Neuroscience and Biobehavioral Reviews 41 (2014) 64–77

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Mind the blind brain to understand the sighted one! Is there a supramodal cortical functional architecture? Emiliano Ricciardi a,b , Daniela Bonino a , Silvia Pellegrini a , Pietro Pietrini a,b,c,∗ a Laboratory of Clinical Biochemistry and Molecular Biology, Department of Surgery, Medical, Molecular, and Critical Area Pathology, University of Pisa, Pisa, Italy b Research Center ‘E. Piaggio’, University of Pisa, Pisa, Italy c Clinical Psychology Branch, Pisa University Hospital, Pisa, Italy

a r t i c l e

i n f o

Article history: Received 5 April 2013 Received in revised form 13 August 2013 Accepted 3 October 2013 Keywords: Blindness Supramodality Cross-modal plasticity Brain imaging Brain functional architecture Mental representation Action recognition

a b s t r a c t While most of the research in blind individuals classically has focused on the compensatory plastic rearrangements that follow loss of sight, novel behavioral, anatomical and functional brain studies in individuals born deprived of sight represent a powerful tool to understand to what extent the brain functional architecture is programmed to develop independently from any visual experience. Here we review work from our lab and others, conducted in sighted and congenitally blind individuals, whose results indicate that vision is not a mandatory prerequisite for the brain cortical organization to develop and function. Similar cortical networks subtend visual and/or non-visual perception of form, space and movement, as well as action recognition, both in sighted and in congenitally blind individuals. These findings support the hypothesis of a modality independent, supramodal cortical organization. Visual experience, however, does play a role in shaping specific cortical sub-regions, as loss of sight is accompanied also by cross-modal plastic phenomena. Altogether, studying the blind brain is opening our eyes on how the brain develops and works. © 2013 Elsevier Ltd. All rights reserved.

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Is vision the only way “to see”? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . To what extent is vision really necessary for the human brain to develop and function? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Supramodal cortical organization subtends a more abstract representation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. How do neocortical (visual) areas develop? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Toward a truly supramodal processing of information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Is supramodality a cortical or a neuronal property? Supramodality versus multisensoriality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Which is the fate of unisensory “visual” brain areas in congenitally blind individuals? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The specificity of cross-modal plastic reorganization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Supramodal, cross-modal and multisensory: mind the difference! . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Where in the occipital cortex? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Which neural pathways may subserve non-visual responses in the “visual” cortex? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Is vision the only way “to see”? When observing a blind individual, people may find themselves wonder whether that person is really visually-deprived.

∗ Corresponding author at: Laboratory of Clinical Biochemistry and Molecular Biology, University of Pisa, Via Roma 67, I-56126, Pisa, Italy. Tel.: +39 050 993951; fax: +39 050 993556. E-mail address: [email protected] (P. Pietrini). 0149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neubiorev.2013.10.006

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Indeed, individuals who lack vision are proficient in everyday’s life activities, are able to interact efficiently with the surrounding objects and tools, move independently in space, and interact socially with others. Although vision offers distinctive information, several observations indicate that the lack of visual experience may have just limited effects on the perception and mental representation of the surrounding world. As a matter of fact, some blind individuals may even excel in activities that would be considered strictly visual: Esref Armagan (www.armagan.com/), John

E. Ricciardi et al. / Neuroscience and Biobehavioral Reviews 41 (2014) 64–77

Bramblitt and Sargy Mann are painters; Michael Naranjo and Steve Handschu are sculptors; Kurt Weston, Evgen Bavcar and Peter Eckert (http://www.peteeckert.com/) are photographers. These are just a few world-known examples of artists who rely on non-visual sensory esthetic to create and make people appreciate a ‘visual’ beauty. Moreover, blind individuals very often may make sighted individuals notice some specific sensorial aspects that the latter are simply ‘unable to see’. Indeed, vision plays a primary role in how we represent and interact with the world around us. Since the early days, sight has always been regarded as the most important sense for humans to interact with the environment and to acquire knowledge. Furthermore, from a neuro-anatomical perspective, approximately 55% of the whole cortex in primates is devoted to visual function, as compared to only 3% for auditory processing and 11% for somatosensory processing (Felleman and Van Essen, 1991). Nonetheless, as mentioned before, vision is not necessary to “see” the world around us, and to form a proficient mental representation of it. In particular, blind individuals who have been visually-deprived since birth show cognitive and social skills that are substantially comparable to those in sighted individuals (Cattaneo et al., 2008; Kupers et al., 2011; Noppeney, 2007). On the other hand, several studies have shown that lack of visual experience often delays the physiological development of cognitive, social and linguistic skills in blind children (Fraiberg, 1997; Peterson et al., 2000; Tobin, 1998) and affect their social functioning. Moreover, while cases of congenitally blindness have decreased significantly over the last decades in the Western countries, both congenital blindness in the developing areas and acquired blindness still represent a major public health issue, as they affect millions of individuals worldwide (http://www.who.int/mediacentre/factsheets/fs282/en/). In the last years, functional brain studies of visually-deprived individuals have offered a unique tool to examine the role of visual experience in forming a representation of the world, as well as to understand to what extent vision is a mandatory prerequisite for the human brain to develop and function. Congenitally blind individuals have provided novel and stimulating insights on many questions regarding not only the cross-modal plastic rearrangements that inevitably take place when vision is absent, but primarily the functional development and organization of the sighted brain itself.

2. To what extent is vision really necessary for the human brain to develop and function? 2.1. Supramodal cortical organization subtends a more abstract representation In order to disentangle how the human brain represents the surrounding world through non-visual sensory modalities, distinct functional brain studies have explored how pieces of information conveyed by touch, hearing, smell or taste, are processed in sighted individuals (e.g. Amedi et al., 2005c; Peelen et al., 2010; Ricciardi et al., 2006). Though many studies reported significant overlapping activations in visual processing areas during these non-visual perception tasks, and thus were in line with the hypothesis of a more abstract representation of the perceived stimuli in ‘visual’ areas (Amedi et al., 2005a, 2005c; Lacey et al., 2007; Pascual-Leone and Hamilton, 2001), they could not rule out that these ‘visual’ activations merely be the effect of the recall of visual imagery-based mental representations (Ricciardi and Pietrini, 2011). Indeed, several independent reports have shown a remarkable similarity in the brain neural response elicited by perception and imagery of the same object category (Ishai, 2010; Ishai et al., 2000).

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A crucial advancement in the demonstration of a supramodal functional cortical organization in the human brain came from the study of visually-deprived individuals, who were either congenitally blind or had become blind at a very early age, and had no visual memories. Indeed, functional brain studies in individuals who have had no vision-based experience or representation made it possible for the first time to demonstrate that neural responses in visual cortex during non-visual sensory processing are not due to visual imagery process (Pietrini et al., 2004). Furthermore, these studies in congenitally blind individuals have been instrumental to understand to what extent visual experience is a mandatory prerequisite for the brain to develop its morphological and functional organization within these “visual” cortical regions. At the same time, if a given feature is also present in sighted individuals, its functional recruitment in congenitally blind individuals has to reflect a more abstract, supramodal representation of a specific content of information, either structurally or semantically, and cannot be simply a consequence of a plastic rearrangement due to the lack of vision (Pietrini et al., 2004, 2009; Ricciardi and Pietrini, 2011). To date, several perceptual, cognitive and, more recently, affective domains have been explored in congenitally blind individuals by combining functional brain imaging methodologies with distinct experimental paradigms. As summarized in Table 1 and Fig. 1, these findings provide a consistent demonstration of the supramodal functional organization of specific task-related cortical networks. For instance, relatively to the well-known organization of the visual system into specialized subregions and distinctive streams of information processing (e.g., the ‘what’, ventral vs. the ‘where/how’, dorsal pathways – Milner and Goodale, 2008; Ungerleider and Haxby, 1994), object representation, motion discrimination and spatial localization have been the most explored abilities. A similar supramodal functional organization for both the ventral temporal occipital cortex of the ‘what’ pathway and the dorsal occipito-parietal stream of the ‘where/how’ pathway has been shown to process, respectively, object form and spatial perception and imagery regardless of the sensory modality through which the information had been acquired, in both sighted and blind individuals (Bonino et al., 2008; De Volder et al., 2001; Lambert et al., 2004; Pietrini et al., 2004; Ricciardi et al., 2010; Vanlierde et al., 2003; Weeks et al., 2000). Thus, highly specialized visual areas, such as the human middle temporal complex (hMT+) or the parahippocampal gyrus, maintain their functional specificity, that is, respectively, motion processing and spatial layout coding, when information are provided through non-visual stimulation tasks, such as tactile or auditory paradigms (Poirier et al., 2006; Ptito et al., 2009; Ricciardi et al., 2007). Interestingly, the functional specificity of this supramodal recruitment in both sighted and blind individuals has been confirmed by many distinct experimental protocols that either conveyed information across different non-visual sensory modalities or via sensory substitution devices, or impaired selective processing by ‘virtual’ (via transcranic magnetic stimulation - TMS) lesions (Collignon et al., 2011a; Frasnelli et al., 2011; Kupers et al., 2011; Kupers and Ptito, 2011; Noppeney, 2007). In addition, connectivity approaches (Klinge et al., 2010; Ma and Han, 2011; Sani et al., 2010; Wolbers et al., 2011), or correlations with behavioral performances (Amedi et al., 2003) further contributed to validate the functional homologies between sighted and blind individuals. A representative case to summarize this experimental route is provided by the studies of object and shape perception. In sighted individuals, visual recognition of distinct object categories elicits distributed and overlapping patterns of neural response in the ventro-temporal extrastriate cortical areas (Haxby et al., 2001). This model, named ‘object form topology’, raises the question whether such a functional organization is strictly visual or rather represents a more abstract, supramodal functional organization

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Table 1 Selected functional imaging studies indicating that the brain functional organization is to a large extent independent from visual experience and able to process information in a supramodal fashion. Subjects

Task

Brain regions

Function

Feature-detection task involving incidental visual/tactile and auditory word processing Auditory-sound localization

Left posterior temporal lobe (BA37) and left frontal operculum Posterior parietal and occipito-parietal areas Occipito-temporal and visual association areas, particularly in the left fusiform gyrus (Brodmann areas 19–37) Left perisylvian language areas The right secondary auditory cortex, left inferior frontal and supramarginal areas

Word processing

Authors

Method

Blinda

Sighted

1

Buchel et al. (1998)

PET

6 + 3L

6

2

Weeks et al. (2000)

PET

9

9

3

De Volder et al. (2001)

PET

6

6

Resting, passive noise sounds listening, object sounds-trigged imagery

4 5

Roder et al. (2002) Ross (2003)

fMRI fMRI

11 5 musicians with absolute pitch

Auditory semantic Analytical solfeggio + a control sound comparison

6

Vanlierde et al. (2003) Noppeney et al. (2003)

PET

10 A musician with absolute pitch 5

5

Spatial imagery task

Dorsal stream activation

Spatial imagery

fMRI

11

12

Semantic decision task of aurally-presented words

Semantic representation

8

Lambert (2004)

fMRI

6

6

9

Pietrini et al. (2004) Ptito (2005)

fMRI

4

5

PET

6

5

Gougoux et al. (2005) and Voss et al. (2006)

PET

12

7

Inferior temporal and ventral occipital extrastriate cortex Posterior parietal and intraparietal cortex Dorsal extrastriate

Category-specific object form representation Orientation discrimination

11

Production of mental images from animal names versus passive listening to abstract words visual and tactile face and manmade objects recognition Orientation detection task using electrotactile stimulation of the tongue Binaural, and monaural sound localization

Left inferior temporal cortex for visual semantics; left posterior middle temporal regions for action semantics Occipital, parietal, premotor and visual associative cortex activation

12

ERP

8

8

Number comparison tasks

Lateral parietal and frontal areas

13 14

Szucs and Csepe (2005) Poirier et al. (2006) Gaab et al. (2006)

fMRI fMRI

6 1 musician

9 musicians

Auditory motion Pitch categorization and identification

15

Goyal et al. (2006)

fMRI

3 + 3L

3

Tactile recognition and imagery

hMT+ Bilateral superior temporal, bilateral inferior and superior parietal, bilateral inferior and right middle frontal, anterior cingulate areas hMT+ and fusiform face area

16

fMRI

4

7

Visual and tactile motion perception

hMT+

17

Ricciardi et al. (2007) Garg et al. (2007)

Moving object or face representation Motion discrimination

fMRI

9

10

Frontal eye field

Orienting

18

Amedi et al. (2007)

fMRI

1 + 1L

10

Lateral occipital cortex (LOtv)

Object form representation

19

Bonino et al. (2008) and Ricciardi et al. (2006)

fMRI

4

7

Covert attention orienting task with endogenous verbal cues and spatialized auditory targets Shape recognition with an auditory-to-visual sensory substitution device Tactile spatial working memory task

Posterior parietal and parieto-occipital cortex

Spatial representation and spatial working memory

Reference to Fig. 1

10

Object imagery

Speech comprehension Music processing

Object imagery

- Binaural localization: decreased occipital activity in sighted only - monaural sound localization: early-blind showed occipital activation Number and quantity representation Motion discrimination Pitch discrimination

E. Ricciardi et al. / Neuroscience and Biobehavioral Reviews 41 (2014) 64–77

7

Spatial processing

Table 1 (Continued) Reference to Fig. 1

Authors

Method

Subjects Blinda

Sighted

Task

Brain regions

Function

Size-judgment task over auditory stimuli (picture viewing task for 20 additional sighted) Performance of kinaesthetically guided hand movements Presentation of hand-executed action or environmental sounds/movies, and a “virtual” tool manipulation task

Ventral and lateral temporo-occipital areas

Category-specific representation for living and nonliving stimuli

Postcentral cortex, superior parietal and anterior intraparietal regions leFt-lateralized mirror network, including premotor, temporal, and parietal regions

Kinaesthetic movements control

Bilateral temporoparietal junction, medial prefrontal cortex, precuneus, and anterior temporal sulci

Theory of mind

Superior temporal cortex

Voice discrimination

hMT+

Motion discrimination

Left parietal lobule (inferior parietal, anterior intraparietal, superior parietal) Amygdala Right middle frontal cortex and the insula during frequency detection; right inferior parietal cortex during spatial location Parahippocampal place area and retrosplenial cortex occipIto-temporal sulcus Spatial processing of sounds in a right-sided dorsal network (superior and middle frontal, inferior and superior parietal, and middle occipito-temporal); pitch processing of sounds in a left temporal network (inferior, middle, and superior temporal and inferior frontal/insula) mediAl prefrontal cortex

Tool use

Mahon et al. (2009)

fMRI

3

7

21

Fiehler et al. (2009)

fMRI

12

12

22

Ricciardi et al. (2009) and Ricciardi et al. (2013) Bedny et al. (2009)

fMRI

8

14

fMRI

10

22 in Exp1 and 13 in Exp 2

fMRI

5 + 10L

14

fMRI

8

9

26

Gougoux et al. (2009) Matteau et al. (2010) Mahon et al. (2010)

fMRI

3 + 3L

7

27 28

Klinge et al. (2010) Renier et al. (2010)

fMRI fMRI

11 12

11 12

Auditory emotional processing Auditory and vibrotactile stimuli modulated in frequency and spatial location

29

Wolbers et al. (2011) Reich et al. (2011) Collignon et al. (2011b)

fMRI

7

7

fMRI fMRI

8 11

11

Delayed matching-to-sample of 3D geometric configurations Tactile Braille word and non-word reading Processing of the spatial or the pitch attributes of sounds

32

Ma and Han (2011)

fMRI

21

47

33 34

fMRI fMRI

10 14

14 14

fMRI

15

15

36

Lewis et al. (2011) Struiksma et al. (2011) Lingnau et al. (2012) Ptito et al. (2012)

fMRI

10

8

37

Kitada et al. (2013)

fMRI

17

22

38

He et al. (2013)

fMRI

16

17

Auditory size-judgment task (plus a passive picture-viewing in sighted)

39

Peelen et al. (2013)

fMRI

14

16

Auditory size-judgment task (plus a passive picture-viewing in sighted)

23

24 25

30 31

35

a

Exp1: answering true/false questions on stories about mental and physical representations Exp2: valence judgment task after listening to stories describing mental experiences Passive listening to vocal or non-vocal sounds Tactile motion discrimination task using electrotactile stimulation of the tongue Auditory size-judgment task

Trait judgments of the self and a familiar other Action sounds recognition Spatial language task based on a sentence verification paradigm Proprioceptively guided reaching Tactile-form recognition task with the tongue display unit Tactile identification of facial expressions

Emotional processing (Frequency and spatial) sound processing

Spatial layout coding Word representation (Pitch and spatial) sound processing

Representation of self-concept

Postero-lateral temporal cortices Left supramarginal gyrus

Action representation (Language) spatial representation

Posterior parietal cortex

Spatial representation

(Right) inferior temporal and lateral occipital (LOtv) areas Left inferior frontal and posterior superior temporal areas Bilateral parahippocampal place area, transverse occipital sulcus and retrosplenial complex Left lateral occipitotemporal cortex

Object form representation Face (expression) recognition Large nonmanipulable object representation Tool representation

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Sample size refers to congenitally or early blind individuals. Late (L) blind sample is also reported when enrolled.

Action representation

E. Ricciardi et al. / Neuroscience and Biobehavioral Reviews 41 (2014) 64–77

20

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E. Ricciardi et al. / Neuroscience and Biobehavioral Reviews 41 (2014) 64–77

Fig. 1. Brain areas showing a supramodal response to different perceptual, cognitive and affective domains. The different brain functional studies are reported with the reference numbers of Table 1, and grouped according to their investigated domain with different colors. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

(Pietrini et al., 2004, 2009; Ricciardi and Pietrini, 2011). Activations in the ventro-temporal and occipital extrastriate cortical areas during non-visual object perception and imagery tasks in both sighted and congenitally blind individuals (Amedi et al., 2001; De Volder et al., 2001; James et al., 2002; Lambert et al., 2004; Pietrini et al., 2004), strongly indicated a supramodal object representation in these cortical areas with category-related patterns of response across sensory modalities (Mahon et al., 2009; Pietrini et al., 2004). As a further support of its more abstract nature, this part of the lateral occipital extrastriate cortex is activated in both sighted and congenitally blind individuals when information on object form is conveyed by visual-to-auditory sensory substitution devices (Amedi et al., 2002, 2005c, 2007; Arno et al., 2001; Kim and Zatorre, 2011), and its response is unrelated to specific object features (e.g. familiarity, spatial localization, etc.) or to distinct sensory and cognitive requests (Amedi et al., 2005c; Lacey et al., 2009; Noppeney, 2007). Finally, the timing of tactile object recognition in the lateral occipital extrastriate cortex overlaps with the timeframe of visual object recognition, thus confirming the direct involvement of this brain area in a supramodal perceptual processing of object forms (Lucan et al., 2010). As shown in Table 1, the ‘congenitally blind brain’ model has offered over the last few years an unprecedented opportunity to define a supramodal functional organization in several cortical networks also outside of the ‘visual’ system – e.g., tool representation in left parietal cortex (Mahon et al., 2009), voice recognition in the superior temporal cortex (Gougoux et al., 2009), spatial attention orienting in frontal eye fields (Garg et al., 2007) – and beyond pure perception or cognition. As a matter of fact, supramodality has been recently described also in those brain areas that modulate affective responses and social interactions. Supramodal responses in the amygdala to fearful and angry voices (Klinge et al., 2010), in the left mirror system to action sounds (Ricciardi et al., 2009), in the Theory of Mind-supporting network (including, bilateral temporoparietal junction, medial prefrontal cortex, precuneus and anterior temporal sulci) to reasoning about the mental states of others (Bedny et al., 2009), and in medial prefrontal regions to

self-representation (Ma and Han, 2011), all indicate that visual experience is not necessary for the development of the functional architecture of the ‘social brain’, and that sensory processing and learning through non visual sensory experiences allow for the acquisition of an efficient knowledge and awareness of other persons’ beliefs and intentions. To summarize, the supramodal nature of a specific brain region reflects a shared, more abstract representation of the perceived stimuli, which does not depend uniquely on the input from a specific sensory modality. This abstract representation can be accessed either through bottom-up mechanisms from distinct direct sensory inputs, or through top-down mechanisms from regions subserving higher cognitive functions (such as working memory, attentional modulation, etc.) (Ricciardi et al., 2011). Moreover, the demonstration of a similar supramodal functional cortical organization in the brain of individuals deprived of sight since birth indicates that visual experience is not a conditio sine qua non for the brain to develop its marvelous architecture. Evidently, a script for such a development must be to some degree encoded in our genes, though it is still an unresolved matter to what extent such a fine cortical functional development may be anyway dependent from non-visual sensory input. 2.2. How do neocortical (visual) areas develop? To approach the last issue raised in the above paragraph, one has to consider what is known about the molecular events that occur during development of the neocortex. According to the Protocortex hypothesis (O’Leary, 1989; Van der Loos and Woolsey, 1973) neocortical areas are formed as a result of extrinsic signals coming from the thalamocortical afferent neurons (TCAs) that project from distinct thalamus nuclei to specific cortical portions. The idea is that the neocortical area patterning is decided exclusively by external factors, as the first developing neuroephitelium is a tabula rasa. On the opposite hand, the Protomap hypothesis (Rakic, 1988) argues that the neocortical arealization is determined by signals

E. Ricciardi et al. / Neuroscience and Biobehavioral Reviews 41 (2014) 64–77

intrinsic to neocortical stem cells. Specifically, post-mitotic cells in the proliferative ventricular and subventricular zones are prespecified to migrate in a certain region of the developing cortex to delineate a specific area. According to the radial unit hypothesis model (Rakic, 1988), they move along a common radial pathway to form ontogenetic columns (Rakic, 2009; Rakic et al., 2009). These two opposite views have been reconciled by supposing that the area pattern is initially defined by signals intrinsic to the neocortical primordium and, then, refined and maintained by the innervating thalamocortical afferents (Sansom and Livesey, 2009). It has been hypothesized that the primordial cortical areas, patterned by intrinsic signals, selectively attract afferents from the appropriate thalamic nuclei (O’Leary and Borngasser, 2006; Rakic, 1981). Thalamic afferents would act only on pre-specified cortical neurons, which express on their surface recognition molecules able to attract these thalamic afferent fibers (Catalano and Shatz, 1998; Torii and Levitt, 2005). Therefore, the molecular mechanisms intrinsic to the developing neocortex seem to play a major role in area patterning. Region-specific gene expressions observed in mutant mice with impaired or absent TCA projections (Liu et al., 2000; Miyashita-Lin et al., 1999), as well as heterotopic transplantation studies in mice, have shown that the neuronal stem cells become regionally specified prior to the thalamocortical afferentation (Cohen-Tannoudji et al., 1994; Gaillard et al., 2003; Gitton et al., 1999). The cortical arealization process starts with the onset of morphogenenetic gradients in the embryonic cerebral vesicles secreted by patterning centers (Rakic et al., 2009). Morphogens act in a concentration-dependent manner to specify cell fate. High rostral concentration of Fibroblast Growth Factors (FGF8 and FGF17) promote the motor cortex development, while their low concentrations direct the somatosensory and visual cortical fates (Bachler and Neubuser, 2001; Fukuchi-Shimogori and Grove, 2001). The FGF signaling also regulates the expression of COUP-TFI, a transcription factor expressed in a caudomedial-high to rostrolateral-low gradient (Zhou et al., 2001) that is crucial to promote caudal identity. Downstream of FGF signaling and COUP-TFI, area patterning is refined by gradients of transcription factor expression. A constantly updated table summarizing the expression of all these molecules in mice and their reciprocal influences is available at http://rakiclab.med.yale.edu/pages/molecules.php. By using mRNA sequencing (mRNA-seq) in cells isolated by laser microdissection (LMD), Ayoub et al. (2011) were recently able to characterize five groups of specific transcribed genes at a level of resolution never achieved before. Moving from the ventricular zone (VZ) to the cortical plate (CP) through the subventricular (SVZ) and the intermediate zone (IZ), these scientists found that the most enriched categories of genes in the VZ were related to cell division, while genes involved in transcriptional regulation were more prominent at the intersection between VZ and SVZ-IZ. Genes enriched in the SVZ-IZ zone included axonal guidance and cell migration transcripts, whereas genes contributing to axonogenesis, synaptogenesis and exocytosis represented the larger fraction at the intersection between SVZ-IZ and CP as well as in the CP zone (Ayoub et al., 2011). These findings define five transcriptional programs that from VZ to CP are responsible for stem cell maintenance, neurogenesis, migration and differentiation. Significant variations in gene expression across cortical areas have been reported also for the adult human brain (Hawrylycz et al., 2012). These regional transcriptional signatures are highly conserved across subjects suggesting the existence of a common “blueprint” for the human brain transcriptome that might explain the ability of neocortex to accommodate changes in the quality and quantity of sensory inputs. Many area markers are therefore already partitioned at the time of thalamic inputs, suggesting that well-defined domains in

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the cortex emerge independently from external inputs and are retained even if regions are aberrantly innervated (for a review, see Sur and Rubenstein, 2005). In other words, an intrinsic genetic program would make stem cells able to develop some degree of preliminary cortical organization prior to any external inputs. Then, attraction of appropriate inputs from the thalamus becomes crucial for achieving neuronal maturation and area patterning. In the event of the lack of a specific sensory input, such as the visual one, this genetically based organization may attract distinct sensory inputs from the thalami to continue the cortical maturation process. This hypothesis may provide an explanation for how specific functional areas can be activated by unusual sensory stimuli as, in the specific instance, the visual area in blind people by auditory or tactile stimuli. That distinct sensory inputs may cooperate to favor cortical maturation in a given cortical area is also suggested by the recent observation that in infants born prematurely tactile stimulation, specifically body massage, accelerates the structural and functional development process in the visual system (Guzzetta et al., 2009a, 2009b). All these findings demonstrate that the visual areas have the ability to functionally integrate at least two, if not more, sensory modalities, thus providing the basis for a supramodal organization and a cross-modal potential readaptation of the cortex. 2.3. Toward a truly supramodal processing of information From a functional perspective, supramodal brain areas are equally recruited and show overlapping patterns of connectivity, mainly directed toward multisensory brain areas, in both sighted and blind individuals and across different sensory modalities. Homologies are not only limited to the topographic localization of the recruited cortical areas but mainly involve the content of the neural responses, as demonstrated, for instance, by the overlapping category-related patterns of response across sensory modalities (Mahon et al., 2009; Pietrini et al., 2004). There is an increasing interest in using machine learning approaches to identify signals that could permit “brain-reading” directly from imaging data (Pereira et al., 2009; Poldrack, 2006; Poldrack et al., 2009). This novel approach to brain functional measures, recently adopted by multimodal research protocols (Klemen and Chambers, 2012), uses pattern-classification algorithms and multivariate analysis to decode the information that is represented in a spatially distributed pattern of neural activity, and to identify those brain regions that significantly contribute to the discrimination of different mental states. Therefore, when applied to the assessment of supramodal functional organization, pattern recognition approaches could be employed to classify neural responses across experimental samples (e.g., congenitally blind and sighted) and sensory modalities, and consequently to localize those cortical regions that functionally contribute to a supramodal representation. Recently, we used multi-voxel pattern analyses-based classifiers to classify the neural responses from congenitally blind and sighted individuals during visual and/or auditory presentation of hand-made actions (Ricciardi et al., 2013). We intended to define to what extent the distributed and ‘more abstract’ representation of actions is truly supramodal, that is, shares a common coding across distinct sensory modalities. Action vs. non-action stimuli were significantly discriminated across sensory conditions (visual and auditory) and experimental groups (congenitally blind and sighted) (Ricciardi et al., 2013). Moreover, discriminative information for the action/non action classification was mainly located in the bilateral, though left-prevalent, network that strongly overlaps with brain regions known to form the action–observation network and the human mirror system (Ricciardi et al., 2009, 2013). Applied to the assessment of supramodal functional organization,

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these pattern recognition approaches can identify common neural responses across experimental samples (i.e., congenitally blind and sighted individuals) and sensory modalities, thus indicating that the homologies in the functional representation are not limited only to a mere overlap in the topographical localization of neural activations, but do involve the content (the distinction of action or non-action stimuli in our study) of the neural responses. Functional MRI adaptation paradigms may also represent an effective strategy to explore supramodality, as the repeated exposure to the same stimulus – even when conveyed through different sensory modalities – results in a progressively decreasing neural response only in brain areas that process that stimulus. Though cortical adaptation has not been investigated yet in congenitally blind individuals (likely for the difficulty of conveying overlapping stimuli across non-visual sensory modalities, such as hearing and touch, in the fMRI environment), these functional protocols have been used to isolate multisensory areas in the brain of sighted individuals. For instance, the supramodal lateral occipital/inferior temporal cortex responsive to object form shows robust crossmodal (visuo-tactile and audio-visual) adaptation during object recognition (Doehrmann et al., 2010; Tal and Amedi, 2009). The observation that visual and non-visual tasks elicit similar patterns of neural activity within supramodal areas in sighted and blind people, however, should not be taken as an indisputable indication that the two groups may adopt identical cognitive strategies or have equal behavioral performances when they are dealing with the same information conveyed through different sensory modalities. As a matter of fact, during spatial processing, blind individuals can count on a limited amount of sensorial information, in terms of both ‘visual’ spatial features (e.g. perspective) and their simultaneous and integrated perception (that is, touch and hearing allow only for a sequential processing of information), which may result in specifically impaired behavioral responses and/or in dissimilar mental strategies (e.g. the employment of allocentric vs. egocentric reference frames) (Cattaneo et al., 2008; Noordzij et al., 2007; Pasqualotto and Proulx, 2012; Struiksma et al., 2009). While brain functional studies have shown a common and more abstract representation of spatial information in parietal regions – Table 1 (Cattaneo et al., 2008; Kupers et al., 2011; Ricciardi and Pietrini, 2011; Ricciardi et al., 2010) – these behavioral findings indicate that vision plays a fundamental role in spatial processing and representation. On this line, in a recently completed fMRI study in sighted and early blind participants of brain activity during a task of auditory – tactile- or visual-prompted mental representation of angles, we showed modality-dependent behavioral discrepancies between the two groups, as well as peculiarities in the pattern of brain response. While both groups did show common activations in intraparietal and inferior parietal regions across experimental conditions (supramodal cortex), preliminary observations indicate that spatial representation in blind individuals, predominantly in the tactile-prompted, but not in the auditory-prompted task, relied more on the right parietal regions, while on the left side regions for the sighted sample (unpublished results). This lateralization in parietal cortex response may reflect distinct spatial mental representations (and strategies) between congenitally blind and sighted individuals. Future brain functional protocols ought to characterize further common and differential brain responses and performances between sighted and blind samples (Collignon et al., 2013; Fiehler et al., 2009). 2.4. Is supramodality a cortical or a neuronal property? Supramodality versus multisensoriality As the current resolution for in vivo brain imaging methodologies in humans does not allow for the acquisition of any specific

information on the activity of single neurons (Cheng, 2011), the question whether overlapping functional activations in a particular brain region elicited by distinct sensory modalities may reflect an identical recruitment of individual supramodal neurons, or rather a selective recruitment of unimodal neuronal subpopulations within the same cortical areas, remains to be addressed (Klemen and Chambers, 2012). Nonetheless, while this observation of non-visual interactions taking place in early stages of sensory processing is providing novel and growing pieces of evidence for the morphological and functional organization of visual striate areas (e.g., Vasconcelos et al., 2011), a more limited knowledge has been acquired on other extrastriate regions or higher-level regions thought to be ‘visual’ in nature. Indeed, most of the observations on extrastriate regions come from sensory deprived animals and findings thus may be related to cross-modal plastic compensation phenomena, as described below – see for example the seminal work by Hyvärinen and colleagues (Hyvarinen et al., 1981a, 1981b) showing how early visual deprivation in monkeys induces part of the extrastriate occipital neurons to respond to tactile inputs. Only a few studies have been conducted in sighted animals. For instance, Haenny et al. (1988) showed that a substantial portion of the neurons in V4 conveys selective information (orientation of a grating) that is not of direct retinal origin: the same neurons showed a stronger supramodal response for a particular orientation for both visual and tactile cues. In the same way, a population of ‘audiovisual mirror neurons’ in the ventral premotor cortex of the monkey was found to discharge both when the animal performs a specific action and when it hears or sees the same action performed by another individual (Keysers et al., 2003). Thus, even if some neurons do show a supramodal behavior, further observations are nonetheless necessary for a more complete definition of the functional organization at a neuronal level of these areas that respond to more abstract representations of information, and to clearly settle the question of a distinction between supramodal and multisensory properties of brain regions. We recently proposed that multisensory regions could instead refer to ‘cortical and subcortical structures [.] that process multiple stimuli conveyed by different sensory modalities at once, both in space and time’ (Ricciardi and Pietrini, 2011), independently of their specific content. Therefore, multisensory regions would account more for sensory spatiotemporal integration and processing rather than information representation. Nonetheless, in sensory deprived individuals, along with supramodal responses, multisensory processes may provide key benefits for the advancement and development of sensory substitution approaches (Proulx et al., 2012). Thus, though not specifically related to the scope of this review, the features of multisensory neural responses have been delineated below (Section 3.2), along with supramodality and crossmodality. To date, multisensory integration in blind individuals has been poorly investigated both behaviorally and functionally.

3. Which is the fate of unisensory “visual” brain areas in congenitally blind individuals? 3.1. The specificity of cross-modal plastic reorganization While the demonstration of supramodality represents one of the most significant contributions of the ‘blind brain’ studies to the understanding and characterization of human brain functioning per se, experimental protocols in individuals with congenitally blindness have focused predominantly on the examination of cross-modal plasticity. In this perspective, the study of early sensory deprivation has emerged as an interesting field of research in neuroscience, as the lack of a sensory input since birth represents

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an exceptional condition to assess properties and potentialities of the human brain to reorganize itself, with potential implications also for other conditions of sensory loss or brain damage (Collignon et al., 2011a; Frasnelli et al., 2011; Pascual-Leone et al., 2005). Several pieces of evidence have now assessed that the brain is capable of remarkable dynamic changes and adaptation, both structurally and functionally (Collignon et al., 2011a; Kupers et al., 2011; Kupers and Ptito, 2011; Noppeney, 2007; Pascual-Leone et al., 2005; Renier et al., 2010, 2013). Since the early cerebral metabolic assessments in congenitally blind individuals that demonstrated the functional activation in early occipital areas at rest and during specific auditory or tactile tasks (Sadato et al., 1996; Veraart et al., 1990; Wanet-Defalque et al., 1988), it has become clearer and clearer that ‘visual’ brain regions undergo a plastic cross-modal functional reorganization in sight-deprived individuals (Collignon et al., 2011a; Kupers et al., 2011; Noppeney, 2007; Renier et al., 2010, 2013). Presumably, as cross-modal connections between early sensory areas are present already in physiological conditions (Cappe et al., 2009), the brain reorganizes and takes advantage of the sensory inputs that are available. Animal studies suggest that the loss of a specific sense leads to the invasion of the deprived cortical area by inputs originating from other primary cortical regions (Kupers et al., 2011; Merabet and Pascual-Leone, 2010; Noppeney, 2007; Pietrini et al., 2009; Ptito and Desgent, 2006; Rauschecker, 1997, 1999; Rauschecker and Korte, 1993). Recruitment of occipital clusters has been shown in congenitally blind individuals for a variety of non-visual perceptual and cognitive tasks, from lexical, verbal and phonological processing, to spatial and object discrimination, to selective attention or working memory (Cattaneo et al., 2008; Kupers et al., 2011; Merabet and Pascual-Leone, 2010; Noppeney, 2007; Pietrini et al., 2009; Ptito and Desgent, 2006). These activations in congenitally blind individuals, mainly in the striate cortex, across a wide variety of experimental tasks, questioned the specialization of this functional recruitment, and made some authors speculate whether occipital regions might just respond to non visual inputs irrespectively from their perceptual or cognitive content (Burton et al., 2010). Several observations, however, strongly indicate that the recruitment of the occipital cortex is specifically related to plastic rearrangement phenomena and is finalized to compensatory processing: - Effects of task difficulty: Only higher cognitive and perceptual level, but not simple sensorimotor, tasks activate occipital regions in congenitally blind individuals (Noppeney, 2007). This observation is in contrast with an aspecific neural response in blind individuals during non-visual tasks, as a consequence of the sensory deafferentation occurring in blindness (Burton et al., 2010). - Correlation with specific cognitive/perceptual performances: Extent and/or magnitude of recruitment within occipital cortical areas across different tasks and perceptual/cognitive abilities (e.g. verbal-memory capabilities, episodic memory, sound localization) in blind individuals is related to task performance levels (Amedi et al., 2003; Gougoux et al., 2005; Noppeney et al., 2003; Raz et al., 2004; Renier et al., 2010). Following loss of vision, cross-modal plasticity may adaptatively reorganize neurons to integrate more efficiently the input of the new sensory modality (Amedi et al., 2005b; Frasnelli et al., 2011). - Real or ‘virtual’ lesions of occipital cortex: There are real examples of specific processes of visual brain plasticity following early brain damage (e.g. the differentiation of functional tissue within a larger dysplastic cortex, or the development of novel thalamo-cortical connections able to bypass the lesion and reach the occipital cortex – reviewed in Guzzetta et al. (2010), not to mention the exceptional clinical case of an early-blind woman who subsequently lost her ability to read Braille after a bilateral

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occipital stroke (Hamilton et al., 2000). Similarly, transient disruption of neural activity induced by TMS on early occipital areas impairs non visual abilities, such as tactile perception, Braille reading and verbal processing (Amedi et al., 2007; Cohen et al., 1997; Kupers et al., 2007; Noppeney, 2007; Zangaladze et al., 1999), and even induces tactile sensations on the tip of the reading fingers in experienced early blind users (Cohen et al., 1997; Kupers et al., 2007; Ptito et al., 2008a). - Sensory overlapping: Some limitations in disentangling the meaning of the differential combinations of cortical activations are mainly related to the difficulty of exploring more than a single perceptual/cognitive function or sensory modality during a single experimental session (Noppeney, 2007). However, a recent study in early blind subjects reported a function-specific overlap for both auditory and tactile spatial-vs.-non spatial processing in the anterior regions of occipital cortex that showed a distributed aspecific cross-modal response to non-visual inputs (Renier et al., 2010). - Connectivity measures: While occipital areas in early blind individuals at rest have an massive reduction in connectivity with the other brain regions, they do show increased correlations with task-related areas when recruited during cross-modal performances (Table 2). For instance, fMRI-measured brain activity in congenitally blind and sighted participants processing either the spatial or the pitch properties of sounds was recently compared (Collignon et al., 2011b). Connectivity analyses revealed that the dorsal occipital regions, cross-modally recruited during auditory-spatial processing, were functionally correlated in blind individuals to brain regions of audio-visual spatial abilities including multisensory regions, such as the inferior parietal, intraparietal, and superior frontal cortex (Collignon et al., 2011b). Consistent with these findings, we recently demonstrated that in sighted individuals the posterior “visual” part of the motionresponsive hMT+ area, that is, the subregion that responds to visual motion only, correlates strongly only with related visual occipital areas; on the contrary, in people who lack visual experience since birth, during tactile motion perception this same subregion extends its functional connections also to areas of multisensory integration, such as somatosensory and posterior parietal cortex (Sani et al., 2010). Therefore, cross-modal reorganization within occipital areas appears to be associated with successful changes in the functional communication with cortical areas related to non-visual processing. - Functional recruitment in early but not late blind individuals: The age of blindness affects cortical reorganization, as late blind individuals show reduced cross-modal functional activations as compared to early blinds (Burton, 2003; Cohen et al., 1999; Noppeney, 2007). This cross-modal plasticity is not only reduced both in magnitude and extension, but also appears to be less specific. For instance, in the study of auditory spatial discrimination mentioned above (Collignon et al., 2011b), spatial processing of sounds recruited task-selective dorsal occipital regions only in the congenitally/early blind group but not in the individuals that lost sight later in life, consistent with a reduced functional specificity of this plastic reorganization (Collignon et al., 2013; Dormal et al., 2012).

In line with what we have previously suggested for the investigation of supramodal functional organization, novel experimental approaches (e.g., multimodal stimuli or combined imaging techniques) and analytical tools should be employed to better define the functional specificity of cross-modal reorganization in blindness, and overcome the difficulty of exploring more than a single mental function or sensory modality during the experimental session.

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Table 2 Selected functional imaging studies in blind individuals investigating structural, effective or functional connectivity. Author

Subjects a

Methodsb

Resultsc

B < S: within occipital, between occipital and BA 3,4,5,6,8,21,22,48 B > S between occipital and BA 44, 45, 47 B < S between left BA17 and precentral, postcentral, superior parietal, superior and middle temporal, bilateral SMA; between right BA17 and precentral, postcentral and bilateral SMA B = S between hMT+ and ventral/dorsal exstrastriate, inferior frontal, inferior and middle temporal; between S1, parietal areas and MTG, OC No FC between posterior parietal and occipital cortex

Blind

Sighted

16

32

FC during resting state (whole brain)

Yu et al. (2007)

16

32

FC during resting state (seed ROI: BA17)

Sani et al. (2010)

4

7

FC during visual and tactile motion perception (seed ROI: hMT+, S1)

Wolbers et al. (2011)

7

7

Striem-Amit et al. (2012)

8

7

Collignon et al. (2013)

12 + 10

12 + 10

FC during tactile and visual delayed matching to sample task of objects and scenes (seed ROI: posterior parietal) FC during complex images recognition using a visual-to-auditory sensory-substitution algorithm PPI during pitch and sound localization

9+6L

24

DCM during Braille reading (ROI: S1, anterior intraparietal, inferior and superior occipital cortex, V1)

Klinge et al. (2010)

10

10

Park et al. (2011)

10

10

DCM during auditory stimulation (ROI: medial geniculate, A1, V1) Granger causality in a 2-back auditory working memory task using words, pitches and sound locations

Collignon et al. (2013)

12 + 10

12 + 10

DCM during pitch and sound localization

17

17

DTT

Shimony et al. (2006)

5

7

DTI

Shu et al. (2009a)

17

17

DTI

Fucntional connectivity Liu et al. (2007)

Effective connectivity Fujii et al. (2009)

Structural connectivity Shu et al. (2009b)

B > S of the visual word fusiform area with both the auditory ventral stream and left inferior frontal cortex Early B > Late B between occipital regions and the right intraparietal sulcus for the spatial processing Early B > S between anterior intraparietal and inferior/superior occipital cortex during baseline and task Early B > Late B between anterior intraparietal and superior occipital, inferior and superior occipital cortex during baseline and task B > S between A1 and V1 B > S from the DMN to the left parieto-frontal network and from the occipital cortex to the right parieto-frontal network during the 2-back tasks Early B: direct connection between auditory and occipital cortex Late B: connection between auditory and occipital cortex via the parietal hub B have disrupted global anatomical connection patterns, lower degree of connectivity, longer characteristic path length and a lower global efficiency. B < S in inferior frontal-occipital fasciculus B < S in the occipital lobe and ventral splenium; between lateral geniculate and calcarine. B = S between visual cortex and orbitofrontal and temporal cortices B < S in the geniculo-calcarine tract

a

Sample size refers to congenitally or early blind individuals. Late (L) blind sample is also reported when enrolled. b FC: functional connectivity; DCM: dynamic causal modeling; DTT: diffusion tensor tractography; DTI: diffusion tensor imaging; ROI: region of interest; and BA: Brodmann area. c B: blind; S: sighted; BA: Brodmann area; SMA: supplementary motor area; A1: primary auditory area; and V1: primary visual area.

3.2. Supramodal, cross-modal and multisensory: mind the difference! As previously discussed, supramodal cortical areas show essentially a similar functional organization between sighted and congenitally blind individuals, while cross-modally reorganized

areas do show a distinct functional behavior between the two groups. Multisensory areas, finally, should be considered conceptually distinct from the previous two categories as well. The following scheme summarizes the main criteria that distinguish these three typologies of cortical organization.

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Activation during non-visual tasks

Connectivity patterns

Multivariate analysis relatively to stimulus content TMS-induced behavioral impairment Behavioral performance related to a specific brain area

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Supramodal

Crossmodal

Multisensory

Overlapping pattern of brain activation across visual and non visual tasks within sighted and between sighted and blind individuals (non visual tasks) Overlapping in sighted and blind individuals. In both groups, correlation from supramodal region are mainly directed to cortical regions of sensorimotor/multisensory integration Overlapping patterns across the sighted and blind groups and sensory modalities Impairment in both sighted and blind groups during both visual and non visual tasks Equal performance between sighted and blind individuals

Present in blind individuals only (more pronounced in early than in late blindness)

Overlapping activations across sensory modalities and across sighted/blind individuals: multisensory response is larger than unisensory responses Expected to be overlapping in sighted and blind individuals during non visual tasks

Different in sighted and blind individuals. In blinds, increase correlation with cortical regions of sensorimotor/multisensory integration

Different patterns between the sighted and blind groups

Independent from stimulus content

Impairment only in blind individuals during non visual tasks

Expected to induce impairment in both sighted and blind groups during non visual tasks Equal performance between sighted and blind individuals, but blind individuals might show selective impairments

Equal performance between sighted and blind individuals, or superior in the blind group

3.3. Where in the occipital cortex? Another critical aspect in the research protocols in blind individuals is the localization and definition of activated/connected areas within the occipital cortex. In fact, as research in blind samples relies on non-visual stimulation paradigms, the functional localization of specific ‘visual’ areas may unavoidably result relatively approximate, and just be defined on the basis of an anatomical/structural framework. Nonetheless, this should not induce to refer generally to the ‘occipital cortex’ as a whole. Indeed, the occipital visual cortex is parcellated into distinct cytoarchitectonic, functional areas, comprising a primary striate cortex and numerous extrastriate areas interwoven in a complex, hierarchical connected processing ‘device’ (Bourne, 2010). The lack of sight may differentially affect cortical subregions, such as V1 and hMT+ that receive direct retinal inputs via thalamo-cortical connections and may consequently result in a distinctive experience-dependent developmental plasticity (Bourne, 2010). Therefore, the request for precise definitions of occipital clusters of recruitment is not only necessary for an adequate comparison across distinct functional studies, but mainly for the consideration that the distinct subregions might respond differentially to early sensory deprivation, and thus may undergo a cross-modal plastic reorganization to a different degree, or disclose a non-visually prompted supramodal response (Bedny et al., 2010; Collignon et al., 2013). Actually, this aspect is certainly mirrored by the significant morphological changes in the visual pathway structures that the lack of sensory input and the consequent reorganization lead to in the brain of blind individuals. These alterations comprise both gray/white matter volumetric loss and cortical thickening in the primary and associative visual cortices of congenitally blind individuals, as a sign of morphological adaptation to new sensory balance (Noppeney et al., 2005; Park et al., 2009; Ptito et al., 2008b).

4. Which neural pathways may subserve non-visual responses in the “visual” cortex? When considering recent observations from in vivo brain functional studies that report how supramodal regions respond to the content of the sensory information independently from visual experience, and that vision-responsive areas concomitantly undergo cross-modal plastic adaptative modifications, one may question how non visual information gets to the occipital areas.

Previous studies in animals and humans have suggested that both cortico-cortical connecting pathways and subcortical loops should be taken into account (Kupers and Ptito, 2011; Noppeney, 2007; Pietrini et al., 2009). In both visually-deprived and sighted individuals, non-visual inputs enter occipital areas directly via heteromodal connections (primary sensory areas do receive inputs from other unimodal regions) or indirectly via multisensory hubs, such as parietal regions, that may integrate signal from different sensory modalities and motor information (Klemen and Chambers, 2012; Kupers et al., 2011; Ricciardi and Pietrini, 2011; Rizzolatti et al., 2006). Before sensory information gets to the neocortex, an earlier multisensory integration may occur in subcortical structures (Ghazanfar and Schroeder, 2006). The thalamus and the superior colliculus are likely candidates for integrating senses, in relation to their strong input–output connections with multiple sensory and motor cortical areas (Cappe et al., 2009). Furthermore, in the particular condition of vision deprivation since birth, possible additional reorganization of the thalamo-cortical and cortico-cortical connections, or of the sense-specific (sub)cortical representation maps, might occur during early life periods. Thus, the interactions among different senses occur across subcortical, lower- and higher-order cortical structures, and multisensory integration accompanies, or even precedes, unisensory processing (Ghazanfar and Schroeder, 2006). Interestingly, these aspects recall to mind the still-open question of whether the recruitment of occipital cortex occurs through anatomical and functional reorganization within the existing neural networks, or through the formation of novel neural connections (Kupers et al., 2011). Up to now, divergent observations have been offered by brain functional studies in sighted and blind individuals. Experimental protocols with sensory substitution devices showed that neural responses are generally observed after a period of training of few days during temporary or permanent visual loss, thus indicating that these changes in brain activity might be mediated by the ‘unmasking’ or strengthening of pre-existing cortico-cortical connections, generally comprising a posterior parietal cortical hub (Amedi et al., 2007; Kupers et al., 2010, 2011; Kupers and Ptito, 2011; Leo et al., 2012; Matteau et al., 2010; Noppeney, 2007; Pascual-Leone et al., 2005; Ptito, 2005). For instance, when tactile processing is concerned, the involvement of a cortico-cortical pathway originating from primary somatosensory cortex, passing through posterior parietal regions to reach extrastriate areas, has

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been supported recently by functional and effective connectivity approaches (Fujii et al., 2009; Sani et al., 2010; see Table 2). These anatomical pathways between occipital and parietal areas are viable also under physiological conditions and may become more ‘robust’ in those individuals who lose sight at birth or in the early post-natal period, as reflected by the increased strength in connectivity in congenitally blind individuals as compared to sighted ones. Consistent with this hypothesis, we compared fMRImeasured BOLD signal temporal variability, a recently proposed index of efficiency of functional information integration (Garrett et al., 2011; McIntosh et al., 2010), across sighted and congenitally blind individuals during two different tactile tasks (Leo et al., 2012). In both tasks, parietal areas in congenitally blind individuals showed higher BOLD signal temporal variability, and were characterized by specific functional networks with strengthened occipito-parietal connectivity as compared to the sighted subjects. As temporal variability reflects neural integration and processing efficiency, these cross-modal plastic changes in the parietal cortex reinforce the hypothesis that this cortical region may play an important role in processing non-visual information in blind subjects, and may act as a hub in the cortico-cortical pathway from the somatosensory cortex to the reorganized occipital areas. In order to overcome the limitations of brain functional methodologies that rely on an indirect measure of brain activity, the effective contribution (and timing) of cortico-cortical or subcortical streams has been also assessed via reversible TMS-induced interference. For instance, event-related TMS has been used to disclose the time course of sound spatial processing in the dorsolateral “where” stream of blind and sighted individuals (Collignon et al., 2008, 2009). TMS applied over the right dorsal extrastriate occipital cortex 50 ms after sound onset disrupted the spatial processing of sounds in both groups, while, when applied over the right intraparietal sulcus 100–150 ms after sound onset, the interference was found in sighted subjects only. Given the short latency of the TMS effect when applied over the occipital but not the parietal cortex, sounds may reach the occipital areas in blind subjects either via subcortical or heteromodal projections. On the other hand, TMS applied over the parietal/somatosensory cortex 20 ms after Braille stimulus presentation disrupted stimulus detection in both groups, while when applied over the occipital cortex 50–80 ms after Braille stimulus presentation, the interference on symbol identification, but not detection, was found in blind subjects only. In congenitally blind subjects, parietal letter detection appears to precedes occipital letter identification, thus implying the involvement of a parieto-occipital connection (Pascual-Leone et al., 2005). The complexity of (multi)sensory processing and the functional alterations occurring with sensory deprivation might explain how (and why) TMS-coupled behavioral protocols are differentially influenced by the changes in stimulation sites. Nonetheless, in the upcoming years, beyond the structural information we would get from animal studies or higher resolution imaging methods in humans (e.g. ultra high-field or diffusion MR imaging techniques), multimodal brain functional methodologies (such as combined fMRI and EEG, or combined TMS with EEG) and novel analytical approaches (e.g. coherence analysis of BOLD latencies – Gaglianese et al., 2012) will likely substantially refine our knowledge on the timing of recruitment of different brain areas during sensory integration and processing in sighted and visually-deprived individuals. 5. Conclusions Combined behavioral, anatomical and functional brain studies in sighted and in congenitally blind individuals are providing novel

insights on the effects of (lack of) visual experience on the development and functioning of the human brain. A great deal of the brain cortical functional architecture appears to be programmed to occur even in the absence of any visual experience and able to process non-visual sensory information, a property that can be defined as supramodality. It is important to emphasize that such supramodal cortical organization is not merely the consequence of the plastic rearrangements – that of course also occur in the brain of individuals deprived of sight and are generally called cross-modal plasticity – but is a characteristic of the (human) brain itself, as it is indeed present also in sighted individuals. These findings have potentially important implications not only for the understanding of how the brain works, but also for the development of novel teaching strategies for people who are born deprived of the sense of sight. The more abstract nature of mental representations in the brain may indeed account for the ability of congenitally blind individuals to acquire knowledge and interact efficiently with a world that they have never seen.

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