addressed the question of remapping of the fingers onto the visual cortex in a group of blind Braille readers and Braille-naive normal sighted controls (Ptito et al., 2008a). Again, TMS of the occipital cortex in control subjects evoked only phosphenes. As predicted, blind subjects reported tactile sensations in the fingers,

Fig. 4. Tactile sensations evoked by TMS of the occipital cortex in congenitally blind subjects. (a) Somatotopically organized tactile sensations in the tongue induced by TMS over the occipital cortex in four blind subjects trained with the TDU. The figure shows the areas of the tongue where tactile sensations were felt after TMS of visual cortex. The numbers on the scales refer to the distance (in centimeters) from the inion (after Kupers et al., 2006). (b) Representation of occipital cortex sites that induced tactile sensations in the fingers in two proficient Braille readers. Shown in colors are the areas of the fingers where tactile sensations were felt after TMS stimulation of the occipital cortex. Color scale, red indicates the highest number of cortical sites that induced paresthesiae in a particular finger and purple the lowest number (after Ptito et al., 2008a).

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varying in intensity, extent, and topography depending on the stimulated occipital area (Fig. 4b). We found again important interindividual differences with respect to the number of sites from which tactile sensations could be induced and in the topography of the referred sensations. The subjects reporting the highest amount of finger paresthesiae were the ones with the best Braille reading performance. The results of these experiments constitute the first direct demonstration that the subjective experience of activity in the visual cortex after sensory remapping is tactile, not visual. They provide new insights into the ongoing scientific debate on cortical dominance or deference (Hurley and Noë, 2003; James, 1890). What is the experience of a subject in whom areas of cortex receive input from sensory sources not normally projecting to those areas? Our studies suggest that the qualitative character of the subject's experience is not determined by the area of cortex that is active (cortical dominance), but by the source of input to it (cortical deference). Our results are also in line with recent evidence that sensory cortical areas receive input from multiple sensory modalities early in development (Falchier et al., 2002; Rockland and Ojima, 2003; Wallace et al., 2004).

Cortical reorganization or unmasking? Two competing hypotheses have been put forward to explain cross-modal plasticity in congenital blindness. According to the cortical reorganization hypothesis, cross-modal brain responses are mediated by the formation of new pathways in the sensory-deprived brain (Bronchti et al., 2002; Chabot et al., 2007, 2008; Desgent et al., 2010). According to the unmasking hypothesis, loss of a sensory input induces unmasking and strengthening of already existing neuronal connections. Although our results with the TDU are compatible with both hypotheses, the rapid onset of cross-modal responses excludes the

possibility of mediation by the establishment of new connections and therefore favors the unmasking hypothesis. One possibility is that training unmasks and strengthens preexisting connections between the parietal and the occipital cortices. There is indeed electrophysiological (Fishman and Michael, 1973) and anatomical (Falchier et al., 2002; Rockland and Ojima, 2003) evidence that primary visual cortex in normal mammals receives input not only from the visual thalamus but also from somatosensory and auditory modalities. These nonvisual inputs conveying tactile and auditory inputs to the occipital cortex may modulate the processing of visual information (Macaluso et al., 2000), while not giving rise to subjective nonvisual sensations under normal circumstances due to masking by the dominant visual input. It is interesting to mention the results of Zangaladze et al. (1999) showing that disrupting the function of the visual cortex by TMS impairs tactile discrimination of grating orientation in normal-seeing subjects. This confirms that although the visual cortex receives tactile input, this normally does not lead to subjective tactile sensations. Thus, in our trained control subjects, TMS over occipital cortex produced only phosphenes, without tactile sensations. However, under certain circumstances, nonvisual processing in the occipital cortex can be strengthened or unmasked. In line with the dynamic sensorimotor hypothesis, training with the TDU device results in new highly specific learned dynamic interaction patterns between sensory stimulation and active movement (O'Regan and Noe, 2001), thereby further strengthening and unmasking existing connections between the parietal and occipital cortices.

Conclusion The study of the blind person's brain has offered new insights regarding the plastic rearrangements that take place when visual input is lacking. It has also lead to a better understanding of the

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functional organization of the sighted person's brain itself. In this respect, the availability of novel noninvasive brain mapping methodologies has provided a framework for our understanding of the neural mechanisms that enable awareness of the surrounding world. New findings from our own studies as well as from others seem to concur that the blind person's brain should not be considered as a “disabled” brain but rather as a truly “differently able” brain.

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