*Citation: Bressan P and Kramer P (2013) The relation between cognitive-perceptual schizotypal traits and the Ebbinghaus size-illusion is mediated by judgment time. Front. Psychol. 4:343. doi: 10.3389/fpsyg. 2013.00343*

*This article was submitted to Frontiers in Psychopathology, a specialty of Frontiers in Psychology.*

*Copyright © 2013 Bressan and Kramer. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.*

# Cognitive and neuroplasticity mechanisms by which congenital or early blindness may confer a protective effect against schizophrenia

# **Steven M. Silverstein1,2\*,YushiWang1 and Brian P. Keane1,2,3**

1 University Behavioral HealthCare, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA

2 Department of Psychiatry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, USA

3 Rutgers University Center for Cognitive Science, Piscataway, NJ, USA

#### **Edited by:**

Michael Green, University of California Los Angeles, USA

#### **Reviewed by:**

Yue Chen, McLean Hospital, USA Jonathan K. Wynn, University of California Los Angeles, USA

#### **\*Correspondence:**

Steven M. Silverstein, University Behavioral HealthCare, University of Medicine and Dentistry of New Jersey, 151 Centennial Avenue, Piscataway, NJ 08854, USA. e-mail<EMAIL_ADDRESS>
Several authors have noted that there are no reported cases of people with schizophrenia who were born blind or who developed blindness shortly after birth, suggesting that congenital or early (C/E) blindness may serve as a protective factor against schizophrenia. By what mechanisms might this effect operate? Here, we hypothesize that C/E blindness offers protection by strengthening cognitive functions whose impairment characterizes schizophrenia, and by constraining cognitive processes that exhibit excessive flexibility in schizophrenia. After briefly summarizing evidence that schizophrenia is fundamentally a cognitive disorder, we review areas of perceptual and cognitive function that are both impaired in the illness and augmented in C/E blindness, as compared to healthy sighted individuals. We next discuss: (1) the role of neuroplasticity in driving these cognitive changes in C/E blindness; (2) evidence that C/E blindness does not confer protective effects against other mental disorders; and (3) evidence that other forms of C/E sensory loss (e.g., deafness) do not reduce the risk of schizophrenia. We conclude by discussing implications of these data for designing cognitive training interventions to reduce schizophrenia-related cognitive impairment, and perhaps to reduce the likelihood of the development of the disorder itself.

**Keywords: schizophrenia, blindness, perception, cognition, vision, vision disorders, plasticity**

# **INTRODUCTION**

Over the past 60 years, several authors (Chevigny and Braverman, 1950; Abely and Carton, 1967; Horrobin, 1979; Riscalla, 1980; Feierman, 1982; Sanders et al., 2003) have postulated that congenital or early (C/E) blindness may serve as a protective factor against the development of schizophrenia. Supporting data derive from several sources, including literature reviews, examination of cohorts of blind patients in psychiatric hospitals, and surveys of agencies that treat large numbers of blind people. The most recent of these Sanders et al. (2003) noted that across all past papers, there has not been even one reported case of a congenitally blind person who developed schizophrenia. While we identified one reported case of a blind "schizophrenic" child (Stewart and Sardo, 1965), the 6-year-old described in that paper had many symptoms of autism and no symptoms of psychosis, and would almost certainly be diagnosed with an autism-spectrum disorder using DSM-III (American Psychiatric Association, 1980) or later criteria. In contrast to the lack of cases of people with C/E blindness who meet modern criteria for schizophrenia, reports do exist of people who develop both blindness and schizophrenia later in life (Checkley and Slade, 1979). We therefore hypothesize that it is the brain changes that occur secondary to C/E blindness – rather than blindness *per se* – that protect against schizophrenia. However, the mechanisms that confer this apparent protection have not yet been identified. In this paper, we advance the hypothesis

that protection occurs by (1) strengthening the perceptual and cognitive functions whose impairment forms the essential nature of schizophrenia; and (2) constraining cognitive processes that are excessively neuroplastic in the illness.

In the discussion below, after briefly summarizing the position that schizophrenia is fundamentally a cognitive (i.e., informationprocessing) disorder, we review evidence that a cluster of perceptual and cognitive functions is at once markedly impaired in schizophrenia and significantly augmented in C/E blindness, compared to healthy sighted individuals (see **Table 1**). In subsequent sections, we explicate the role of neuroplasticity in driving these perceptual and cognitive differences, we provide evidence that C/E blindness does not confer protection against other mental disorders (e.g., depression, anorexia nervosa) and finally we argue that other forms of C/E sensory loss (e.g., deafness) do not reduce the risk of schizophrenia. We conclude by noting the implications of these data for designing cognitive training interventions for patients and people at high risk for the disorder, and for developing interventions to prevent schizophrenia.

# **SCHIZOPHRENIA AS A COGNITIVE DISORDER: KRAEPELIN AND DEMENTIA PRAECOX REVISITED**

Although the most obvious clinical features of schizophrenia include psychotic symptoms such as hallucinations, delusions, and bizarre behavior, it has long been thought that such symptoms **Table 1 | Summary of cognitive and brain function enhancements (**+**) and impairments (**−**), compared to healthy sighted individuals, in C/E blindness and schizophrenia.**

\*Faster than normal.

\*\*Slower than normal.

are secondary, compensatory, features of the disorder. In contrast, much evidence suggests that the core features of schizophrenia are cognitive in nature, involving disturbances in perception, attention, memory, learning, language, and context-based modulation of these processes as a function of expectations and action plans (Kraepelin, 1903; Bleuler, 1950; Weiss, 1989; Phillips and Silverstein, 2003; Nuechterlein et al., 2012; Tamminga, 2013; Khan, in press). In this way, schizophrenia can be viewed as similar to brain disorders such as Parkinson's disease dementia and dementia with Lewy bodies,in which psychotic symptoms can occur, but are often late-developing phenomena, and are not considered the defining features of the disorder (Ballard et al., 2001; Williams-Gray et al., 2006; Ffytche, 2007). A large body of research evidence now indicates that perceptual and cognitive impairments are found in nearly all people with schizophrenia, and occur with greater frequency than psychotic symptoms (Palmer et al., 2009). Significant cognitive impairment is also easily detectable in most schizophrenia patients even when psychotic symptoms are in remission (Altshuler et al., 2004). In addition: (1) low intelligence is a risk factor for schizophrenia; (2) cognitive decline and intellectual

underperformance precede the onset of psychotic symptoms (and therefore the diagnosis) by many years; (3) decline in cognitive functioning continues after psychosis onset; and (4) this pattern of changes is not found in other major mental illnesses, even those that can include psychotic symptoms, such as bipolar disorder (Neumann et al., 1995; Schenkel and Silverstein, 2004; Khan, in press). Cognitive impairments in schizophrenia are also significantly correlated with level of functional disability (Green, 1996; Silverstein et al., 1998), and are therefore important treatment targets.

# **DOMAINS OF PERCEPTUAL AND COGNITIVE FUNCTIONING THAT ARE STRENGTHENED BY C/E BLINDNESS AND IMPAIRED IN SCHIZOPHRENIA**

# **AUDITORY PERCEPTION**

Compared to sighted people (and in some cases to late-blind people), C/E blind individuals are characterized by enhanced auditory acuity for pitch, better pitch discrimination, better pitch-timbre categorization (Wan et al., 2010), better speech discrimination (Hertrich et al., 2009), better sound localization, better temporal auditory resolution, better noise-embedded speech discrimination (Niemeyer and Starlinger, 1981; Muchnik et al., 1991), lower sound threshold for identification of pseudo-words (Rokem and Ahissar, 2009), shorter latencies for auditory event-related potentials (ERPs;Roder et al.,1996,1999), and greater tolerancefor short stimulus-onset asynchronies in an auditory backward masking task (Stevens and Weaver, 2005). C/E blindness is also associated with comprehension of ultra-fast synthetic speech at a rate of ∼25 syllables per second, which is close to three times the rate at which non-blind individuals can comprehend such speech (Hertrich et al., 2009). In addition, C/E blind subjects have shown larger mismatch negativity (MMN) components of the ERP, suggesting a compensatory improvement in pre-attentional processes (Kujala et al., 1995). It has been demonstrated that these sensory and perceptual processing differences are due to enhanced basic perceptual skills, not to "higher order"functions such as attention, memory, language, or executive functions (reviewed in Cattaneo and Vecchi, 2011).

The above findings are in contrast to what has been observed in schizophrenia, in which, for example, patients are typically characterized by poor auditory acuity, precision, and discrimination (including in tone matching) (Javitt et al., 1997; Rabinowicz et al., 2000; Li et al., 2002; Rojas et al., 2007; Turetsky et al., 2009; Perrin et al., 2010; Kantrowitz et al., 2013), impairments in sound localization (Perrin et al., 2010), temporal resolution of sound (Foucher et al., 2007), auditory backward masking (Kallstrand et al., 2002), pre-attentional processing as indicated by the (smaller) MMN ERP component (Umbricht et al., 2003), and longer latency of post-attentional auditory ERPs (Ward et al., 1991; Sevik et al., 2011; Iyer et al., 2012). Individuals with schizophrenia also have abnormal processing of speech sounds (Ngan et al., 2003; Hirano et al., 2008), are worse than other groups at detecting speech embedded in noise, and are more likely than controls to identify non-speech sounds as speech (Vercammen et al., 2008). Importantly, it has been shown that these impairments in pitch processing in schizophrenia are not secondary to symptoms, medication, or poor attentional functioning (Rabinowicz et al., 2000).

The impaired auditory functions noted above are not mere laboratory curiosities; they have important clinical and functional implications. For example, poor sound localization is thought to be associated with an externalization bias in which there is a reduced ability to recognize that the sound of one's own voice is coming from the self, as opposed to an external cause, which may contribute to delusional thinking (Johns et al., 2001; Ilankovic et al., 2011). At a more general level, perception has been conceptualized as an active, hypothesis-generating function that involves generating a model of the world, and then updating this model via coding of prediction error (i.e., the degree to which continued incoming sensory input does not conform to the current perceptual model of the world; Corlett et al., 2009; Clark, in press). It has been postulated that symptoms of schizophrenia, such as hallucinations and delusions may result from an impaired ability to detect inconsistencies between what would normally be expected (based on past experience) and incoming sensory information (Corlett et al., 2007, 2009; Clark, in press). Both faulty bottom-up processing and poor quality top-down feedback, as have been demonstrated in schizophrenia (Silverstein and Keane, 2009, 2011a,b), would degrade the quality of perceptual representations and the extent to which they are modified by context to most accurately reflect the nature of reality (Corlett et al., 2007, 2009;Clark, in press; Silverstein, in press). The result can be abnormal perceptions, hypersalience of normally ignored stimuli, and new and unusual beliefs to account for these changes in subjective experience – in short, an internal representation of the world that can deviate markedly from reality, and increasingly so over time (Clark, in press). In contrast, as C/E blindness is associated with enhanced sensory and perceptual processing, it can be seen how this would reduce the likelihood of the sort of prediction coding failures, and their sequelae, associated with schizophrenia. The auditory impairments in schizophrenia described above have also been shown to have other important consequences, which would not occur in people with C/E blindness, such as problems decoding cues to emotion in speech (Leitman et al., 2011; Gold et al., 2012) and impaired semantic analysis (Leitman et al., 2007).

#### **AUDITORY ATTENTION**

Blindness has been associated with enhancements in several components of attention that are impaired in schizophrenia. For example, on reaction time tasks, blind subjects are superior to sighted individuals in responding to auditory and tactile cues (Collignon and De Volder, 2009). On tactile and auditory *selective* attention tasks involving spatial discrimination, blind people are more efficient than sighted subjects (Roder et al., 1996, 1999; Hotting and Roder, 2004; Collignon et al., 2006). Since these studies demonstrated that blind and sighted participants did not differ in sensory sensitivity on these tasks, these findings appear to reflect superior attentional capabilities (Cattaneo and Vecchi, 2011), although teasing apart attentional and perceptual deficits is often difficult. Blindness is also associated with superior performance on tasks of *divided* attention, such as dichotic listening (Hugdahl et al., 2004), and tasks requiring dividing attention across more than one sensory modality (Kujala et al., 1995). Again, such a pattern of performance contrasts sharply with what has been long been observed in schizophrenia, namely, severely impaired selective and divided

#### **WORKING AND LONG-TERM MEMORY**

Compared to healthy, sighted individuals, C/E blind individuals have superior working memory capacity, in terms of both the amount that can be processed, and the ability to recall the sequence in which information was presented (Hull and Mason, 1995;Amedi et al., 2003; Roder and Neville, 2003; Raz et al., 2007). The authors of a recent study that matched perceptual threshold of blind and sighted subjects concluded that superior short-term memory in C/E blind people was due to enhancement of stimulus encoding (related to the processes reviewed above), rather than to differences in storage or recall processes (Rokem and Ahissar, 2009). In addition, it is thought that, in C/E blindness, primary reliance on controlled, sequential processes (i.e., via haptic and auditory perception) during navigation – as opposed to the more automatic and parallel processing normally afforded by vision – leads to superior working memory abilities (Raz et al.,2007; Salillas et al., 2009;Cattaneo and Vecchi, 2011). C/E blind people have also demonstrated superior long-term memory compared to sighted controls (Bull et al., 1983; Roder et al., 2001). All of this is in stark contrast to schizophrenia, in which working memory (Silver et al., 2003; Conklin et al., 2005; Brahmbhatt et al., 2006; Horan et al., 2008; Silverstein et al., 2010) and long-term memory (Van Snellenberg, 2009) impairments are typically observed, along with problems in stimulus organization during encoding (Harvey et al., 1986; Brebion et al., 1997, 2004; Landgraf et al., 2011).

These data have important clinical implications. A critical function of WM is to integrate perceptual information with information stored in long-term memory, to allow for efficient learning, memory, and reasoning (Cattaneo and Vecchi, 2011). Enhanced WM abilities would thus facilitate these other processes, as is the case in C/E blindness (Cattaneo andVecchi,2011),whereas impairment would have the opposite effect, as is the case in schizophrenia (Tek et al., 2002). Thus, it can again be seen how C/E blindness could protect against development of the cognitive impairments that comprise the syndrome of schizophrenia.

#### **LANGUAGE**

Congenital or early blind children often experience language delays and abnormalities related to semantic, syntactic, and phonological processing (Perez-Pereira and Conti-Ramsden, 1999). One possible consequence of these is a reduction in the risk of developing disordered thought,which is commonly seen in schizophrenia. For example, many thought-disordered patients with schizophrenia have a tendency toward overabstraction and overinclusion in their thinking, as well as overly elaborated (and more easily primed) semantic networks (Siekmeier and Hoffman, 2002; Lerner et al., 2012). In addition, compared to healthy controls, individuals with schizophrenia more often use language in odd ways, including

generating neologisms (i.e., novel words; Solovay et al., 1987; Kreher et al., 2008). In contrast, it has been shown that compared to sighted children, blind children are characterized by a lack of overgeneralization of concepts and categories, and a reduced number of word inventions (Andersen et al., 1984, 1993). It has also been shown that semantic networks in blind children are more dependent on language, and less dependent on sensory experience, than sighted children (Pring, 1988). This could be a protective factor against delusion formation secondary to altered sensory experience, as has been hypothesized to exist in schizophrenia (Maher, 1974; Uhlhaas and Mishara, 2007).

#### **OLFACTION**

Cuevas et al. (2009) demonstrated that congenitally blind males were better at discriminating odors, and at naming familiar odors, compared to sighted subjects. Other studies have reported mixed results, for example, demonstrating superior odor identification but not odor sensitivity (Wakefield et al., 2004). However, studies with mixed findings have grouped early blind and late-blind subjects together, and did not match groups on gender (women are typically better than men at olfaction tasks; Cattaneo and Vecchi, 2011). While more research is needed on this issue, evidence does suggest that people born blind may develop increased olfactory abilities (Kupers et al., 2011). This is in contrast to people with schizophrenia, in which olfactory impairments have been reported (Nguyen et al., 2010; Kamath et al., 2011). Although the functional consequences of olfactory impairment in schizophrenia are not well understood, such deficits could impair self-regulation, learning, attachment, and interpersonal functioning (see Sullivan, 2003). For example, the detection of maternal odor can promote attachment to the mother, reduce stress, and help normalize the sleep-wake cycle in infants (Goodin-Jones et al., 1997; Sullivan and Toubas, 1998). In addition, odor perception is important in forming bonds with peers in childhood (Sullivan, 2000). It is therefore interesting that risk for schizophrenia is associated with problems in maternal attachment (demonstrated at 3 days, 1, and 6 years of age; Naslund et al., 1984; Persson-Blennow et al., 1984; McNeil and Kaij, 1987),increased stress reactivity (Myin-Germeys and van Os, 2007), and fewer peer relationships (Schenkel and Silverstein, 2004), as well as olfactory processing deficits (Brewer et al., 2003).

#### **CONSTRUCTION OF SUBJECTIVE EXPERIENCE**

In this section, we discuss: (1) differences between people who are C/E blind and people with schizophrenia with regard to the relative importance of parallel versus serial data acquisition in the generation and quality of subjective experience; and (2) the role that preservation of a form of visual imagery in C/E blindness may play in the integration of experience. As noted above, C/E blind people rely to a much greater extent than sighted people on serial processing due to primary reliance on haptic and auditory processing, and lack of visual input. That is, due to the temporalsequential nature of data acquisition about objects in auditory and haptic perception, the relatively smaller amounts of information available at any one time in haptic perception compared to vision (Barber and Lederman, 1988; Amadeo and Speicher, 1995; Herssens, 2010), and the more rapidly changing nature of information flow in audition relative to vision (Shamma et al., 2011), formation of coherent mental representations in haptics and audition requires that information must be "built up" over time to a greater extent than in vision (Geenens, 1999). One result of this imposed learning style is that C/E blind individuals develop abilities in sequential and controlled processing that may be superior to those of sighted people (Vecchi et al., 2004; Raz et al., 2007). In addition, as we argue below, compensatory processes involving working memory capacity, perceptual organization via controlled processing, multisensory integration, learning, and a preserved form of visual imagery lead to a rich, seemingly automatic, and non-fragmented flow of experience (seeCattaneo et al., 2008; Salillas et al., 2009 and above; Cattaneo and Vecchi, 2011). In contrast, in schizophrenia, impairments in working memory capacity, perceptual organization, and multisensory integration,which develop long after birth and for which there appear to be no compensation, contribute to an over-reliance on serial processing that is often inefficient, and that can lead to fragmented subjective experience (Chapman, 1966; Knight, 1984; Carr and Wale, 1986; Knight and Silverstein, 1998; Silverstein and Keane, 2011a). This is illustrated in the following quote from a person with schizophrenia: "Everything I see is split up. It's like a photograph that's torn in bits and put together again. If somebody moves or speaks, everything I see disappears quickly and I have to put it together again" (Chapman, 1966, p. 229).

Interesting examples of how blind individuals construct mental representations incrementally via haptic perception come from Helen Keller's (1908) book *The World I Live In*; her descriptions also illustrate how this process can be facilitated by prior knowledge and augmented with imagery. For example, she noted: "My fingers cannot, of course, get the impression of a large whole at a glance; but I feel the parts, and my mind puts them together" (p. 7). Similarly: "My hand has its share in this multiple knowledge, but it must never be forgotten that with the fingers I see only a very small portion of a surface, and that I must pass my hand continually over it before my touch grasps the whole. It is still more important, however, to remember that my imagination is not tethered to certain points, locations, and distances. It puts all the parts together simultaneously as if it saw or knew instead of feeling them." (pp. 28–29). It is true of course that vision also incrementally builds distal representations, viz, through saccades or shifts in attention (Ullman, 1984), but because this process is not limited by the speed of grasping and reaching, it plausibly occurs over a much shorter time scale, lessening the load on working memory. In short, while C/E blindness is characterized by a greater than normal reliance on serial processing, compensatory processes lead to superior serial processing abilities and to integrated subjective experience.

In addition, we speculate that a preserved form of visual imagery is involved in the spatial integration abilities of C/E blind people. A reasonable amount of evidence supports the presence of imagery in C/E blindness, including: (1) visual cortex areas are activated by input from other senses in blind and non-blind people (Amedi et al., 2001, 2002; Ortiz et al., 2011); (2) the occipital lobe helps generate mental representations even when there has been no prior visual input (Amedi et al., 2008); (3) after training with tactile stimulation, blind people reported visual qualia, and the extent of these reports were related to ERP activity in the lateral occipital complex (Ortiz et al., 2011); (4) C/E blind people have visual content in their dreams, and can draw it, and the extent of their dream imagery is negatively correlated with EEG alpha band power, just as it is in sighted individuals (Bertolo et al., 2003); (5) C/E blind people report visual imagery (Cornoldi et al., 1979; Zimler and Keenan, 1983), although this is reduced, and more verbally mediated, compared to sighted people (Cornoldi et al., 1979); (6) however, spatial representation is not completely verbally mediated in blind people; during the encoding and working memory maintenance phases of a haptic mental rotation task, both sighted and blind subjects demonstrated increased parietal activation (as demonstrated in ERP data; Roder et al., 1997); (7) spatial images are supramodal, in that they are not simply the sum of modality-specific inputs; (8) there are several characteristics of visual experience, such as size, contour, and edge information, shape and texture that can be perceived through touch, and blind people can generate visual representations of haptically explored objects (reviewed in Cattaneo et al., 2008; Cattaneo and Vecchi, 2011); (9) vision and haptics may share common representations (Aleman et al., 2001); and (10) both the dorsal and ventral pathways are thought to contain supramodal regions to code shape and location of objects, respectively, regardless of the nature of the sensory input (Pietrini et al., 2009). We suggest, based on the quotes cited above, and others in the literature, that these "visual" experiences and supramodal representations aid in integrating subjective experience in C/E blindness. However, direct evidence for this claim has not yet been reported.

#### **C/E BLINDNESS IS PROTECTED FROM NEGATIVE DEVELOPMENTAL EFFECTS OF VISUAL PROCESSING IMPAIRMENTS**

Vision allows for the simultaneous perception of a great deal of information, and therefore for attention to be spread over many stimuli, or to be switched between stimuli. In schizophrenia, with its related sensory gating deficits, this can lead to the experience of being flooded with stimuli, and of stimuli being more intense than usual (Carr and Wale, 1986). In contrast, blindness is associated with touch as the primary method of exploring the environment. The nature of haptic perception is such that the person can only attend to the object currently being touched, and in this way attention cannot be involuntarily drawn to other objects (unless there are auditory or olfactory cues to other objects; Cattaneo and Vecchi, 2011).

Of course, we are not saying that vision is, by itself, a risk factor for schizophrenia. However, in combination with sensory gating, perceptual organization, and working memory impairments, visual processing, with its parallel inputs, may contribute to sensory flooding and subsequent disorganized cognition and behavior in schizophrenia. That is, visual *impairment* may be a risk factor for schizophrenia, not only in being reflective of abnormal neural development but also by being a cause of it. Conversely, C/E blindness may exert its protective effects against schizophrenia, in part, by preventing the possibility of abnormal visual input. Evidence consistent with this comes from several sources, including: (1) visual dysfunction in children of mothers with schizophrenia predicts the later development of schizophrenia (Schubert et al., 2005); (2) children (regardless of parental history) who later developed schizophrenia-spectrum disorders had significantly higher eye exam scale and strabismus scale scores compared to children who developed other non-psychotic psychopathology and children who did not develop a mental illness, while functioning in other sensory domains was far less impaired (Schiffman et al., 2006); and (3) the high specificity of visual abnormalities for predicting transition to schizophrenia among at-risk youth (Klosterkotter, 1992). In all of these cases, even if the presence of visual dysfunction is a reflection of the diathesis for schizophrenia rather than a primary cause of it, the continued state of abnormal visual input may lead to further perceptual and cognitive problems throughout development that increase the risk of developing the full-blown disorder.

Impaired visual functioning may also compromise multisensory integration,which,in turn,may lead to other cognitive deficits in schizophrenia. Efficient integration of different sensory inputs requires remapping these into an external spatial reference frame (Roder et al., 2007), which requires normal vision to properly develop (Collignon et al., 2009). However, in schizophrenia, there are multiple visual processing impairments (e.g., in gain control, perceptual organization, motion perception, etc.; Butler et al., 2008). Multisensory integration is also impaired in schizophrenia (Williams et al., 2010), and it is thought that deficits in visual processing contribute to this (Landgraf et al., 2012). In contrast, blind people appear to rely on somatotopic spatial coordinates as opposed to external, visual, coordinates (Roder et al., 2004). Therefore, in contrast to schizophrenia, in C/E blindness, the primary sense used to create a reference frame for multisensory integration (i.e., touch) is associated with superior perceptual abilities compared to sighted people.

Blind people rely primarily on vestibular and somatosensory feedback for motor control. This leads to enhanced voluntary motor control and motor-kinesthetic processing (Deutschlander et al., 2009). In contrast, schizophrenia is associated with impaired motor control (Cortese et al., 2005; Putzhammer and Klein, 2006; Velasques et al., 2011), and it has been hypothesized that this could be related to passivity phenomena and the development of delusions of control (e.g., the belief that one is not the agent of one's own actions, and/or that an external entity is controlling one's thoughts and/or actions; Danckert et al., 2004). Abnormalities in movement have also been observed in people at high risk for schizophrenia (Mittal et al., 2008). Therefore, the enhanced development of motor control and kinesthetic processing in C/E blindness can be viewed as protective against these schizophrenia-related symptom formation processes.

Finally, it has been recently proposed that visual processing disturbances in individuals at-risk for schizophrenia may contribute to the later development of the disorder by causing impairments in body perception, involving the senses of "ego boundaries," body ownership, body agency, and sense of self in space. These phenomena may then lead to problems in sense of identity, and in awareness of symptoms and insight into illness (Landgraf et al., 2012). Body ownership and agency can be measured experimentally with the "rubber hand illusion" (Ehrsson et al., 2004). In this paradigm, subjects have the experience that they are touching their own right hand with their left index finger, when in reality they are touching a rubber hand with their left index finger while the

experimenter touches their right hand in a synchronized manner. This effect is enhanced in schizophrenia and is thought to reflect abnormal body perception including a reduction in sense of body ownership (Thakkar et al., 2011). In contrast, in people with C/E blindness, the illusion is not experienced (Petkova et al., 2012). These results have been interpreted as indicating that C/E blind people have a more veridical perception of self-touch, along with a *less* flexible and dynamic representation of their own body in space compared to sighted individuals (Petkova et al., 2012). We believe that this reduced flexibility in dynamic representation of the body, secondary to loss of vision, is a protective factor against the body perception abnormalities associated with schizophrenia that were noted above.

# **NEUROPLASTICITY**

In this section we review evidence on how and where in the brain changes occur in response to C/E blindness, and how these subserve the changes in cognitive functioning discussed above. There is a large literature on brain plasticity in blind people, including evidence for developmental crossmodal plasticity (see below) – where areas of the occipital lobe are recruited for auditory and haptic perception (see Cattaneo and Vecchi, 2011 for a review), and also for olfaction (Kupers et al., 2011). Beyond this, however, other changes in developmental *intra*modal plasticity can occur which appear to result in perceptual and cognitive abilities that are opposite to those found in schizophrenia. For example, a magnetic source localization study (Elbert et al., 2002) indicated that dipoles associated with processing low- and high-frequency tones were more distant in blind people than in sighted subjects, suggesting an expansion of regions in the auditory cortex, supporting the superior pitch discrimination abilities noted above. Further evidence for intramodal plasticity in blind individuals is *reduced* hemodynamic responses to auditory stimulation in comparison to sighted subjects, which is thought to reflect *increased* efficiency in auditory signal processing within the temporal lobe, in light of the generally superior auditory processing abilities in this population (Stevens and Weaver, 2009). Evidence for changes regarding haptic perception comes from findings of *reduced* accuracy in identifying which finger is touched during a sensory threshold task (Sterr et al., 1998, 2003), within the context of overall superior tactile perception (Wong et al., 2011). These data suggested altered cortical representations for touch in the sense that the cortical representations of individual fingers are "fused" together due to their simultaneous use during Braille reading. Moreover, these data are strongest for the hand used to read Braille, and do not generalize to other body parts that are not used for reading, such as lips. Of note, the "holistic" processing of Braille letter patterns and reduced precision of individual finger-level input is in contrast to what is often observed in the visual processing of people with schizophrenia, where processing of holistic visual patterns is impaired, sometimes with enhanced processing of individual visual details (reviewed in Uhlhaas and Silverstein, 2005; Silverstein and Keane, 2011a).

Developmental crossmodal plasticity can lead to superior performance compared to sighted subjects, and there are several interesting instances of this relevant to schizophrenia. For example, somatosensory and auditory ERP data from oddball and MMN

tasks (which involve detection of a deviation from a sequential pattern in an attended or unattended sequence of stimuli, respectively),indicate normal ERP amplitude,with more activity over the occipital cortex in blind subjects, and enhanced pre-attentional processing in blind compared to sighted subjects (Kujala et al., 1995; Roder et al., 1996). This is in marked contrast to abnormal ERP amplitudes during oddball and MMN tasks in people with schizophrenia (e.g., Kayser et al., 2001) as noted above. Aside from developmental neuroplasticity, other ERP data from oddball tasks in people with schizophrenia suggested reduced short-term neuroplasticity. For example, when people with schizophrenia are presented with a high-frequency sequence of individual auditory stimulations, their ERP signatures reveal abnormally reduced long-term potentiation (Mears and Spencer, 2012). In contrast, short-term neuroplasticity, at least involving the occipital cortex, may be greater in people with C/E blindness (De Volder et al., 1999).

A major focus of research on visual processing in schizophrenia is impaired functioning in the dorsal and ventral visual streams. Therefore, we briefly summarize evidence that, in contrast to what is observed in schizophrenia, functioning in these pathways is intact in C/E blindness, *despite the absence of visual input*. Much evidence suggests that the dorsal stream is specialized for determining where an object is and for guiding action, whereas the ventral stream is specialized for analyzing form and color for determining what an object is (Goodale, 1993; Goodale et al., 2005). Many studies indicate impaired functioning of both of these streams in schizophrenia (e.g., King et al., 2008; Silverstein et al., 2009; Sehatpour et al., 2010; Lalor et al., 2012; Plomp et al., 2012). Surprisingly, these pathways appear to subserve similar functions in blind people as they do in psychiatrically healthy sighted people, suggesting that they can develop even in the absence of visual experience, and therefore that their representations are supramodal (Cattaneo and Vecchi, 2011; Ptito et al., 2012). For example, during spatial imagery tasks using auditory or tactile stimuli, early blind and sighted individuals demonstrated similar dorsal stream and frontal eye field activation, as assessed via PET or fMRI (Vanlierde et al., 2003; Garg et al., 2007;Bonino et al., 2008). In addition, dorsal areas devoted to processing motion information in sighted people (e.g., V5/MT) are employed in blind people in response to tactile and auditory motion cues (e.g., Ptito et al., 2009; Bedny et al., 2010; Matteau et al., 2010). These areas are notably underactivated during perception of visual motion in schizophrenia, in the context of impaired motion perception (Chen, 2011). In the ventral stream, blind subjects demonstrated similar activation during tactile object perception to that shown by sighted subjects during visual and haptic exploration of the same objects (Pietrini et al., 2004; Ptito et al., 2012).

It should be noted that while occipital lobe activity can occur in sighted subjects during tactile and auditory processing tasks, this has been found to be due to visual imagery (Sathian, 2005), which activates early visual cortex areas in a retinotopic fashion (Slotnick et al., 2005), and to calibration of head-centered sound localization (Zimmer et al., 2004). In contrast, occipital cortex activity in C/E blind subjects appears to support actual non-visual stimulus processing, and to represent a true crossmodal reorganization (see Roder et al., 1997; Cattaneo and Vecchi, 2011 for a

review). Consistent with this, transcranial magnetic stimulation (TMS), applied to the occipital cortex, disrupts Braille reading ability in blind individuals, but not in sighted individuals, whereas the reverse is true when TMS is applied over the somatosensory cortex in the parietal lobe (Cohen et al., 1997). Similarly, TMS over the occipital cortex induces tactile sensations in blind readers' fingers, but only phosphene perception for sighted subjects (Ptito et al., 2008).

As noted above, schizophrenia patients have demonstrated olfactory deficits in several studies, while C/E blind individuals have demonstrated superior olfactory abilities. A recent study, comparing congenitally blind subjects to blindfolded sighted controls, demonstrated that this is due to enhanced processing in areas normally dedicated to olfaction (e.g., amygdala, hippocampus) *and* in multiple regions of the occipital cortex (Kupers et al., 2011). This is further evidence of both the supramodal nature of representations in the C/E visually deprived occipital lobe, and also of crossmodal plasticity in C/E blindness.

In addition to subserving enhanced non-visual sensory processing, fMRI data indicate that the occipital lobe in C/E blind individuals also supports syntactic and semantic (more so than phonological) aspects of language processing (Roder et al., 2002; Burton et al., 2003), as well as verbal memory, episodic memory, and verbal fluency (Amedi et al., 2003; Raz et al., 2005), all of these being processes that are impaired in schizophrenia (Tendolkar et al., 2002; Fisher et al., 2009; Costafreda et al., 2011). For example, in addition to occipital lobe activation during memory retrieval, and a correlation between occipital activation and episodic memory in blind but not sighted subjects (Raz et al., 2005), repetitive transcranial magnetic stimulation (rTMS) over the occipital lobe impaired performance in a verb generation task for blind but not sighted subjects (Amedi et al., 2004).

Another consequence of blindness may be increased communication between brain regions. Several studies have demonstrated increased effective connectivity between the occipital lobe and temporal and prefrontal regions in early blind individuals (e.g., Noppeney et al., 2003; Leclerc et al., 2005). This is in contrast to schizophrenia, where reduced connectivity is typically found (e.g., Kim et al., 2008; Dima et al., 2009, 2010), including between occipital and temporal and frontal regions (Rigucci et al., 2012).

Finally, Sanders et al. (2003), based on evidence of visual cortex plasticity in dark-reared animals (Chen and Bear, 2007; Chen et al., 2007), proposed that an effect of early blindness is increased NMDA-receptor activity (although accompanied by reduced numbers of receptors) in visual cortex, and in regions with which this has many connections, primarily the anterior cingulate cortex (ACC), which is involved in resolving response competition and context sensitivity, two cognitive domains that are impaired in schizophrenia (Cohen and Servan-Schreiber, 1992; Dolan et al., 1995; Phillips and Silverstein, 2003). Moreover, schizophrenia has been characterized by NMDA-receptor hypofunction (Phillips and Silverstein, 2003), and, in numerous studies, by ACC hypoactivation (Dolan et al., 1995). The consequences of NMDAreceptor hypofunction in schizophrenia have been hypothesized to include impairments in sensory gating, perception, working memory, learning, and the full range of positive and negative symptoms (Phillips and Silverstein, 2003; Coyle, 2012). Therefore, an increase in NMDA-receptor activity in C/E blindness could have widespread positive effects on cognition, and protective effects against symptoms.

In short, there are several ways in which the neuroplasticity that results from C/E blindness results in changes that are opposite to those observed in schizophrenia, and that may represent protective effects. Specifically, the evidence reviewed above suggests that, in C/E blindness: (1) despite the loss of visual input, cortical reorganization during early development leads to accurate form and space perception (via auditory and tactile processing) which is supported by brain areas that function abnormally in schizophrenia (e.g., dorsal and ventral visual streams); (2) this developmental plasticity also leads to use of occipital areas for functions such as preattentive processing (e.g., as reflected in the MMN), language, memory, and olfaction – all of which are impaired in schizophrenia – which may underlie the superior functioning in those areas in C/E blindness reviewed above; and (3) in addition to these sequelae of developmental plasticity in C/E blindness, there is also evidence of normal later-onset plasticity, which may in part reflect prolonged plasticity of the occipital cortex in C/E blindness (De Volder et al., 1999), and which is the basis for the success of sensory substitution devices (Ward and Meijer, 2010). In contrast, later-onset plasticity has been shown to be reduced in schizophrenia in several domains (Fitzgerald et al., 2004; Oxley et al., 2004; Daskalakis et al., 2008;Hasan et al., 2011, 2012; Mears and Spencer, 2012).

# **CONGENITAL OR EARLY BLINDNESS IS NOT PROTECTIVE AGAINST MENTAL DISORDERS IN GENERAL**

While C/E blindness may protect against schizophrenia, they do not protect against mental illness in general. A range of mental and behavioral disorders has been reported in blind people. For example, anxiety levels have been reported to be higher in congenitally blind than sighted adolescents (Bolat et al., 2011), and autistic symptoms and autism are common in blind children (Keeler, 1958;Wing, 1969;Chess, 1971;Chase, 1972; Fraiberg, 1977; Rogers and Newhart-Larson, 1989; Brown et al., 1997; Ek et al., 1998; Carvill, 2001). Sharp (1993) reported a case of anorexia nervosa and depression in a woman blind since the age of 9 months. A recent case study (Kocourkova et al., 2011) described a case of an adolescent patient, blind from early childhood,who showed symptoms of anorexia, depression, suicidal behavior, and self-harming. A conclusion in this report was that body image is a mental construct that is not dependent on sensory perception. Finally, Musial et al. (2007) reported a case of arachnophobia in a congenitally blind person, suggesting that visual cues are not necessary for the development of phobic disorders.

# **CONGENITAL DEAFBLINDNESS IS NOT PROTECTIVE AGAINST SCHIZOPHRENIA**

Protective effects of blindness may not exist if other forms of severe sensory loss are present. For example, congenital deafblindness is associated with elevated rates of psychosis, as well as mental retardation (Dammeyer, 2011). Also, children with Usher syndrome, in which people are typically deaf from birth and then develop retinitis pigmentosa leading to blindness in childhood, has been associated with psychotic symptoms and schizophrenia

(Dammeyer, 2012). The reason why adding deafness to blindness removes the apparent effect of the latter against schizophrenia is not clear at present. One possibility is that blindness by itself presents a surmountable challenge to cope with the environment and thereby fosters compensatory sensory, perceptual, and cognitive changes that lead to a surprisingly high level of functioning. Deafblindness, on the other hand, may so seriously restrict the opportunity for environmental interaction that it also stunts the development of cognitively based coping strategies. For example, congenital deafblindness typically leads to significant delays in achieving several cognitive milestones, and to profound impairments in speed of processing, the ability to integrate disparate items of information, attention, communication, and the capacity for symbolic understanding and expression (Geenens, 1999; Bruce, 2005; Shamma et al., 2011). It is worth noting here that although C/E blindness and C/E deafblindness are both relatively rare, there are no published cases of the former being comorbid with schizophrenia, whereas there are many reported cases of this comorbidity with the latter.

# **SENSORY LOSS IN GENERAL DOES NOT PROTECT AGAINST SCHIZOPHRENIA**

Another important consideration is that sensory loss *per se* does not protect against schizophrenia. For example, deafness occurs in schizophrenia at as high a rate as in the general population (Kitson and Fry, 1990), and congenital deafness is a risk factor for the development of psychotic symptoms (Thewissen et al., 2005; Atkinson, 2006), including, interestingly, higher rates of visual and somatic hallucinations than are found in the non-deaf people with schizophrenia (Cutting, 1985), which often co-occur with reports of hearing voices (Du Feu and McKenna, 1999). And, while deafness may be associated with compensatory cognitive changes (see Bross, 1979; Dye and Bavelier, 2010; e.g., heightened attention to visual peripheral cues in people who use sign language; Proksch and Bavelier, 2002), these appear to not protect against schizophrenia, although they may lead to subtle differences in profiles of cognitive impairment between deaf and hearing people with schizophrenia (Horton and Silverstein, 2007, 2011). Moreover, in some cases, compensatory changes may not develop until adulthood (Rettenbach et al., 1999).

# **MEDIATING BIOLOGICAL VARIABLES**

The hypothesized protective effects of blindness on schizophrenia may be mediated by other factors. For example, Horrobin (1979) proposed that abnormal pineal gland function and resulting prostaglandin activity are etiological factors in schizophrenia. This is supported by evidence of increased inflammation and reduced melatonin levels in schizophrenia patients (Anderson and Maes, 2012; Muller et al., 2012).  Another potential mechanism involves cortical thickness and pruning. Schizophrenia is typically characterized by cortical thinning (Cobia et al., 2012), and it has been hypothesized that excessive neuronal pruning takes place during adolescence (Boksa, 2012). In contrast, the visual cortex of C/E blind people – which

as noted above is involved in multiple perceptual and cognitive processes – is thicker than in sighted people, and is thought to be characterized by a less than normal amount of pruning, due to deprivation of visual experience (Jiang et al., 2009). A consequence of this thickening is that, even if genes related to schizophrenia cause excessive pruning in someone with C/E blindness, the remaining number of neurons may still be greater than normal in some areas. This, in combination with the cortical reorganization noted above, leading to occipital regions being used for non-visual cognitive processes, may protect blind people against crossing the threshold needed for psychotic symptoms to emerge (i.e., an adequate number of neurons devoted to specific types of processing may be present even if pruning is excessive).

# **CONCLUSION**

This paper builds on previous reports of a lack of schizophrenia in people with C/E blindness by advancing the hypothesis that the latter alters cognition and fosters neuroplasticity in ways that confer protective effects against schizophrenia. The reviewed evidence indicates that: (1) schizophrenia is primarily a cognitive disorder; (2) many of the cognitive functions that are impaired in schizophrenia are enhanced among the C/E blind; (3) C/E blindness involves *reduced* flexibility in language and in dynamic representation of the body, and these reductions may protect against thought disorder and alterations in experience of the self, respectively; (4) the mechanisms noted in 2 and 3 above are significantly less affected if the onset of blindness is after the first few months of life; (5) other forms of C/E sensory loss do not protect against schizophrenia; and (6) C/E blindness does not protect against other disorders, suggesting that there is a special link between schizophrenia and visual processing.

Of course, schizophrenia is characterized by cognitive impairments in addition to those described here, such as in executive functioning, that are thought to rely heavily on functioning of the dorsolateral prefrontal cortex (DLPFC). There appears to be almost no research comparing blind (congenital or acquired) and sighted people on these functions, however, and so whether blindness confers any protective effects on them remains an open question. Note, however, that the DLPFC does not fully develop until late adolescence or early adulthood. In contrast, cognitive and academic decline, and interpersonal dysfunction, typically begin in late childhood or early adolescence in people who go on to develop schizophrenia, and this age range corresponds to the time frame in which the visual system in humans is most plastic (i.e., until ∼14– 16 years of age;Cohen et al.,1999). This suggests that the protective sequelae of C/E blindness involve changes in more basic sensory, perceptual, and cognitive (i.e., non-executive) functions.

While the idea of one abnormal condition having a protective effect against another condition may seem unusual, it is not unknown. For example, several studies have now replicated the finding that schizophrenia appears to have an inverse relationship with rheumatoid arthritis (RA), with some estimates putting the risk for RA among schizophrenia patients at 30% that of control counterparts (Eaton et al., 1992; Mors et al., 1999; Oken and Schulzer, 1999). Conversely, there may also be a reduced risk for developing schizophrenia among individuals with RA (Gorwood et al., 2004). This is especially low considering smoking is a risk factor for developing RA (Stolt et al., 2003) and that a disproportionally large percentage (60–90%) of individuals with schizophrenia smoke (Dervaux and Laqueille, 2008). As noted, we hypothesize that the cognitive benefits conferred by C/E blindness act as a prophylactic for schizophrenia but not other mental disorders. This hypothesis, if confirmed, has implications for determining when cognitive training should occur for people with, or at-risk for, schizophrenia, and for the nature of such training. It also has implications for whether insights from C/E blindness can be used to design interventions to prevent schizophrenia. Each of these issues will be addressed in turn below.

Evidence from animal studies indicates that prevention of schizophrenia-related cognitive impairment can be achieved by early cognitive training. For example, in one study, rats received a ventral hippocampus lesion that induces a spatial working memory deficit similar to that found among schizophrenia patients. It was found that among animals that had been provided with pre-lesioning cognitive training, the typical post-lesion working memory deficit did not arise (Lee et al., 2012). While similar preventive data do not exist in humans, a recent study of cognitive remediation in first-episode schizophrenia demonstrated that it significantly slowed the typical gray matter loss associated with the first years after an initial psychotic episode (Eack et al., 2010). Therefore, it is reasonable to study whether the long-term effects of cognitive training in people at high risk for the disorder could be at least as strong, if not stronger, than effects of cognitive training introduced after a diagnosis of schizophrenia is made, given that the effects are occurring in the context of a healthier and younger brain.

But when should training occur? Evidence indicates that intervening when people first begin to show psychotic symptoms or functional decline (i.e., in the "ultra high-risk" state) can delay, but does not prevent, schizophrenia (Yung and Nelson, 2011). Therefore, it has recently been proposed that intervening at a "pluripotent risk stage" – the time of the earliest emergence of behavioral and cognitive difficulties (typically 9–13 years of age) that are non-specific as to final diagnosis – would be more effective (Agius et al., 2010; McGorry, 2010; McGorry et al., 2010; Morgan et al., in press). Whether or not such a strategy can prevent schizophrenia, it may be an ideal time for intensive cognitive training, in terms of affording protection against later and severe schizophrenia-related cognitive impairment. Of course, even earlier training could be effective, but the feasibility of identifying people at high risk for mental illness at younger than 9-years old has not been well-established, except in cases where an identical twin or first-degree relative has the disorder.

What sort of training would be effective? Based on the evidence reviewed above, we suggest that cognitive training in young people at-risk for schizophrenia should be *comprehensive in nature*, and should focus to a greater degree than it has in the past on sensory and perceptual functioning. For example, in addition to a focus on improving aspects of attention, it should focus on improving sensory tuning and the accuracy of sensory representations, perceptual organization, multisensory integration, and controlled processing including integration of bottom-up sensory data with stored information (see Heller quotes above, and Hemsley, 1996). Some interventions have already demonstrated

success in improving functioning in these specific areas in humans (Temple et al., 2003; Mahncke et al., 2006; Genevsky et al., 2010) and animals (Polley et al., 2006; Zhou et al., 2011). In addition, although schizophrenia patients often demonstrate reduced plasticity, it is not absent, and capacity for perceptual and cognitive change has been demonstrated (Fisher et al., 2009, 2010; Silverstein and Keane, 2009) both in and outside the context of specific interventions. Therefore, it is possible that even greater plasticity can be harnessed earlier in the developmental course of the illness, before psychotic symptoms emerge and near the onset of, or prior to, cognitive and functional decline. In addition, it has already been demonstrated in schizophrenia that improving auditory precision by repeated practicing of tone discrimination leads to improvements in auditory and (more interestingly) higher level cognitive functions (e.g., verbal learning and memory; Adcock et al., 2009; Fisher et al., 2009). Therefore, broader improvements (beyond the trained task) may occur in at-risk youth with similar practice.

An additional strategy for people at-risk for schizophrenia involves increasing reliance on non-visual sensory modalities to enhance their functioning. Already it has been shown in people with established schizophrenia, for example, that steady-state auditory responses, which are typically abnormally reduced and associated with an increase in broadband noise, can be significantly improved, and to a greater degree than occurs in healthy people, by closing the eyes during task performance (Griskova-Bulanova et al., 2012). Fostering cognitive reserve, and trying to prevent schizophrenia, or at least minimize later illness-related cognitive impairment, by strengthening capacity and efficiency in non-visual domains is an as yet untested strategy. However, the goal of creating a schizophrenia-specific, *acquired* cognitive reserve, in a manner guided by compensatory changes observed in C/E blindness, would appear to be a reasonable and promising direction to pursue, given that premorbid cognitive reserve predicts later cognitive functioning in normal aging (Steffener and Stern, 2012), neurodegenerative disorders (Koerts et al., 2012; Stern, 2012), and schizophrenia (de La Serna et al., 2013).

Can an understanding of cognition and neuroplasticity in C/E blindness be used to reduce the likelihood of schizophrenia? At first glance, the answer seems to be "no" since: (1) only C/E blindness (but not blindness acquired after the first few months of life) is associated with a protective effect; (2) it is difficult to identify most people who will develop schizophrenia during the first year of life; (3) it is not clear what type of training could be given to people less than 1-year old, given limited attention span and undeveloped verbal abilities; and (4) the presence of vision is likely to reduce the extent of developmental neuroplasticity. However, the ultimate answer to this question may not be this simple. For example, much remains to be learned about biological and computational changes associated with C/E, and later-developing, blindness, and so further investigation into these issues may reveal clues for intervention development. Also, it is not known beyond what age fostering neuroplasticity and cognitive enhancement might no longer be able to prevent schizophrenia, but only reduce schizophrenia-related cognitive impairment. Third, since it is not C/E blindness *per se*, but rather, the corresponding brain and cognitive changes that are protective against schizophrenia, it is possible that methods other than naturally occurring C/E blindness can confer protective effects. For example, an open question is the extent to which particularly intensive sensory-perceptual-cognitive interventions delivered to at-risk youth past the first year of life can create some of the protective changes associated with naturally occurring C/E blindness.

#### **REFERENCES**

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#### **ACKNOWLEDGMENTS**

We thank Thomas Papathomas, Matt Roche, Keith Feigenson, James Gold, and Judy Thompson for their helpful comments on earlier drafts of this manuscript.We also thank Ms. Arwen Lockley for her helpful insights on blindness and schizophrenia, and the two reviewers for their helpful suggestions. This work was supported by a National Research Service Award (F32MH094102) to Brian P. Keane, and R01MH093439 to Steven M. Silverstein.

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*in Blind Children with Retrolental Fibroplasia*. New York: Grune & Stratton.

in an auditory detection and discrimination task: exploring the 'selfmonitoring' model of hallucination. *Schizophr. Res.* 55, 115–128.

*Schizophrenia: Evolution and Synthesis*, eds M. B. Silverstein and T.Wykes (Cambridge: MIT Press).

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individuals. *Neuropsychologia* 47, 843–848.

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

*Received: 03 November 2012; accepted: 31 December 2012; published online: 21 January 2013.*

*Citation: Silverstein SM, Wang Y and Keane BP (2013) Cognitive and neuroplasticity mechanisms by which congenital or early blindness may confer a protective effect against schizophrenia. Front. Psychology 3:624. doi: 10.3389/fpsyg.2012.00624*

*This article was submitted to Frontiers in Psychopathology, a specialty of Frontiers in Psychology.*

*Copyright © 2013 Silverstein, Wang and Keane. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, providedthe original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.*

# Base rates, blindness, and schizophrenia

# *Steven M. Silverstein1,2\*, Yushi Wang1 and Matthew W. Roché1*

*1 University Behavioral HealthCare, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA*

*2 Department of Psychiatry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA*

*\*Correspondence<EMAIL_ADDRESS>
#### *Edited by:*

*Michael Green, University of California, Los Angeles, USA*

*Reviewed by:*

*Michael Green, University of California, Los Angeles, USA*

#### **A commentary on**

**Cognitive and neuroplasticity mechanisms by which congenital or early blindness may confer a protective effect against schizophrenia**

*by Silverstein, S. M., Wang, Y., and Keane, B. P. (2012). Front. Psychol. 3:624. doi: 10.3389/fpsyg.2012.00624*

Our paper on congenital and early (C/E) blindness and schizophrenia was an effort to account for the previously reported negative relationship between these conditions, in light of recent work indicating what the study of C/E blind people reveals about brain function and organization (Cattaneo and Vecchi, 2011; Kupers et al., 2011; Ricciardi and Pietrini, 2011). In particular, we hypothesized that the neuroplastic changes inherent to C/E blindness protect against schizophrenia by promoting strengths in those cognitive domains where schizophrenia is characterized by deficits.

Since our paper was published, we have received several comments asking a version of this question: can the lack of reports of people with both conditions be explained simply by the rarity of each condition, so that the chances of a person having both are so low that even if such people existed, it is unlikely their condition will have been reported? This is an important question, as when studying low base rate phenomena, distorted conclusions can easily be reached (Meehl and Rosen, 1955). We addressed this issue in the original version of our manuscript, but then removed it from the final version due to length considerations. Here, we note our earlier comments.

The conclusion that there are no C/E blind people with schizophrenia is based on a small number of studies that involved relatively small samples. Clearly, this argument would be strengthened by larger, population-based studies. This is because, as a simple calculation demonstrates, a case of congenital blindness and schizophrenia would be extremely rare even if there was no protective effect of blindness: if schizophrenia occurs at a rate of 0.72% in the population (McGrath et al., 2008), and congenital blindness occurs at an estimated rate of 0.03% in people born in the 1970s and 1980s (based on Robinson et al., 1987), then the joint probability of a person having both conditions, if the two are independent, would be 0.02% or 2 out of every 10,000. Although this is a low prevalence rate, it is higher than the rates for childhood-onset schizophrenia (Remschmidt and Theisen, 2005), and many other well-known medical conditions (e.g., Hodgkin's lymphoma, Prader Willi syndrome, Rett's Syndome). Based on this estimated prevalence rate, in the United States alone (with a population of 311, 591, 917, as of July 2011, according the US census), there should be approximately 620 congenitally blind people with schizophrenia. When cases of blindness with an onset in the first year of life (i.e., early blindness) are taken into account, the percentage would be larger. Therefore, it is remarkable that in over 60 years, and with several investigations [including several before DSM-III (1980) when criteria for schizophrenia were broader than at present], not a single case of a C/E blind schizophrenia patient has been reported. Moreover, several published studies, and our experience as well, included surveying Directors of agencies that serve large numbers of blind people, and none of them could recall ever seeing a person who

had both conditions. It is also interesting that rates of C/E blindness are significantly higher in developing, compared to industrialized, countries. Therefore, if C/E blindness did *not* protect against the development of schizophrenia, comorbidity would be more likely to be reported in such countries. However, this has not occurred. In short, available evidence, probabilistic estimates, and the striking contrasts, within the same domains of cognition, between superior functioning in C/E blindness and impaired functioning in schizophrenia, combine to suggest a protective relationship. If the conditions did co-occur at chance levels, reports of such cases should appear at least somewhat as often as those of many other rare medical conditions, especially since reports of an absence of schizophrenia in C/E blind people have appeared since 1950 (Chevigny and Braverman, 1950). The absence of such reports is noteworthy.

One research strategy that could generate further evidence on this issue is the study of schizotypal symptoms in the C/E blind. These subsyndromal psychotic symptoms have a higher base rate than schizophrenia itself (i.e., 10–15% vs. ∼1%) (Fossati and Lenzenweger, 2009), and people with these symptoms share some of the same cognitive and biological impairments as people with the full disorder (Aichert et al., 2012; Cochrane et al., 2012). Studies of schizotypal symptoms would allow for the determination of whether C/E blindness protects against the full spectrum of schizophrenia-related illness or just schizophrenia itself. If no schizotypal symptoms were observed, this would be evidence for the existence of protective mechanisms against all schizophrenia-related psychopathology. If, however, schizotypal symptoms were found, samples of C/E blind people could be studied to gain insight into the neurobiological changes that protect against the development of clinical psychosis. As such, expanding the schizophrenia phenotype studied in the C/E blind holds potential for increasing our understanding of the mechanisms involved in schizophrenia.

In addition to these points, we noted in our original paper that other congenital sensory impairments have not been associated with absence of schizophrenia, that congenital deafness and later blindness, such as found in Usher Syndrome, whose prevalence has been estimated at 0.005% (Rosenberg et al., 1997) has been associated with psychotic disorders at rates between 4–24% (Waldeck et al., 2001), and that non-psychotic psychiatric disorders are observed in C/E blindness. These data suggest a unique relationship between C/E blindness and schizophrenia. However, we acknowledge that the absence of evidence (of people with both conditions) is not evidence of absence. That said, given the potentially important lessons for understanding, preventing, and treating schizophrenia that brain reorganization in C/E blindness provides, we believe it is useful to pursue this line of thought. At the very least, if C/E blindness did *not* prevent schizophrenia, then in light of the cognitive changes secondary to C/E blindness, it would be informative to determine whether it mitigates the associated cognitive impairment. Finally, we hope to raise awareness in the psychiatric community of past literature relating to C/E blindness and schizophrenia, so that if people with both conditions exist, their cases will be reported.

#### **ACKNOWLEDGMENTS**

We thank Michael Green for his constructive criticism on an earlier draft of this commentary.

# **REFERENCES**

incidence, prevalence, and mortality. *Epidemiol. Rev.* 30, 67–76.

*Received: 10 March 2013; accepted: 13 March 2013; published online: 03 April 2013.*

# "To see or not to see: that is the question." The "Protection-Against-Schizophrenia" (PaSZ) model: evidence from congenital blindness and visuo-cognitive aberrations

# *Steffen Landgraf 1,2\* and Michael Osterheider 1*

*1 Department for Forensic Psychiatry and Psychotherapy, District Hospital, University Regensburg, Regensburg, Germany 2 Berlin School of Mind and Brain, Humboldt Universität zu Berlin, Berlin, Germany*

#### *Edited by:*

*Steven Silverstein, University of Medicine and Dentistry of New Jersey, USA*

#### *Reviewed by:*

*Mahesh Menon, University of Toronto, Canada José Alberto González-Hernández, Hermanos Ameijeiras Hospital, Cuba*

#### *\*Correspondence:*

*Steffen Landgraf, Department of Forensic Psychiatry and Psychotherapy, District Hospital, University Regensburg, Haus 45, Raum 001, Universitätsstraße 84, 93053 Regensburg, Germany e-mail<EMAIL_ADDRESS>
The causes of schizophrenia are still unknown. For the last 100 years, though, both "absent" and "perfect" vision have been associated with a lower risk for schizophrenia. Hence, vision itself and aberrations in visual functioning may be fundamental to the development and etiological explanations of the disorder.In this paper, we present the "**P**rotection-**A**gainst-**S**chi**z**ophrenia" (PaSZ) model, which grades the risk for developing schizophrenia as a function of an individual's visual capacity. We review two vision perspectives: (1) "Absent" vision or how congenital blindness contributes to PaSZ and (2) "perfect" vision or how aberrations in visual functioning are associated with psychosis. First, we illustrate that, although congenitally blind and sighted individuals acquire similar world representations, blind individuals compensate for behavioral shortcomings through neurofunctional and multisensory reorganization. These reorganizations may indicate etiological explanations for their PaSZ. Second, we demonstrate that visuo-cognitive impairments are fundamental for the development of schizophrenia. Deteriorated visual information acquisition and processing contribute to higher-order cognitive dysfunctions and subsequently to schizophrenic symptoms. Finally, we provide different specific therapeutic recommendations for individuals who suffer from visual impairments (who never developed "normal" vision) and individuals who suffer from visual deterioration (who previously had "normal" visual skills). Rather than categorizing individuals as "normal" and "mentally disordered," the PaSZ model uses a continuous scale to represent psychiatrically relevant human behavior. This not only provides a scientific basis for more fine-grained diagnostic assessments, earlier detection, and more appropriate therapeutic assignments, but it also outlines a trajectory for unraveling the causes of abnormal psychotic human self- and world-perception.

**Keywords: schizophrenia, blindness, visual aberrations, Protection-Against-Schizophrenia (PaSZ), vision therapy, continuous diagnostic criteria, early detection, cognition**

# **INTRODUCTION**

#### **THE PROTECTION-AGAINST-SCHIZOPHRENIA MODEL**

"To see or not to see" may be the fundamental question by which we can elucidate the still unknown causes (Insel, 2010) of one of the most devastating human experiences – schizophrenia. For the last 100 years, both "absent" and "perfect" vision have been associated with a lower risk for the disorder (Landgraf et al., 2012; Silverstein et al., 2013). Therefore, we argue that vision itself and aberrations in visual functioning may be fundamental to the development of the disorder and, thus, may provide important information about its causes. In this article, we present the "**P**rotection-**A**gainst-**S**chi**z**ophrenia" (PaSZ) model by reviewing human visual functioning from two perspectives: (1) "Absent" vision or how congenital blindness contributes to PaSZ and (2) "perfect" vision or how aberrations in visual functioning are associated with an increased risk for psychotic symptomatology. Grading the risk for developing schizophrenia as a function of an individual's visual capacity, we argue that (early) diagnostic and interventional approaches need to be specific to the patient's visual capacity. On the one hand, individuals who suffer from visual deterioration (who previously had "normal" visual skills) may reduce their risk for developing schizophrenia through an *improvement* in visual capacity. On the other hand, individuals who suffer from visual impairment (who have never developed "normal" vision) may, in fact, reduce their risk for schizophrenia through a *decline*in visual capacity (**Figure 1**). Hence, rather than categorizing human behavior into, e.g., "normal" and "mentally disordered," as has traditionally been the practice of diagnostic manuals (APA, 2000; WHO, 2007), our approach may be the first to use a continuous scale to represent psychiatrically relevant human behavior. This not only provides a scientific basis for more fine-grained diagnostic assessments, earlier detection, and more appropriate therapeutic assignments, but this model also outlines a trajectory for unraveling the causes of the schizophrenia disorder.

Current models of developmental trajectories of schizophrenia emphasize the prognostic value of subclinical disease expressions.

**FIGURE 1 | The "Protection-Against-Schizophrenia" (PaSZ) Model.** The continuous PaSZ model depicts the relative risk for schizophrenia as a function of the continuous variable visual capacity. Whereas both "absent" vision (congenital blindness) and "perfect" vision ("supernormal" vision) may be associated with a decreased risk for schizophrenia, the model suggests that the risk for developing schizophrenia increases from both ends of the visual capacity continuum toward a "peak risk" (Landgraf et al., 2012; Silverstein et al., 2013). The location of this peak risk has yet to be determined experimentally. However, the peak has important implications for the understanding of the etiology, development, and therapy of the disorder: individuals suffering from visual impairment (located to the left of the peak), who never developed "normal" vision, may reduce their risk for developing schizophrenia through a *decline* in visual capacity. Individuals suffering from visual deterioration (located to the right of the peak), who previously had "normal" visual skills, may reduce their risk for developing schizophrenia through an *improvement* in visual capacity. Note that the

In his inspirational *Nature* article, National Institute of Mental Health Director Insel (2010) describes

*"psychosis as a late, potentially preventable stage of the illness" (p. 187).*

Thus, current diagnostic criteria and etiological models of the disease may be indicative of only ultimate disease stages. Even more problematic, the *prognostic* or prodromal1 criteria of schizophrenia model does not make a concrete assumption on the association between vision capacity and risk for schizophrenia (linear, exponential, etc.). Instead, we suggest that extensive longitudinal and epidemiological investigations, also controlling for age-related visual capacity decline (Ofan and Zohary, 2007; Cattaneo et al., 2008), are necessary to elaborate this issue. In this context, visual capacity may comprise but is not limited to measures of visual acuity (near/far), sensitivity to light, motion, and color, visual field size, and stereoscopic vision. To the best of our knowledge, this is the first model that uses a continuous (more vs. less psychotic) rather than a categorical ("normal" vs. "mentally disordered") approach to represent psychiatrically relevant human behavior. Abbreviations: PaSZ = Protection-Against-Schizophrenia; SZ = schizophrenia; Prodromals = individuals identified at ultra-high risk for developing schizophrenia; 1st episode patients = patients with schizophrenia that have had one (identified) psychotic episode; Chronic patients = patients with schizophrenia that have had at least three (identified) psychotic episodes.

are still being defined in terms of diagnostic symptomatology, i.e., sub-threshold phenotypic expressions of actual full-blown psychotic episodes (Klosterkotter et al., 2001; McGorry et al., 2003; Yung et al., 2005). Currently, to be identified as prodromal for an impending psychosis, individuals need to present one of the following three criteria: (1) attenuated (sub-threshold) psychotic symptoms, (2) BLIPS or brief limited intermittent psychotic symptoms (lasting less than 1 week and disappearing spontaneously), and (3) functional deterioration in the presence of vulnerability (they must suffer from schizotypal personality disorder or have a first-degree relative who has psychosis) (McGorry et al., 2003; Miller et al., 2003; Yung et al., 2005). Other descriptions

1For intelligibility, we use the term "prodromal" to refer to prodromal, ultra-high risk (UHR), or other patients assumed to experience signs of an impending psychotic episode.

of prodromal individuals, such as basic symptoms (Moyer and Landauer, 1967; Gross, 1969, 1989; Klosterkotter et al., 1997, 2001) by which early and late prodromal phases are distinguished (Niendam et al., 2007; Schultze-Lutter et al., 2007; Simon et al., 2007),2 also presume symptom continuity along with the progression of the disease. The (scientifically) recognized stages of schizophrenia include, in fact, the prodrome, the first-episode, and the stabilized chronic syndrome. Problematically, current early detection and intervention are based on the theoretical yet unproven assumption that symptoms of schizophrenia extend continuously from the prodrome to the stabilized syndrome (Gross, 1969, 1989; Klosterkotter et al., 1997, 2001; Simon et al., 2006; Niendam et al., 2007; Schultze-Lutter et al., 2007; McGorry, 2010). Consequently, prodromal approaches have not yielded high predictive power in their ability to identify transitions to full-blown psychosis (Gottesman and Erlenmeyer-Kimling, 2001; Miller et al., 2002; McGorry et al., 2003; Yung et al., 2003, 2004, 2005; Haroun et al., 2006; Olsen and Rosenbaum, 2006a,b). In their recent review, Gee and Cannon (2011) found that only about one third of prodromal individuals eventually convert to psychosis. Two thirds remain symptomatic at a sub-threshold level or recover completely. Hence, we and other researchers argue that current diagnostic criteria (APA, 2000) systematically underestimate the individuality of symptoms (Andreasen, 2007; Nelson et al., 2008), neglecting, for example, the fact that psychoses are often experienced in phases that include self-disturbances (Parnas et al., 1998; Sass and Parnas, 2001, 2003) and visuocognitive impairments (Elvevag and Goldberg, 2000; Andreasen and Black, 2006; Keefe and Harvey, 2012; Landgraf et al., 2012). This means, first, that prodromal extrapolations of current diagnostic criteria become less valid or less useful the earlier the prognostic verdict is acquired. Second, there may be underlying factors that are not included in the diagnostic criteria of schizophrenia and treatment options; nevertheless, these factors may be crucial for understanding the ontogenetic development and etiology of the disorder. Thus, there is still an imperative need for stage-specific disease progression markers to precisely predict deterioration and the functional outcome. One promising factor for this kind of progression marker is visually mediated cognition.

#### **GOALS OF THE REVIEW**

Since the introduction of the term *"Schizophrenia"* by Bleuler (1908), a plethora of scientific articles have stressed the importance of vision aberrations in schizophrenia. By contrast, "absent" and "perfect" vision have, to the best of our knowledge, been associated with a lower risk for developing schizophrenia. Hence, visual information acquisition and/or processing at some point in life appears to be necessary but not sufficient for the human brain to develop psychosis. Only disturbed visual processing may be sufficient. We therefore present the idea of the continuous PaSZ model, for which we review two vision-related indicators of the etiology and development of the disease.

In the first part of this paper – the blindness perspective – we review cognitive alterations with regard to real-world mental representations, neurofunctional reorganization, and multisensory integration in congenitally blind individuals. We assess how these altered functions provide insight into the developmental causes of schizophrenia and the protection against it.

In the second part – the vision perspective – we provide evidence for how abnormalities in the visual system can lead to schizophrenia. Specifically, we show that visual information acquisition and processing deficits progress along with the progression of the disease. We describe how perceptual abnormalities contribute to higher-order cognitive dysfunctions and subsequently lead to diagnostic phenotypic expressions (symptoms).

Finally, in the third part – the therapeutic perspective – we review interventional implications of the PaSZ model. Specifically, we show how both an *increase in visual impairment* and a *decrease in visual deterioration* may contribute to lowering a person's risk for schizophrenia.

# **THE BLINDNESS PERSPECTIVE ON SCHIZOPHRENIA A WHOLE WORLD WITHOUT VISION**

Understanding blindness may shed light on the nature and etiological causes of schizophrenia. Specifically, the ways in which blind individuals perceive and mentally represent the world may hold the key to identifying vision-specific mediations of schizophrenia. Some information can be perceived by only one modality; for example, vision is needed to perceive stars in the sky or hue, and audition is needed to perceive pitch. More importantly, amodal world representations have been proposed to have fundamental importance for the development and expression of schizophrenia (Andreasen, 2007; Fletcher and Frith, 2009; Insel, 2010). Interestingly, since the famous example of William Molyneux's letter to John Locke in 1688, some people have questioned whether or not blindness affects amodal world representations:

*"Suppose a man born blind, and now adult, and then taught by his touch to distinguish between a cube and a sphere of the same metal, and the same bigness, so as to tell, when he felt one and the other, which is the cube, which is the sphere. Suppose then, the cube and the sphere placed on a table, and the blind man to be made to see. Query, whether by sight, before he touched them, he could distinguish, and tell, which is the globe, which is the cube?"* (Degenaar, 1996)

Almost two and a half centuries later, Von Senden (1932) studied patients in whom blindness was surgically cured. These patients could localize but not discriminate between a cube and a sphere immediately after the operation. However, because other researchers have refuted Von Senden's results (Gregory and Wallace, 1963; Morgan, 1977; Hollins, 1989; Cattaneo and Vecchi, 2011) and rapid cross-modal transfer indicates that the underlying mental representations may be rather similar in nature (Held et al., 2011), an ultimate conclusion to the question is still missing.

According to the International Classification of Diseases (ICD-10) (WHO, 2007), visual impairment is defined as 6/18–3/60 of the visual acuity of an unimpaired sighted individual. Being blind entails less than 3/60 of a sighted person's visual acuity or a central

2Substantial overlap exists between the different approaches (Simon et al., 2006).

visual field of less than 10◦. Whereas 161–259 million individuals suffer from visual impairment worldwide, 37–42 million individuals of the world's population fulfill ICD-10's criteria for blindness (Resnikoff et al., 2004; Dandona and Dandona, 2006). About 1.4 million of them are younger than 15 years; 30 million are older than 50. In contrast to individuals with schizophrenia, only 12% of all blind individuals live in developed countries. The most common causes of blindness are cataracts, glaucoma, and age-related macular degeneration (Resnikoff et al., 2004).

Schizophrenia affects approximately 70–80 million individuals worldwide, independent of cultural background, ethnicity, or social status (Andreasen and Black, 2006). Men and women are similarly affected (Markowitch, 1997). Given the prevalence estimates of both diseases, at least 0.00605% of the world's population, or approximately 450,000 individuals should suffer from both blindness *and* schizophrenia. Whereas it is important to keep in mind that the absence of proof (of individuals suffering from both conditions simultaneously) is not proof of absence, the protection mechanism appears specific to blindness (e.g., there are congenitally deaf individuals who become psychotic) and to schizophrenia (e.g., individuals are not protected against other psychiatric diseases) (Silverstein et al., 2013). To account for the lack of individuals who meet the diagnostic criteria for both congenital blindness and schizophrenia, Sanders et al. (2002, 2003) have suggested that dynamic adaptations of NMDA (N-Methyl-D-Aspartic) receptor channels in the visual cortex may account for cognitive functioning that is insusceptible to psychosis in the blind. However, this point of view may be incomplete because functional reorganization in visually deprived individuals also occurs in brain areas other than the visual information processing sites of sighted individuals (Weeks et al., 2000; Burton et al., 2006; Silverstein and Keane, 2011b).

Silverstein and colleagues have a different point of view. According to these authors, cognitive coordination is impaired in patients with schizophrenia due to impaired NMDA ion receptor flow (Phillips and Silverstein, 2003; Silverstein and Keane, 2011a). Because occipital (perceptual) and non-occipital (cognitive) activity is required for cognitive organization to occur, early AND late visual processing deficits are associated with the progression of the disease and altered cognitive performance. Psychotic symptoms are, therefore, closely related to disturbed visual information acquisition and processing, which may, in turn, result in brain networks and functionality that are susceptible to psychosis. Stated differently, experiencing the world without vision may be qualitatively similar to but functionally different from experiencing the world as a sighted individual. We consequently consider the following questions in this first part of the review: (i) What evidence is there that blind individuals cognitively represent and experience the world similarly to sighted individuals? (ii) What changes in neurofunctional organization and multisensory integration are necessary for blind individuals to experience the world similarly to sighted individuals? (iii) And most decisively for the present review, how do these changes contribute to PaSZ?

# **"BLIND" PERCEPTION AND COGNITION**

On the one hand, there is no doubt that non-visual perceptual advantages are present in blind individuals (Cattaneo and Vecchi, 2011). Congenitally blind individuals have shown superior performance compared to sighted controls, for example, in auditory sound localization and speech discrimination tasks (Muchnik et al., 1991; Lessard et al., 1998; Roder et al., 1999; Kujala et al., 2000) as well as in haptic two-point discrimination tasks (Roder and Neville, 2003). Interestingly, cognitive and behavioral development can be delayed to up to 2 years in congenitally blind children compared to sighted ones (Warren, 1994). This may be due to the fact that visual information is memorized, discriminated, and explored more quickly than auditory or haptic information. In fact, auditory and haptic *memory* is limited due to *serial* information channeling; auditory *discrimination* and tactile *exploration* is limited due to *simultaneous* information channeling. This means that specific attention-orienting and stimulus-awareness mechanisms are necessary for visual but not other perceptual domains (Posner et al., 1976; Phillips and Silverstein, 2003). These mechanisms, in turn, have been described as relevant for the development of schizophrenia (Butler et al., 2005, 2007; Johnson et al., 2005; Kim et al., 2005; Haenschel et al., 2007).

On the other hand, amodal mental representations, e.g., how the idea of a "tree" is represented in the brain, are independent of their perceptual source (Avraamides et al., 2004; Barsalou, 2008). In other words, no matter which modality this information is perceived through (e.g., audition, touch, vision), the ultimate mental representations are similar. And this is true for real-world mental representations of blind and sighted individuals as Cattaneo and Vecchi (2011) put it so eloquently:

#### *"Our brain, indeed, doesn't need our eyes to 'see'..."* (p. 3).

In line with this argument, Pascual-Leone and Hamilton (2001) proposed that specialized neural functionality is formed as a consequence of receptive field input to brain structures. Hence, there may be no *a priori* functional segregation of the human brain. Instead, the existence of small receptive perceptual fields, which are required for quick categorization, and large receptive fields, which are necessary to coordinate thought processes, result in the specialization of cortical regions for processing "visual" or "auditory" information. The authors refer to the *metamodal* brain as a "mixture of expert architecture" (p. 15) (Pascual-Leone and Hamilton, 2001) and argue that sighted and congenitally blind individuals have an equivalence of amodal representations.

A plethora of investigations have, in fact, provided evidence of this equivalence. First, higher-order cognitive abilities, and spatial abilities in particular, have shown no differences between congenitally blind and sighted individuals, for example, in mental scanning and rotation (Craig, 1973; Marmor and Zaback, 1976; Carpenter and Eisenberg, 1978; Kerr, 1983; Zimler and Keenan, 1983; Vecchi et al., 2004) or allocentric referencing tasks (Tinti et al., 2006). Investigations of the mental number line (Moyer and Landauer, 1967; Dehaene et al., 1999; Krueger et al., 2008, 2011; Landgraf et al., 2010b) have shown similar spatial representations in congenitally blind and healthy sighted individuals (Castronovo and Seron, 2007). Hence, in congenitally blind individuals, equivalent amodal (spatial) representations can apparently be formed

from perceptual cues other than vision. Interestingly, in this same experiment, congenitally blind individuals were able to classify the numbers one and two more quickly than sighted individuals. The authors attributed this effect to the serial processing of tactile and auditory information. Blind individuals may be more accustomed to the idea of distinguishing perceptual phenomena with regard to number counting, especially one and two (e.g., counting steps).

Second, whereas a lack of visual input is detrimental to some tasks, the superior performance of sighted individuals has been shown to disappear when visual task demands are increased. For example, in a 3-D working memory task, congenitally blind individuals performed as well as sighted individuals when information input exceeded visual information processing capacities (Cornoldi et al., 1991). Furthermore, in matching standard figures and line drawings, congenitally blind and late blind individuals did not differ in their reaction times and error rates (Heller and Kennedy, 1990). The authors interpreted their results as indicating that visual imagery and visual experience appear unnecessary for tactile perspective taking. Interestingly, Vecchi et al. (2004) reported that the memory of locations decreased with an increasing number of visuo-spatial (VS) representations that had to be held in working memory. This shows that higher task demands, such as speed, interactive images, and movement, may account for performance decreases in blind individuals. Remarkably, the performance of schizophrenia patients also declines when task demands are increased, indicating a coping mechanism for imprecise visual information acquisition (Landgraf et al., 2011a,b).

Third, it has been proposed that visual input deprivation may lead not only to perceptual enhancement in congenitally blind individuals (Rauschecker, 1995; Lessard et al., 1998; Roder et al., 1999) but also to improved attentional capacities (Cattaneo et al., 2008). Better performance in higher-order cognitive abilities has, in fact, been observed in various memory span (Tillman and Bashaw, 1968; Smits and Mommers, 1976; Pozar, 1982; Hull and Mason, 1995; Roder et al., 2001; Amedi et al., 2003; Roder and Rosler, 2003; Raz et al., 2007) and auditory attention tasks (Roder et al., 1996, 1999, 2001; Roder and Rosler, 2003). Van Velzen et al. (2006) investigated early and late attention indicators in congenitally blind and sighted individuals with electroencephalographic (EEG) recordings. The authors found that early but not late attention modulation could be elicited in blind individuals, indicating that late cognitive coordination mechanisms may be important for the development of psychosis. Late attention indicators also depended heavily on having the individual focus on task-relevant external spatial reference frames, an ability that has been compromised in patients with schizophrenia (Dreben et al., 1995; Parnas et al., 2001; Johnson et al., 2005; Cavezian et al., 2007; Coleman et al., 2009; Landgraf et al., 2011b). In fact, patients with chronic schizophrenia have been found to display a deficit in the disengagement and reorientation of attention (Posner et al., 1988; Daban et al., 2004; Gouzoulis-Mayfrank et al., 2007; Kebir et al., 2008, 2010) even without medication (Amado et al., 2009). Hence, the interaction between bottom-up and top-down processes may provide insight into the immunity against psychosis that blind individuals appear to have (see the Protective Mechanism "Cognition" in **Table 1**).

#### **NEUROFUNCTIONAL REORGANIZATION AND COMPENSATION**

The ability to behaviorally compensate for visual deprivation is another indication that there are equivalent amodal representations in sighted and congenitally blind individuals (Pascual-Leone and Hamilton, 2001; Knauff and May, 2006; Cattaneo et al., 2008). However, because up to 35% of neocortical functioning in sighted humans is devoted to visual information processing (Gilbert and Walsh, 2004), blind and sighted individuals may differ considerably in their neurofunctional processing. In sighted individuals, cortical activity has traditionally been ascribed to region-specific functionality (Kanwisher, 2010), such as visual information processing being ascribed to occipital activity. However, blindfolding sighted individuals for a 5-days period has been found to lead to behaviorally relevant neurofunctional changes (Kauffman et al., 2002) that mimick the supranormal auditory performance of blind individuals (Rauschecker, 1995; Lessard et al., 1998; Roder et al., 1999). This not only implies that neurofunctional reorganization occurs in the adult human brain (Kujala et al., 2000), but also indicates that cortical functionality may be determined by information processing necessities (Cohen et al., 1997) and innate pathways (Striem-Amit et al., 2012c) rather than brain regions.

Blind individuals have been found to employ compensatory neurofunctional strategies to overcome visual information deprivation. Using positron emission tomography (PET), Sadato et al. (1996, 1998) were the first to find a relation between activity in the occipital cortex and non-visual perception and cognition. Specifically, the authors found that during braille reading and nonbraille haptic tasks, the primary, and medial occipital lobes were activated in individuals who became blind both early and late in life. In sighted individuals, on the other hand, these haptic tasks were associated with activity in non-occipital regions, such as the bilateral inferior parietal lobes, as well as the left primary sensorimotor area, insula, and prefrontal regions. In subsequent studies, congenitally blind individuals have shown recruitment of the occipital cortex during higher linguistic and (Cohen et al., 1997; Burton et al., 2003, 2006; Gilbert and Walsh, 2004; Raz et al., 2005; Amedi et al., 2007) auditory motion processing (Poirier et al., 2006), as well as during the localization of auditory signals (Weeks et al., 2000), tactile processing (Sadato et al., 2002), and tongue stimulation (Kupers et al., 2006). Finally, even sighted individuals have shown non-visual information processing in visual areas. In a sophisticated transcranial magnet stimulation (TMS) paradigm, Lewald et al. (2004) demonstrated that the temporary disruption of occipital activity can deteriorate auditory localization in sighted individuals.

These results led us to postulate the following two assumptions: first, neurofunctional plasticity in congenitally blind individuals includes reorganization in non-visual cortical areas, which has been confirmed, for example, in lingual and posterior fusiform gyri (Smith and Gasser, 2005; Striem-Amit et al., 2012a). Therefore, the reorganization of non-visual cortical areas in patients with schizophrenia may be important for the development of the disorder. Second, non-visual information processing in the occipital lobe of blind individuals resembles visual information processing in the occipital lobes of sighted individuals (Burton

et al., 2010). Thus, whereas functional and most likely also structural processing mechanisms are similar between blind and sighted individuals, the contents of the information (visual vs. non-visual) are different.

This has direct consequences for the development of schizophrenia (see also the Protective Mechanism "Neurofunctioning" in **Table 1**). If brain structures are not utilized according to their functional and structural specificity, this could result in psychosis or at least in subclinical symptoms. For example, as mentioned above, depriving sighted individuals of their vision for 5 days can lead to neurofunctional and cognitive changes (Kauffman et al., 2002). This means that not only eyerelated dysfunction but also functional changes in the primary and secondary occipital cortex can lead to hallucinations (Kazui et al., 2009; Schadlu et al., 2009). Further, individuals suffering from the so-called Charles Bonnet Syndrom (CBS) have reported visual hallucinations as a consequence of visual deterioration (ffytche and Howard, 1999; ffytche, 2009). Hallucinations due to the CBS can vary widely, comprising abstract geometric patterns, mosaic vision (tessellopsia), increased color vision (hyperchomatopsia), and miniturizations and magnifications of objects (micropsia and macropsia), and can occur for several minutes (70%), seconds

(18%), or hours (12%) (Hughes, 2013). There are two main theories about how CBS develops. The release theory claims that a mixture of impaired and unimpaired neuronal signals from the visual cortex lead to hallucinatory interpretations in the higher-order association cortices. This is similar to our argument that schizophrenia patients can profit from giving *more* weight to visual information in multisensory integration tasks. Hence vision training may be supplementarily useful to cognitive remediation programs. On the other hand, the deprivation theory of CBS argues that reduced sensory input may result in spontaneous image production in the visual association cortex, thus leading to visual hallucinations. This implies, as indicated by the PaSZ model, that perceptual deprivation *per se* is not sufficient for psychosis protection to occur. Instead, functional and possibly structural cortical reorganization need to be taken into consideration to avoid psychosis. In fact, there is strong evidence that brain regions are not adequately utilized in schizophrenia because patients use more sequential information processing strategies (Fatemi and Folsom, 2009; Landgraf et al., 2011a,c) possibly due to impaired higher-order cognitive deficits, i.e., in single- or multisensory integration (Park and Holzman, 1992; Park et al., 2002; Tek et al., 2002; Landgraf et al., 2008; Fuller et al., 2009).

#### **MULTISENSORY INTEGRATION**

The integration of information from multiple modalities has been found to improve performance compared to using one single perceptual channel alone (Calvert et al., 2003). In fact, multisensory integration allows the brain to generate a coherent amodal view of the self and the world (Smith and Gasser, 2005). Supramodal information, such as spatial and temporal information, is coded by all human perceptual systems and allows the comparison of multisensory integration between, for example, blind and sighted individuals. For the scope of this review, we restrict our considerations of multisensory integration to temporal and spatial processes that involve haptic, auditory, and, for sighted individuals, visual capacities. For a review of olfactory and gustatory perception regarding visual and auditory multisensory integration, please refer to Walla (2008) or Zampini and Spence (2012).

Efficient multisensory integration remaps information into amodal representations. In the absence of visual input, this remapping may develop differently (see Protective Mechanism "Multisensory Integration" in **Table 1**) (Hotting et al., 2004; Roder et al., 2004; Wallace et al., 2004). For example, in congenitally blind individuals, judging the temporal order of tactile stimuli with the right or left hand is not affected by whether the hands are in normal or crossed-over positions. By contrast, sighted individuals show longer reaction times when their hands are crossed, implying interference between visual and tactile external frames of reference (Roder et al., 2004, 2007; Collignon et al., 2007). Hotting et al. (2004) reported that the influence of task-irrelevant auditory tones for tactile discrimination is stronger in sighted than in congenitally blind individuals. Interestingly, humans deprived of vision between 5 and 24 months after birth due to retinal cataracts showed less auditory-visual interference and integration later in life than normally developing sighted individuals (Putzar et al., 2007). In line with these observations, the brain regions responsible for visual imagery (e.g., the fusiform face area) may retain their functional specificity even decades after the onset of blindness in late blind individuals (Goyal et al., 2006). In fact, there may be a specific critical period during which neurofunctional plasticity to sensory loss is maximal (Sathian, 2005). Until now, the duration of that time window has been unclear, but it has been proposed to be between 10 and 14 years for visual information processing (Cohen et al., 1999; Ofan and Zohary, 2007), implying that this may be a critical period for cortical changes regarding the protection and development of schizophrenia as well. Although changes in cortical functioning might not occur until several years after sensory deprivation (Cattaneo et al., 2008), the overall evidence implies that ontogenetic development must occur to establish the multisensory integration interferences observed in sighted individuals. Therefore, it can be hypothesized that this development may be impaired in patients with schizophrenia, thus leading to impaired or unusual performances in multisensory integration tasks.

In sighted individuals, auditory information processing is heavily influenced by other modalities and prior knowledge. Alain and Arnott (2000) distinguished between auditory attention (allocation of attentional resources to perceptual objects), auditory object discrimination (perception of sound attributes across a certain time period), and auditory event perception (perception of sound at a particular time, in a certain place, and having specific characteristics). The authors argue that auditory information quality impacts cognitive performance in all of these stages. For example, degradation of auditory information influences comprehension and memory differently in younger and older listeners (Pichora-Fuller and Singh, 2006). Furthermore, the characteristics of speakers are processed in parallel with semantic information. Whereas female voices are associated with more extraversion and openness, male voices are associated with higher emotional stability and greater agreeableness (Imhof, 2010). This is in line with other studies that have shown that identical semantic information is interpreted differently depending on whether the person is perceived as male or female (Addington, 1968; Knapp and Hall, 2002). Hence, auditory processing is inextricably linked to non-auditory information, thus implying that the working memory demands of listeners include the stream of the sound, semantic cues, and perceptual voice cues. Patients with schizophrenia have been shown to struggle when asked to integrate these perceptual cues with other cues (Hardoy et al., 2004; Leitman et al., 2005; Butler et al., 2008a, 2009). Interestingly, integrating non-auditory and auditory information directly from perceptual cues can be tested in multisensory integration tasks. For example, clustering task-irrelevant stimuli should not affect the performance of blind individuals if multisensory integration occurs in a manner that is similar to what has been observed in healthy individuals (Alain and Arnott, 2000).

Another auditory phenomenon is the so-called "right ear advantage," which refers to the observation that auditory information is processed with greater ease (more quickly, less erroneously) by the right ear compared to the left. In fact, it has been observed that left frontal lobe lesions diminish the advantage of the right ear (Hugdahl et al., 2003), indicating a functional preference for auditory information processing in the left frontal lobe. Congenitally blind individuals have shown a less pronounced right ear advantage, thus outperforming sighted individuals in, for example, dichotic listening tasks (Hugdahl et al., 2004; Castronovo and Seron, 2007). It may be interesting to investigate whether patients with schizophrenia would perform like sighted or blind individuals in this paradigm. If schizophrenia patients' performance more closely resembles the performance of sighted individuals, this would be an indication of their local processing preference. If, however, the patients' performance was more like that of blind individuals, this may be attributable to a lower reliance on multisensory integration.

Congenitally blind individuals have been found to rely less on multisensory integration, thus leading to strategic compensatory behavior. On the one hand, they recognize haptic stimuli more quickly than sighted individuals, due to, for example, more efficient sensory information processing during the first 100 ms after stimulus onset (Roder et al., 1996). On the other hand, however, if blind individuals were to employ an adequate multisensory integration strategy, they might perform equally as well as sighted individuals. In a haptic mental imagery memory task, Cornoldi et al. (2009) showed that congenitally blind individuals performed worse than healthy controls only when they adopted a spatial strategy but not when they adopted a verbal strategy. Mental representations of size are more erroneously influenced by multisensory information in sighted than in blind individuals (Bartley et al., 1955; Bolles and Bailey, 1956). Smith et al. (2005) showed that size estimations of real objects are less error-prone in congenitally blind individuals compared to sighted controls. Instead, blind individuals rely more on a haptic memory strategy to perform these tasks. This implies that multisensory integration involving touch depends on task characteristics, and a lack of visual input can be compensated for by adequate strategies (Postma et al., 2007). In fact, perceptual and long-term memory may be used to encounter multisensory integration deficits in blind individuals. Possibly patients with schizophrenia may profit from this strategy as well.

It is noteworthy that multimodal integration has been found to change with age. Warren and Pick (1970) found that auditory localization is strongly influenced by visual perceptual input in sighted adults but not in sighted children. Furthermore, auditoryproprioceptive integrations may be influenced by the increasing importance of vision with increasing age in sighted individuals. Pitch direction changes are better discriminated by blind individuals than by sighted controls even when the stimuli are presented 10 times more quickly but only when individuals became blind at an early age (Gougoux et al., 2004). Age at the onset of blindness has been shown to regulate the use of visual reference frames in haptic and auditory perception (Roder et al., 2004, 2007). However, these effects may also be attributable to the fact that blind individuals show better skills in processing unimodal perceptual inputs (Hotting and Roder, 2004; Hotting et al., 2004). More importantly, for congenitally blind individuals, if no change was observed across time in these functions, the weighing of intermodal information could be assumed to follow different developmental trajectories in blind and sighted individuals. Regarding schizophrenia, patients may start out with already impaired preconditions in their multisensory integration abilities. Hence, visual information in patients with schizophrenia may not be given enough multisensory integration weight. Instead, in their attempt to compensate perceptually, schizophrenia patients would integrate more perceptual information from other modalities than sighted controls, possibly leading to their preference for local information processing (Landgraf et al., 2011b).

# **THE VISION PERSPECTIVE ON SCHIZOPHRENIA THE VISION-SPACE-BODY-AND-COGNITIVE-IDENTITY MODEL OF SCHIZOPHRENIA**

Thus far, we have argued that the inability to perceive and process visual information prevents congenitally blind individuals from becoming psychotic. Specifically, we have shown that PaSZ in congenitally blind individuals may be associated with the acquisition of information and reorganizations of processing at cognitive, neurofunctional, and multisensory levels of integration. It appears that more than "zero" vision AND impaired visual processing must occur simultaneously in order to render the human brain susceptible to psychosis. This determines the visual impairment part of the PaSZ model (left side of the curve in **Figure 1**).

In our laboratory, we have developed a model that shows the processing levels at which the deteriorations in visual capacity contribute to the development of psychosis. The ViSBI, short for **Vi**sion-**S**pace-**B**ody-and-cognitive-**I**dentity, model of schizophrenia (Landgraf et al., 2012) shows that deficits in the acquisition and processing of visuo-cognitive information increase along with the progression of the disorder and are, indeed, associated with higher-order cognitive dysfunctions and expression of symptoms. We now turn our attention to "Biomoehrchen schmecken gut" the corresponding visual deterioration part of the PaSZ model (right side of the curve in **Figure 1**).

# **VISUAL INFORMATION ACQUISITION**

Visual information acquisition accounts for more than 80% of the perceptual input in humans and is therefore considered to provide the foundation for amodal world representations (Lüer et al., 1988; Becker, 1991; Leigh and Zee, 1999). Deficits in visual information acquisition have been described extensively in patients with schizophrenia (see "Vision" complex in **Figure 2**). Deficits deteriorate along the continuum from the prodrome to the full-blown syndrome, i.e., with the progression of the disease. One of the longest and best-studied types of deteriorations is that of oculomotor deficits. They not only jeopardize the availability of visual information but also impair the spatial and temporal accuracy of individuals. Hence, they are crucial for the formation of concepts of the self and the surrounding world.

Oculomotor deficits are least pronounced in prodromal individuals. Only a few studies have demonstrated that prodromal individuals show an increased rate of errors in the antisaccade paradigm (Nieman et al., 2007). In first-episode schizophrenia patients, deficits have been described with regard to antisaccade errors, reaction time, and accuracy (Broerse et al., 2001; Ettinger et al., 2004; Hutton et al., 2004). Furthermore, deficits such as a higher error rate in memory-guided saccades and lower acuity in predictive saccades have been reported (Krebs et al., 2001; Hutton et al., 2004; Keedy et al., 2006). In chronic patients, all these deficits have been observed (e.g., Karoumi et al., 2001; Brownstein et al., 2003; Reuter et al., 2006; Radant et al., 2007; Amado et al., 2008; Landgraf et al., 2008). In addition, chronic patients have shown lower acuity in memory-guided saccades (Crawford et al., 1995a; Park et al., 1995; McDowell and Clementz, 1996; Radant et al., 1997; Karoumi et al., 1998; McDowell et al., 2001).  Furthermore, oculomotor aberrations have been found to fulfill some endophenotypic characteristics (Gottesman and Gould, 2003; Calkins et al., 2008).

Another interesting phenomenon regarding the acquisition of visual information is eye-movement strategies. Eye-movement strategies allow for a meaningful and useful succession of visual information input with regard to, for example, goal attainment or planning behavior (Land and Furneaux, 1997). Deficits in eye-movement strategies may lead to inefficient visual input and may thus alter an individual's perception of the world. As seen in oculomotor deficits, the severity of eye-movement-strategy

**FIGURE 2 | The Progressive Vision-Space-Body-and-Cognitive-Identity (ViSBI) model of schizophrenia.** Source: Reprinted with kind permission from Bentham Science Publishers. Note. The progressive ViSBI model stresses vision-related deteriorations from prodrome to chronic syndrome that may lead to schizophrenia. The model comprises four complexes: "Vision," "Space," "Body," and "cognitive Identity. "The "Vision," "Space," and "Body" complexes are reviewed in the sections on "The Vision Perspective on Schizophrenia" in the current paper. The "Cognitive Identity" complex (shadowed in gray) is hypothesized as a part of the model (see Landgraf et al., 2012). Complexes are sub-divided into specific research areas (e.g., in the "Vision" complex: oculomotricity and scanning) and disease progression status (prodromal, first episode, and chronic schizophrenia patients). Tasks listed in each row indicate deficient performance of the corresponding patient group. Some areas have not been investigated in schizophrenia patients ("suggestions for further research").The "Visual Input" triangle in the middle indicates that (congenital) blindness may prevent these mechanisms from taking place because visual perceptual input is required for this pattern of aberrations to occur. Abbreviations: prodromal = individuals identified at ultra-high risk for developing schizophrenia; first episode = patients with schizophrenia that have had one (identified) psychotic episode; chronic = patients with schizophrenia that have had at least three (identified) psychotic episodes; SPEM = smooth pursuit eye movements; n-back = spatial n-back task.

deficits increases with the increasing progression and severity of schizophrenia. Prodromal individuals have rarely been studied in visual scanning paradigms. Koethe et al. (2006, 2009) showed that abnormal binocular depth inversion was specific to prodromal individuals. Furthermore, first-episode schizophrenia patients have shown an abnormal clustering of fixations and shorter visual scanpaths when scanning faces, landscapes, and abstract patterns (Benson et al., 2007). The largest deteriorations have been reported for stabilized chronic patients with schizophrenia, with fewer fixations, shorter scanpaths, narrower clustering of fixations, and avoidance of predefined features in different visual scanning tasks (e.g., Gaebel et al., 1987; Gordon et al., 1992;

Kurachi et al., 1994; Phillips and David, 1997; Williams et al., 1999; Loughland et al., 2002, 2004; Minassian et al., 2005; Koethe et al., 2006).

In our own laboratory, we found that, in contrast to healthy controls, chronic schizophrenia patients do not adapt their eyemovement strategies to task demands but instead use similar strategies regardless of task difficulty (Landgraf et al., 2011b). In other words, patients employ the same visual scanning strategy no matter whether the task is easy or difficult. In another study, we even found that chronic schizophrenia patients use a less efficient information acquisition strategy more often than healthy controls (Landgraf et al., 2011a). This implies that inefficient visual information acquisition impedes patients from obtaining (task-) relevant information. Patients have probably noticed that inflexible visual scanning suits most of the demands they encounter in their daily lives. One intriguing question concerning the discussion of blindness and schizophrenia is whether patients are unable to develop other strategies from birth on or whether patients develop the use of only one strategy despite being able to develop others.

These findings imply the following. First, patients with schizophrenia attribute less weight to visual information and are not able to integrate visual information as well as healthy sighted individuals. This means that patients' deficient performances on higher-order cognitive tasks, therefore, can be accounted for by lower-level visual aberrations. Second, patients' visual channels are still "open." Hence, they are unable to obtain cognitive and neurofunctional reorganization in the same way as blind individuals. This suggests that PaSZ may be available in two directions. On the one hand, if patients learn to put *more* weight on visual information in the same way that healthy sighted individuals do, they may lower their risk for a psychotic episode. On the other hand, if patients are taught to put *less* weight on visual information and reorganize their neurofunctional information processing, they might be able to stabilize their self and world perceptions in the same way that blind individuals do (See "Vision Training: Decline vs. Improvement" for further details on vision training).

#### **VISUAL INFORMATION PROCESSING**

Aberrant visual information processing (see "Space" complex in **Figure 2**) deteriorates thought processes, contributing to cognitive dysfunctions. It has been acknowledged that cognitive deficits may be one of the best predictors of the development of psychosis (Elvevag and Goldberg, 2000; Insel, 2010; Keefe and Harvey, 2012), and this link could provide the basis for quantitative stage markers of the disease. Most of the paradigms used in schizophrenia cognition research are visual tasks. Moreover, fundamental associations between visuo-spatial (VS) abilities and oculomotor capacities (Leigh and Zee, 1999; Hutton et al., 2004; Lawrence et al., 2004; Pierrot-Deseilligny et al., 2005; Milea et al., 2007) indicate that disturbances in the VS domain may stem from oculomotor dysfunctions in patients with schizophrenia. Some of the cognitive domains deficient in patients with schizophrenia include but are not limited to VS memory (Goldman-Rakic, 1994; Green et al., 2000; Piskulic et al., 2007; Landgraf et al., 2011c), VS attention (Posner et al., 1988; Danckert et al., 2004; Granholm and Verney, 2004; Gouzoulis-Mayfrank et al., 2007), and VS executive functions (Laws, 1999; Eisenberg and Berman, 2010; Landgraf et al., 2011a,b,c). An impressive number of studies have actually shown that the development of schizophrenia may be associated with these cognitive deficits and that these cognitive deficits could be stage-specific (Heaton et al., 1994; Niendam et al., 2006; Fusar-Poli et al., 2007; Lysaker et al., 2007; Langdon and Ward, 2008; Picard et al., 2009; Barlati et al., 2012).

Visuo-spatial cognitive deficits in prodromal individuals are controversial. Some studies have shown a greater number of errors and inferior performance in prodromal individuals compared to healthy controls on spatial delayed-response tasks (Wood et al., 2003; Bartok et al., 2005; Smith et al., 2006; Kimhy et al., 2007;

Nieman et al., 2007). Other investigations have not confirmed this observation (Brewer et al., 2005; Lencz et al., 2006; Niendam et al., 2006; Pukrop et al., 2007). The reasons for this controversy have not yet been resolved. Possibly, heterogeneous results are due to imprecise diagnoses of the schizophrenia prodrome (high rate of false negatives), demographic differences between participating groups, or task simplicity (Wood et al., 2003; Conklin et al., 2005; Longevialle-Henin et al., 2005; Fusar-Poli et al., 2007; Pukrop and Klosterkotter, 2010). Nevertheless, prodromal individuals have been consistently reported to display deficient performances on the Trail Making Tests (TMT) A and B and the Wechsler Memory Scale (WMS-R) visual reproduction task parts I and II (Hawkins et al., 2004; Brewer et al., 2005).

First-episode patients have shown deficient performances on a number of VS cognitive tasks. For example, they have shown aberrant memory on VS delayed-response tasks (Goldman-Rakic, 1994; Park et al., 1995; Rybakowski and Borkowska, 2002; Simon et al., 2007), Gestalt perception (Parnas et al., 2001), and the TMT (Rybakowski and Borkowska, 2002; Simon et al., 2007). This implies moderate deficits in these patients.

Chronic patients have shown the strongest aberrations on VS tasks.  According to a meta-analysis, there is an overall effect size of −1.00 regarding VS working memory deficits in chronic schizophrenia patients (Piskulic et al., 2007), and these deficits are independent of gender differences (Albus et al., 1997; Reichenberg et al., 2002; Voglmaier et al., 2005; Halari et al., 2006; Wolitzky et al., 2006). Hence, visual information processing appears to be deteriorated in schizophrenia, increases with the progression of the disease, and is related to basic visual acquisition. It may be interesting to compare patients' performance to the performance of the blind in non-visual versions of these paradigms. Even though they have never been able to integrate visual information, blind individuals should outperform patients with schizophrenia on spatial tasks. This would indicate that schizophrenia patients' severely altered visual information processing is strongly associated with their deficits in visual information acquisition. We hypothesize that patients with schizophrenia could especially profit from the neurofunctional and cognitive reorganization observed in blind individuals. The most important question, however, for the consideration of PaSZ is whether or not VS deficits are associated with higher-order cognitive dysfunctions and the symptoms of schizophrenia.

#### **FROM VISUAL DETERIORATION TO SYMPTOMS**