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Neural reorganization following sensory loss: the opportunity of change

Lotfi B. Merabet and Alvaro Pascual-Leone Abstract | There is growing evidence that sensory deprivation is associated with crossmodal neuroplastic changes in the brain. After visual or auditory deprivation, brain areas that are normally associated with the lost sense are recruited by spared sensory modalities. These changes underlie adaptive and compensatory behaviours in blind and deaf individuals. Although there are differences between these populations owing to the nature of the deprived sensory modality, there seem to be common principles regarding how the brain copes with sensory loss and the factors that influence neuroplastic changes. Here, we discuss crossmodal neuroplasticity with regards to behavioural adaptation after sensory deprivation and highlight the possibility of maladaptive consequences within the context of rehabilitation.

6 Cooperative advantage Equipped with multiple senses and specialized sen­ brain . In particular, it seems that these changes involve With regards to multisensory sory organs, we capture and interact with a rich multi­ not only areas of the brain that are responsible for the integration, refers to the sensory world. The unified and salient nature of our processing of the remaining senses but also areas nor­ interaction of sensory sensory experiences is the product of extensive and mally associated with the processing of the sensory information from the different sensory modalities that can dynamic neural connections, which in turn are highly modality that is lost. Furthermore, these changes might lead to an enhanced influenced by our experiences and developmental translate into behavioural skills and task performance perceptual experience. constraints. Current evidence supports the notion that levels that are equal and in certain cases even superior multisensory integration enhances overall perceptual to those of individuals with intact sensory function. In Neuroplastic changes cooperative advantages1,2 neuroplastic changes The ability of the nervous accuracy and saliency through other situations, however, might system to change its functional and provides the redundancy of cues that is necessary be maladaptive, particularly in light of rehabilitative and structural organization in to fully characterize objects in our environment3. efforts that attempt to restore sensory function after it response to development, This integrative strategy and organization might also has been lost or fails to develop. Thus, at one extreme experience, the environment, account for compensatory behaviours that follow the there seems to be an underestimation of the adaptive damage or insult. loss of a sensory modality. potential of the brain, whereas at the other there is an Traditionally, life without a particular sense has been assumption that neuro plasticity always leads to posi­ viewed as ‘impoverished’ and many early theories pos­ tive and advantageous outcomes. Understanding the tulated that sensory deprivation would have devastat­ nature of these neuroplastic changes is important not Berenson-Allen Center for Noninvasive Brain ing effects on development, learning and cognitive just in terms of establishing the brain’s true adaptive Stimulation, Department of behavioural performance (for example, REFS 4,5). The potential but also in elucidating intervening develop­ Neurology, Beth Israel ‘deficiency’ theory purports that a lack of perceptual mental constraints and guiding future rehabilitation Deaconess Medical Center, sensory experience leads to an overall impairment in strategies. The study of neuroplasticity is an extremely Harvard Medical School, 330 Brookline Avenue, KS-158 cognitive task performance given that proper multisen­ broad field that is investigated at multiple levels from Boston, Massachusetts sory integration can result only from the normal devel­ molecules, to neural systems, to behaviour. Much of 02215, USA. opment of each sense. However, it is clear that blind the seminal work regarding neuroplasticity has arisen Correspondence to L.B.M. and deaf individuals make striking adjustments to from investigations of the somatosensory and motor e-mail: lmerabet@bidmc. their sensory loss in order to operate effectively within systems. Here, we focus on behavioural and neuro­ harvard.edu doi:10.1038/nrn2758 their environment. Growing evidence from human and physiological evidence in relation to visual and Published online animal research indicates that these adaptations are auditory deprivation (for reviews of sensorimotor 25 November 2009 inextricably linked to changes at multiple levels of the plasticity, see REFS 7–9).

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Adaptation to sensory loss discrimination39, auditory motion perception40, auditory Blindness. There has long been anecdotal evidence change detection41 and sound localization17,42. occipital that blind individuals compensate for the loss of vision cortex activation has also been reported in conjunction through more effective use of their remaining senses10,11. with auditory linguistic tasks such as speech process­ a systematic review of this issue reveals that blind indi­ ing43, semantic judgment44, auditory verb generation45 viduals (particularly if blind from birth or very early in and verbal­memory tasks23. Finally, similar to obser­ life) show comparable, and in some cases even superior, vations in the tactile domain, the use of visual­to­ behavioural skills to sighted subjects. This includes finer auditory SSDs is also associated with activation in occipital tactile­discrimination thresholds12–15 and superior per­ cortical areas46–49. formance in auditory­pitch discrimination16 and spatial The specific cortical areas implicated in this form sound localization17–20. Superior performance has also of crossmodal plasticity (for example, primary ver­ been shown in other behavioural and cognitive tasks sus higher­order visual areas) vary across studies and including spatial navigation21, speech discrimination22 are likely to relate to the behavioural tasks being per­ and verbal recall23,24. formed. It is also important to note that there is consid­ Given that the blind rely heavily on touch and hearing erable variability in terms of the spatial and temporal to interact with their environment, it would seem rea­ resolution of the methodologies used, the nature of the sonable that neurophysiological changes would manifest tasks and analyses performed and the types of patients themselves within regions of the brain responsible for investigated, making comparisons across studies diffi­ somatosensory and auditory processing. Expansion and cult. However, there is direct experimental and clinical reorganization of the cortical finger representation have evidence that the recruitment of occipital areas is caus­ been reported in blind proficient Braille readers (detected ally related to compensatory behaviours in the blind. The by somatosensory evoked potentials25 and magneto­ experimental evidence comes from a series of studies encephalography (MEG)26,27). This reorganization has demonstrating impairments in crossmodal behavioural been interpreted to reflect an adaptation that might allow tasks following the transient and localized disruption more enhanced processing and efficient reading skills in of occipital cortex function with transcranial magnetic these individuals26,27. Changes at the level of auditory stimulation (TMS)50. For example, TMS delivered to the cortical areas in the blind have also been investigated. occipital cortex impairs Braille reading performance in For example, responses to tone bursts and tonotopic proficient Braille readers51–53. Using a similar approach, mapping studies (using MEG) have revealed an expan­ TMS delivered to occipital cortical targets has been N1 potential sion in areas that respond to auditory stimuli, and signal shown to disrupt verb generation performance54 and A large negative-direction response latencies (specifically the N1 potential, which also the use of auditory SSD systems48,55. In the clini­ evoked potential (measured by electroencephalography) is associated with acuity in central auditory areas) are cal setting, there is also a case report of a congenitally detected over the significantly shorter in blind individuals than in sighted blind patient rendered alexic for Braille after suffering fronto-central region of the controls28. In a recent functional MrI (fMrI) study, indi­ a bilateral occipital stroke56. although the patient could scalp and peaking between viduals who had been blind from an early age showed discriminate everyday objects by touch, she was no 80 and 120 ms after the onset of a stimulus (typically signal alterations in the auditory cortex that were consist­ longer able to read Braille and showed striking deficits 56,57 auditory). This potential has ent with more efficient processing of auditory stimuli as in tasks requiring fine tactile spatial discrimination . been found to be sensitive to opposed to an altering of inherent patterns of tonotopic The deficits described in this case are in line with the features of sounds associated organization29. Structural changes outside somatosen­ functional impairments described following reversible with speech. sory and auditory cortical areas have also been reported. cortical disruption using TMS. Together, these findings Sensory substitution device For example, superior spatial navigation performance support the idea that the recruitment of occipital cortex (SSD). A device that transforms in the blind has been correlated with a larger volume of in high­level cognitive processing and within the context the characteristics of one the hippocampus (assessed by morphometric MrI21), a of visual deprivation is functionally relevant. sensory modality (for example, structure with a well­established role in navigation and vision) into stimuli that can be 30 perceived by another sensory spatial memory . Deafness. like blind individuals, deaf people rely strongly modality (for example, touch or In parallel to these reported physiological and mor­ on their intact senses to interact with their surroundings. hearing). This strategy is often phological changes, areas within the occipital cortex For example, deaf individuals use visual or tactile stimuli used in assistive technology to (normally attributed to visual processing) are function­ to alert attention and many use visuospatial forms of lin­ access sensory information ally recruited in blind persons to process non­visual guistic communication such as sign language. as a corol­ normally perceived by an impaired sensory modality by information obtained from intact sensory modalities lary to the findings described in the blind, deaf individuals using the remaining intact (FIG. 1a). This form of crossmodal plasticity has been show superior skills in certain perceptual tasks compared senses. demonstrated repeatedly using various neuroimaging with hearing control subjects (FIG. 1b). For example, methods31,32 and numerous subsequent reports have enhanced tactile sensitivity (using vibrotactile stimuli) Alexia 58 A neurological disorder demonstrated task­specific activation related to tac­ has been reported . In the visual domain, deaf subjects 33–36 characterized by the loss of the tile processing tasks such as Braille reading , haptic perform better than hearing controls in distinguishing ability to read. Alexia typically object identification37 and the use of visual­to­tactile emotional expression and local facial features59,60. Deaf occurs following damage to sensory substitutive devices (SSDs)38. occipital visual individuals are also better than hearing controls at per­ specific language-relevant cortical areas also seem to be recruited in response to forming peripheral visual tasks and distributing attention areas of the brain (particularly 61–64 within the left hemisphere) as auditory stimuli. neuroimaging studies have demon­ to the visual periphery . This augmentation of atten­ well as the occipital and strated crossmodal activation of occipital cortical areas tional resources towards the periphery might be adaptive parietal lobes. by sound­processing tasks, including sound­source and serve as a compensatory means to direct attention or

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abCrossmodal changes following blindness Crossmodal changes following deafness and BOX 1). Finally, a series of neuroimaging studies (recruitment of occipital visual cortex) (recruitment of auditory cortex) combined with visual peripheral tasks have also reported evidence that deaf individuals show greater recruitment of occipital­parietal cortical areas related to attention processing than hearing controls61,63,75,76. It has been difficult to demonstrate experimentally the causal role of crossmodal recruitment of auditory cortex in non­auditory tasks. This might relate to tech­ nical issues with the experimental methodologies used. For example, TMS must be delivered close to the ear to transiently disrupt the function of auditory temporal regions, and the audible click generated by a discharg­ • Braille reading and tactile discrimination • Sign langauge ing TMS coil could interfere with task performance. • Auditory localization and discrimination • Visual tasks Furthermore, apart from such stimulation being quite • Verbal memory and language • Vibro-tactile stimulation uncomfortable (owing to stimulation of the overlying Figure 1 | summary of crossmodal neuroplasticity following sensory loss. temporalis muscle), the sulcal geometry and orientation of auditory cortical areas make them difficult to stimulate Crossmodal recruitment of occipital visual cortex in the blindNa andture auditory Reviews |cortex Neuroscienc in e the deaf have been reported. a | Occipital recruitment for tactile processing such as optimally. Braille reading, sound localization and verbal memory. b | Recruitment of auditory and although these technical issues might have limited language-related areas for viewing sign language, peripheral visual processing controlled experimental investigations, several case and vibro-tactile stimulation. reports describing deaf patients with circumscribed brain lesions have provided clinical evidence regarding sign language production and comprehension. For example, orient towards objects of interest outside the central field lesions of the left temporal cortex lead to impairments of view62. Superior performance in visual motion detec­ in sign language comprehension, consistent with the tion and discrimination has been described in the deaf, notion that sign language comprehension depends pri­ particularly with respect to the right visual field65,66. This marily on the left hemispheric structures that mediate right visual field advantage might be related to the later­ language function in hearing subjects77,78. There have alization of language function, which is typically ascribed also been reports of ‘sign blindness’ in a deaf signer fol­ to the left hemisphere. Thus, there might be a preferential lowing damage to the left occipital cortex79. This patient association regarding the processing of motion informa­ exhibited severe impairments in comprehension but not tion within the right visual field and the left (that is, the in the production of signs, analogous to alexia. Similarly, contralateral) hemisphere, which is normally associated a left occipital lesion in a deaf signer caused acquired with language processing65,66. sign language aphasia with severe impairment in word In deaf humans, there is less evidence for large mor­ production as well as comprehension, reading and writ­ phological changes in brain areas that process intact ing80. Thus, consistent with neuroimaging data, it seems sensory modalities. one study found no differences in that temporal­auditory and occipital­visual cortical areas responsivity or in the size of early visual cortical areas have specialized functions that are crucial for language (assessed with fMrI) in deaf subjects compared with abilities in deaf signers. hearing controls67. However, this lack of observed changes does not rule out the possibility of potential morphologi­ Adaptation to multiple sensory loss cal differences in higher­order visual areas or even other Deaf-blindness. Few studies have examined the behav­ sensory cortices. Thus, further investigation of this issue ioural and physiological consequences of multiple sen­ seems necessary. as in blind individuals, there is evidence sory loss, particularly in humans. The development of that auditory cortical areas are recruited by tactile, lan­ language function and communication skills in deaf­ guage and visual processing tasks. For example, activ­ blind individuals provides an interesting opportunity to ity in the auditory cortex has been detected by MEG in investigate this issue. Deaf­blind individuals commu­ response to vibrotactile stimulation in congenitally deaf nicate using tactile­based languages, including Braille subjects68. also, fMrI has detected activity in the audi­ and various haptic forms of sign language. In a study tory cortex of subjects deaf from an early age in response of one late­blind, post­lingual deaf­blind subject, MEG to vibration stimuli derived from speech and fixed fre­ and positron emission tomography (PET) imaging were quencies69. Several studies have shown crossmodal used to investigate the neural activity associated with recruitment of auditory areas in deaf individuals viewing identifying japanese words using a tactile mode of letter 70–72 Aphasia sign language . Crossmodal activation of auditory cor­ spelling (that is, by touching and stroking the fingertips 80 A neurological disorder tex by non­linguistic visual stimuli (for example, moving representing different consonants and vowels) . In line characterized by impaired dot patterns) has also been demonstrated using MEG73 with the crossmodal changes described in blind and deaf expression and understanding and fMrI74. Interestingly, this pattern of activation was individuals, the identification of tactile words was asso­ of language, as well as reading not found in hearing signers (specifically, the children ciated with activation of visual and auditory language and writing. It is usually the result of damage to areas of of deaf parents), indicating that auditory deprivation (as cortical areas. These results indicate that in the case of the brain involved with opposed to sign language experience) might be crucial dual sensory deprivation, dramatic crossmodal recruit­ language processing. for this form of crossmodal recruitment (see also REF. 67 ment of cortical areas associated with visual, auditory

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Usher syndrome and language processing is possible. However, the sub­ combined early onset deprivation, a control experiment A relatively rare genetic ject’s late­blind and post­lingual deaf status makes it dif­ used the same word identification task in a normally disorder with clinical subtypes ficult to disentangle the contribution of prior sensory hearing and sighted interpreter for the deaf­blind. as characterizing the degree of experience with regards to the pattern of crossmodal with the deaf­blind subject, the identification of words severity and a leading cause 81 of combined deafness and cortical recruitment observed. Indeed, visual imagery through haptic aSl was associated with left­lateralized 82 blindness. Hearing loss is and inner speech and auditory verbal imagery activate activation of inferior frontal language areas (including associated with a defective corresponding occipital, auditory and language process­ Broca’s area). However, robust occipital cortex activation inner ear whereas the visual ing areas. To rule out this possible confound, the neural was not observed83 (FIG. 2b). The crossmodal recruit­ loss is associated with correlates of language processing in a congenitally deaf ment observed in this deaf­blind individual is striking, degeneration of retinal cell function. and early­blind individual who is highly proficient in given that he never developed articulated speech or, communicating through a haptic form of american unlike deaf signers, learned aSl through visual asso­ Sign language (aSl) were explored83. By placing his ciations. Furthermore, these results suggest that follow­ hand over a signer’s hand, he could capture the meaning ing early onset visual and auditory deprivation, tactile of word signs and gestures. Functional MrI showed that communication is associated with the recruitment of word identification (compared with non­words) acti­ occipital and auditory cortical areas, further demon­ vated areas of occipital cortex (including calcarine­striate strating the remarkable neuroplastic changes that follow and extrastriate regions), left posterior superior­temporal sensory loss. areas (including wernicke’s area and the superior tem­ poral gyrus (Brodmann area 22)) and inferior frontal Underlying mechanisms cortical areas (including Broca’s area (Brodmann area The exact mechanisms that underlie crossmodal plas­ 44)) (FIG. 2a). To further distinguish between activation ticity and the neural basis of behavioural compensa­ related to haptic language processing and areas related to tion remain largely unknown. However, animal studies have provided important insights based on physiologi­ cal, behavioural and anatomical data (for reviews, see Box 1 | The heterogeneity of sensory loss: a potential confound REFS 2,6,84,85). Similar to the behavioural results The World Health Organization (WHO) defines legal blindness as a best-corrected visual described in blind humans, animal models of visual dep­ acuity worse than 20/200 (Snellen equivalent) or a visual field less than 20° (note that rivation also show evidence of crossmodal compensatory legal blindness does not necessarily imply profound blindness). Current estimates changes. For example, experimentally visually deprived suggest that blindness afflicts 45 million individuals worldwide, with cataracts, cats6,86 and ferrets87 possess superior sound localization age-related macular degeneration and glaucoma being leading causes135. In terms of hearing impairment, the WHO has estimated that 278 million individuals worldwide have abilities to normal animals. at a neurophysiological level, moderate to profound hearing loss in both ears (profound hearing loss being defined as single­unit recordings from a multisensory region called not being able to detect a tone of 90 dB or greater), and causes are typically associated the anterior ectosylvian cortex (aES; FIG. 3a) show that in with sensorineural deficits of the auditory nerve136. As with visual impairment, the visually deprived cats, cortical areas that respond to audi­ aetiology is highly variable and includes hereditary causes as well as acquired causes tory stimuli expand significantly88 and neurons in this including infections and trauma. Combined vision and hearing loss (or dual sensory loss) is region are more sharply tuned to auditory spatial loca­ more prevalent with increasing age. However, certain hereditary conditions such as Usher tion89. Investigations of the development and maturation syndrome137 can also lead to combined, early-onset visual and auditory impairment. of multisensory circuits within the cat aES confirm that When interpreting the experimental evidence, it is important to underscore the the capacity for multisensory integration is rudimentary tremendous degree of heterogeneity with regards to sensory impairment in both blind during early postnatal life, that it gradually develops over and deaf populations. Important factors include the aetiology, severity, onset and time and that it is highly influenced by timing and the developmental time course of the sensory loss. Furthermore, many of the human 90,91 studies demonstrating superior performance abilities in blind and deaf persons have animal’s overall sensory experience . To investigate been carried out in highly specific population subsamples, such as in congenitally blind the contribution of early visual sensory experience to individuals or deaf native signers (that is, children who have had early exposure to sign cortical multisensory development, further work was language and achieve language development milestones similar to hearing carried out on dark­reared cats92. In these experiments, individuals127). In addition, many of these studies have been carried out under very semichronic single­unit recordings in the aES (in anes­ controlled experimental conditions and/or high task demands (for example, monaural thetized animals) were made at weekly intervals from testing18) or by comparing performance against control subjects but under acute birth until adulthood. The results confirmed that visual 12 sensory deprivation conditions (for example, by blindfolding sighted participants ). deprivation (and non­visual multisensory experiences) Finally, it is important to disentangle evidence of brain activation related to long-term had a striking effect on the integrative capabilities of skill training (for example, Braille and ASL) from activation due to the sensory deprivation itself56,67,73,138. multisensory neurons in the aES. Specifically, there At the other extreme, studying specialized population subgroups and highly was a significant increase in the proportion of multisen­ controlled experimental conditions might allow ‘cleaner’ interpretation of data but sory neurons modulated by a second sensory modality potentially at the expense of a loss in generalizability across the entire population. (FIG. 3b). These results confirm that early deprivation Finally, vision and hearing loss typically occur progressively, later in adult life, and has a significant impact on crossmodal function and individuals often maintain some degree of residual sensory function. Future studies show how the senses interact to reflect specific features might benefit from considering variables beyond simply the aetiology and strict age of an animal’s environment and ultimately optimize cut-offs for acquiring total sensory deprivation. For example, functional (such as adaptation to that environment91. language experience and travel independence), personal (such as confidence and Parallel studies of auditory cortical plasticity have also motivation) and behavioural (such as degree of instruction and level of proficiency) been carried out. These are not as extensive as those car­ criteria may prove helpful in grouping and comparing study subjects in terms of ried out within the visual and somatosensory systems, underlying neuroplastic change (see also REFS 62,127,139 for related discussion). possibly owing to technical challenges in developing

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a Deaf-blind subject b Hearing and sighted signer areas, and also to depend on whether the cortical rep­ resentations are central or peripheral98. a more recent anatomical tracing study (using marmosets) found that unimodal sensory areas were linked by multiple hetero­ modal connections including visuo­somatosensory, visuo­auditory and somatosensory­auditory projec­ tions101. Furthermore, electrophysiological evidence in monkeys confirms multisensory convergence at the neu­ Occipital cortex ronal level and in early stages of cortical sensory process­ Inferior frontal Superior temporal Inferior frontal ing, including auditory­visual convergence within V1 cortex language areas cortex (REF. 102) and somatosensory­auditory interactions within a region caudal­medial to primary auditory Figure 2 | crossmodal neuroplasticity in dual sensory loss (vision and hearing). cortex103. as these connections exist in the intact adult Nature Reviews | Neuroscience Localization of activation (revealed by functional MRI) associated with identifying words brain, one possibility is that sensory deprivation leads through haptically presented American Sign Language (ASL) in both a pre-lingually deaf and early-blind individual (a) and a hearing and sighted control (b) subject (for simplicity, to more pronounced changes in relative connectivity only the left hemisphere is shown). Crossmodal networks associated with the between cortical areas. identification of words (as opposed to non-words) include the inferior frontal cortex in It is unclear whether these connections and mecha­ the left hemisphere (corresponding to Broca’s area (Brodmann area 44)) in both subjects. nisms underlie crossmodal neuroplastic changes in The white dashed circle identifies activation in superior temporal language areas humans. However, there is evidence consistent with the (including Wernicke’s area and the superior temporal gyrus). Occipital cortex activation notion of enhanced cortico­cortical inter­sensory inter­ is also labelled. Activation in occipital and temporal cortical areas seems to be specific to actions. Specifically, effective connectivity between som­ the combined loss of vision and hearing. Data from REF. 83. atosensory and visual cortical areas was demonstrated in early­blind humans using a combination of TMS (to appropriate animal models and controlled restricted stimulate primary somatosensory areas) and PET imag­ environments (see REF. 93 for a review). The organiza­ ing (to visualize the effect of somatosensory stimulation tion of auditory receptive fields and cortical mapping in early visual cortical areas)104. Furthermore, evidence of have been actively studied using various electrophysio­ functional crossmodal sensory processing in the occipi­ logical techniques (reviewed in REF. 94). The extent of tal visual cortex in adult sighted subjects57,105 and rapid cross modal reorganization has been investigated in and reversible crossmodal recruitment of the occipital congenitally deaf cats. Electrophysiological recordings cortex in response to sudden and complete visual depri­ from the primary auditory cortex (a1) of congenitally vation (prolonged blindfolding and sensory training) in deaf cats failed to find crossmodal responses to visual or adult humans with intact senses are consistent with the somatosensory stimuli95 (although it is unclear whether notion that existing connections can be unmasked as a such responses exist in higher­order, associative audi­ response to sensory processing and afferent demand106. tory areas). The investigators proposed that in the case Thus, it is possible that the unmasking of pre­existing of congenital deafness, the ability to learn and develop connections and shifts in connectivity might underlie higher­order auditory representations is substantially rapid, early plastic changes that can lead, if sustained affected in the absence of auditory experience and that and reinforced, to slower but more permanent structural very early onset auditory deprivation cannot be com­ changes, such as dendritic arborization, sprouting and pensated for by top-down influences arising from higher­ growth with rewiring of connections107. tier auditory and associative areas96. Thus, the degree of crossmodal plasticity might be related not only to the Critical periods and adult plasticity timing and profoundness of sensory deprivation but also Pioneering work in sensory deprivation (for example, to whether one considers primary or associative areas. REF. 108) showed that the brain is most receptive to along these lines, there has been speculation that a1 change during an early period of postnatal life referred might represent higher processing complexity than V1 to as the critical period109. Critical periods are specific to (that is, processing stimuli beyond simple feature detec­ sensory modality, function and species109. Furthermore, tion) and would therefore be more analogous to higher­ experimental evidence is consistent with the notion that order areas along the visual processing stream97. In other the earlier the sensory loss, the more striking the neuro­ words, differences in the functional contribution of pri­ plastic effects109. In fact, many of the studies reporting Top-down mary auditory and visual areas within the context of superior behavioural performance and crossmodal Pertaining to information sensory deprivation might be based on their inherent neuro plastic changes have been carried out in subjects processing strategies, a abilities to retain their intrinsic processing in response to who have been blind from birth or early in life (BOX 1). In top-down approach describes the flow of sensory information crossmodal influences from other sensory modalities. the case of blindness, this idea has led some authors to from higher-order cortical one possible explanation for the recruitment of corti­ suggest the existence of a precise critical period (around areas to lower-order processing cal areas following sensory deprivation is through direct 14 (REF. 110) to 16 (REF. 111) years of age) beyond which levels. This is opposite to neural connections with intact sensory areas. anatomical functionally relevant crossmodal recruitment of occipi­ ‘bottom-up’ processing, in studies in cats98 and non­human adult primates have tal cortex (particularly V1) does not occur, theoretically which information being processed from lower-order demonstrated direct connections between auditory and limiting the extent of potential adaptive compensa­ 99,100 regions flows to higher-order visual cortical areas . The patterns of these connec­ tory behaviour. However, the current view regarding areas of sensory cortex. tions seem to differ between primary and associative plasticity is not one of a finite window of opportunity,

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abNormal Dark-reared

No response 13% No response 10% Somatosensory 23% Somatosensory 13% VAS (<1%) VAS (1%) AS (5%) AES AS (4%) VS (3%) VS (3%) FAES AEV VA (13%) VA (18%) SIV

Visual 17% Auditory 29% Visual 12% Auditory 39% Figure 3 | effects of early visual deprivation in cats. Dark rearing alters the distribution of sensory responsive neurons in the anterior ectosylvian sulcus (AES). a | The lateral surface of the adult cat cortex, with theNa locationture Revie ofws the | NeurAES osciencand thee relative positions of its three major subdivisions: SIV (fourth somatosensory area), FAES (auditory field of the AES) and AEV (anterior ectosylvian visual area). b | The distribution of sensory unresponsive, unisensory and multisensory mature AES neurons in normally reared and dark-reared animals. Values are rounded to the nearest percent. AS, auditory- somatosensory; VA, visual-auditory; VAS, visual-auditory-somatosensory; VS, visual-somatosensory. Part a is modified, with permission, from REF. 2 © (2008) Macmillan Publishers Ltd. All rights reserved. Data in part b from REF. 92.

but rather one in which the brain retains a high level using perceptual learning tasks)116. Thus, the possibil­ of neuroplasticity well into adulthood, although not ity of ‘reopening’ critical periods in the adult animal to the same extent as in the young developing brain107. through intensive behavioural and perceptual train­ admittedly, neuroplastic changes and associated behav­ ing has important implications for regaining function ioural gains in the case of late­onset sensory deprivation in adults even after early­onset sensory deprivation. are less clear and relatively few studies have addressed Furthermore, given that typical ageing trends suggest this issue. In one study, the occipital activation related that individuals are more likely to acquire sensory loss to a verb generation task (using a Braille­presented cue) with increasing age as opposed to early in life (BOX 1), in congenitally and late­blind subjects was compared. the issue of neuroplasticity in the context of late­onset The occipital cortex (including early visual areas) was sensory deprivation also deserves careful investigation. activated in both study groups34. However, congenitally blind individuals showed greater activity (in terms of Restoring sensory function magnitude and spatial extent) than late­blind partici­ although crossmodal plasticity following sensory dep­ pants34. In terms of compensatory behaviours in the rivation can translate into compensatory behavioural auditory domain, enhanced auditory spatial abilities gains, it cannot be viewed as universally adaptive, and (for example, peripheral sound localization) have also unintended consequences are possible. In fact, neuro­ been reported in subjects with late­onset blindness com­ plastic changes might undermine the ability of reorgan­ pared with sighted controls20,112. with regards to auditory ized cortex to perform its primary function, particularly deprivation, the effect of timing on the acquisition of in the context of rehabilitative training (for example, language function through the use of a cochlear implant learning to read Braille proficiently or other forms of lan­ provides parallel insight. Traditionally, language acquisi­ guage training). Take, for example, crossmodal changes tion following implantation has been approached with in the case of blindness. Proficient Braille readers who the mantra of ‘the earlier the better’113 and was once con­ use multiple fingers to read text can mis­identify fingers sidered to be feasible only in post­lingual deaf patients. and mis­localize tactile stimuli117. as another example, More recently, the indications for cochlear implantation TMS delivered to the occipital cortex of blind proficient have expanded to include pre­lingual deaf patients. with Braille readers can induce phantom tactile sensations at very intensive and rigorous training, improved language the finger tips51,118 as well as at the tongue in users of performance has been reported in these patients114. certain tactile SSDs119. Perhaps the most striking exam­ work in animal models might help to uncover the ples come from historic case studies of surgical sight 120,121 Cochlear implant potential underlying neuroplastic mechanisms and their restoration following long­term visual deprivation . A surgically implanted relationship to critical periods, learning and develop­ In the case of patients with treatable early­onset blind­ electronic device that provides mental experience. analogous to the visual deprivation ness (treated by cataract removal or corneal transplanta­ the sense of sound in individuals with profound studies mentioned earlier, it has been shown that rear­ tion), restoring vision in adulthood reportedly leads to hearing loss. The device works ing infant rats in a low­frequency­modulated noise envi­ profound difficulties in visual tasks, particularly those by electrically stimulating ronment leads to profound deficits in primary auditory requiring the visual identification and recognition of nerve fibres of the cochlea to cortex that endure throughout adulthood (specifically, objects. These outcomes have largely been attributed transmit sensory information with regards to the spatial and temporal selectivity of to the idea that early visual deprivation has striking provided by external 115 components including a neurons) . Intriguingly, these deficits incurred dur­ effects on the development of the visual cortex and its microphone and speech ing the critical period of development can be reversed ability to process complex visual information. However, processor. in the adult through intensive training (for example, more comprehensive behavioural and neuroimaging

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studies have revealed a different potential explanation this issue by assessing the ability to segregate conflicting (for example REFS 122–125). Specifically, results from auditory and visual information in an auditory speech adults with early­onset blindness whose sight has been recognition task132. Key to the study design was the fact surgically restored suggest that visual areas that proc­ that hearing control subjects were matched to patients ess different visual attributes might vary in their sus­ with cochlear implants for gender, age and hearing ceptibility to visual deprivation and in their recovery performance. Impaired task performance was particu­ rates. Furthermore, although patients might not show larly evident when comparing non­proficient cochlear­ a striking improvement in measured visual acuity fol­ implant users with their hearing­matched controls132. lowing surgery, other aspects of their visual perception These findings highlight how functional reorganization can improve, disproving the assumption that if acuity following auditory reafferentation might be beneficial does not progress then neither do other aspects of visual in certain cases but detrimental to audiovisual perform­ function126. These studies also reveal that after years of ance in others, and could help to explain the striking blindness from an early age the brain retains an impres­ variability in performance outcomes observed following sive capacity for visual learning. Furthermore, these cochlear implantation. observations might lead to new strategies of visual reha­ In summary, these reports of sensory restoration bilitation that take advantage of the crossmodal trans­ in both the blind and the deaf highlight how evolving fer of sensory information (for example, registering plastic changes might lead to a gradual deterioration in the direction of motion signalled through touch with the ability to process the missing sense and potentially what is perceived through vision) or using one visual render an individual a poor candidate for procedures attribute to ‘bootstrap’ and enhance the development of aimed at restoring the lost sensory function. Thus, the another (for example, learning to perceive object form decision to implant a prosthetic device or implement a as defined by its motion)124. given rehabilitative strategy needs to consider not only its Deaf individuals have often been characterized as effects on residual sensory function but also the poten­ more easily distracted by irrelevant information in the tial to interfere with evolving crossmodal processing visual periphery than their hearing peers (see REFS 62,127 in response to sensory loss133. for further discussion). as in the blind, there might be trade­offs in terms of adaptive gains and maladaptive Conclusions and the implications for rehabilitation outcomes resulting from underlying crossmodal neuro­ In light of the striking neuroplastic changes that plasticity following auditory deprivation. Detailed work follow sensory deprivation, it seems that compensatory on this issue has also been carried out with regards to behaviour is not so much the result of sensory depriva­ hearing and language development in patients with coch­ tion alone, but rather the consequence of how the entire lear implants. For example, in profoundly deaf cochlear brain maintains function in the context of sensory implant recipients, speech performance outcomes are deprivation107. worse in those patients who showed near­normal rest­ as a result of sensory deprivation, some of these plas­ ing levels of metabolic activity in auditory cortical areas tic changes lead to crucial functional advantages, such as (assessed with PET imaging)128,129. This sustained meta­ enhanced localization of sound sources and improved bolic activity (attributed to evolved crossmodal neuro­ verbal memory in the blind, and enhanced visual periph­ plastic changes) can ultimately interfere with the ability to eral sensitivity in the deaf. However, not all neuroplastic recover auditory processing function after implantation changes represent behavioural gains and the restoration of a cochlear implant. The duration of auditory depriva­ of a deprived sense does not automatically translate to tion remains an important factor, but the results of this its eventual functional restitution. neuroplasticity clearly study highlight the importance of investigating under­ affects an individual’s rehabilitative outcome and new lying neuroplastic changes directly as potential predic­ strategies are needed to leverage crossmodal interactions tors of rehabilitative and functional outcomes128. as with in a manner that promotes functional adaptation in par­ the case of sight restoration, these results raise questions allel to rehabilitative and restorative approaches. These as to how restored and intact sensory modalities interact will require a careful consideration of brain plasticity following the restitution of sensory afferents. There is mechanisms, perhaps even modulating brain activity evidence that crossmodal interactions between auditory (such as with non­invasive brain stimulation combined and visual cortical areas tend to increase following coch­ with rehabilitation) on an individual basis to therapeuti­ lear implantation and that these interactions might even cally guide synaptic plasticity mechanisms and enhance mutually reinforce one another130. Such language­related those that promote behavioural gains and suppress those crossmodal changes could allow visual sign language to that may be maladaptive107,134. exploit existing connectivity between auditory cortex In conclusion, it is not possible to understand nor­ and neighbouring semantic and language processing mal physiological function, the manifestations or con­ areas. Interestingly, there is evidence that some cochlear sequences of sensory loss, or the possibility of restoring implant users can integrate congruent auditory and vis­ sensory function without incorporating the concept of ual information better than hearing control subjects131. brain plasticity. In considering the rehabilitation of an However, these beneficial effects cannot be considered individual following sensory loss, it is crucial to con­ universal and there remains the possibility that, under sider each individual’s specific needs and goals in the certain circumstances, these crossmodal sensory inter­ context of how his or her plastic brain interacts with a actions might be intrusive. a recent study investigated multisensory world.

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