Brain, Vol. 125, No. 3, 479-490,
March 2002
© 2002 Guarantors of Brain
Changes in visual cortex excitability in blind subjects as demonstrated by transcranial magnetic stimulation
,11 Unit of Motor Disturbances and Cortex Function, Department of Neurology, Charité, Humboldt University, Berlin 2 Institute of Medical Psychology, University of Magdeburg, Germany
Correspondence to: Dr S. A. Brandt, Department of Neurology, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, 13348 Berlin, Germany E-mail: stephan.brandt{at}charite.de
*Both authors contributed equally Deceased November 24, 2001
Received April 5, 2001. Revised August 16, 2001. Second revision October 8, 2001. Accepted October 15, 2001.
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Any attempt to restore visual functions in blind subjects with pregeniculate lesions provokes the question of the extent to which deafferented visual cortex is still able to generate conscious visual experience. As a simple approach to assessing activation of the visual cortex, subjects can be asked to report conscious subjective light sensations (phosphenes) elicited by focal transcranial magnetic stimulation (TMS) over the occiput. We hypothesized that such induction of phosphenes can be used as an indicator of residual function of the visual cortex and studied 35 registered blind subjects after partial or complete long-term (>10 years) deafferentation of the visual cortex due to pregeniculate lesions. TMS was applied over the visual cortex in 10 blind subjects with some residual vision (visual acuity <20/400; Group 1), 15 blind subjects with very poor residual vision (only perception of movement or light; Group 2), 10 blind subjects without any residual vision (Group 3) and 10 healthy controls. A stimulation mapping procedure was performed on a 1 x 1 cm skull surface grid with 130 stimulation points overlying the occipital skull. We analysed the occurrence of phosphenes at each stimulation point with regard to frequency and location of phosphenes in the visual field. Previous experiments have shown that repetitive TMS reliably elicits brief flashes of white or coloured patches of light. Therefore, stimulation was performed with short trains of seven consecutive 15 Hz stimuli applied with an intensity of 1.3 times the motor threshold. Under such conditions, phosphenes occurred in 100% of subjects in Group 1, in 60% of Group 2 and in 20% of Group 3. Phosphene thresholds were normal, but the number of effective stimulation sites was significantly reduced in Groups 2 and 3. The results indicate that in blind subjects there is alteration in TMS-induced activation of the deafferented visual cortex or processes engaged in bringing the artificial cortex input to consciousness. The ability to elicit phosphenes is reduced in subjects with a high degree of visual deafferentation, especially in those without previous visual experience.
Keywords: blindness; visual cortex; plasticity; transcranial magnetic stimulation; phosphenes
Abbreviations: TMS = transcranial magnetic stimulation
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Introduction |
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In order to achieve a limited degree of functional vision in totally blind people, efforts have been made to develop techniques of cortical surface or intracortical microstimulation of the visual cortex (Buton and Putnam, 1962
; Brindley and Lewin, 1968; Brindley et al., 1972; Schmidt et al., 1996). These ‘visual prostheses’ elicit small, circumscribed subjective sensations of light (phosphenes). The aim is to produce patterns of phosphenes that resemble low-resolution mental pictures, thus allowing information transfer from a camera to the primary visual cortex (Hambrecht, 1995). In this context, one unsolved question is whether long-standing visual deafferentation leads to impairment of human visual cortex function that might hamper such an approach beyond all technical solutions. We used transcranial magnetic stimulation (TMS) mapping to study changes in visual cortex excitability by analysing phosphene thresholds and the distribution of stimulus-effective sites on the occipital skull. We hypothesized that these parameters reflect cortical excitability and depend on the amount of residual visual function. Thus, we compared normal subjects with blind subjects without and with different degrees of residual visual function.
Since the observation that humans who have been blind throughout childhood face great difficulties in regaining vision if their eyes are operated on late in life (Senden, 1932; Valvo, 1971), several studies have led to a debate about the long-term consequences of the deafferentation of the visual cortex. In this debate, one can differentiate between monocular and binocular deprivation. For example the latter occurs spontaneously in patients with congenital cataracts or can be induced experimentally by raising animals in complete darkness. Studies on the influence of this condition on striate and extrastriate visual functions are still rare. The effects on pre- and postgeniculate structures were studied by Hyvärinen and Hyvärinen (1983). In stump-tail macaques, bilateral lid closure immediately after birth led to no particular irregularities of the eyes between 7 and 11 months of age. However, after reversing lid closure, the visual behaviour of the animals was grossly impaired, the animals appearing to be functionally blind (Hyvärinen et al., 1981).
In humans, non-invasive methods, such as PET, single photon emission computed tomography and MRI have been used to study morphological and overall functional aspects of early visual deprivation. Although an overall increase in glucose utilization (De Volder et al., 1997) and regional cerebral blood flow (Uhl et al., 1991) and the absence of gross anatomical changes in the visual cortex (Breitenseher et al., 1998) were observed, specific visual functional aspects could not be explored with such methods. By using TMS over the visual cortex to interfere with Braille reading, it was shown that there is cross-modal plasticity of the visual cortex in early-onset blind humans (Cohen et al., 1997; Hamilton and Pascual-Leone, 1998). By contrast, the present study shows that the deafferented visual cortex can also remain linked to visual perceptions.
Non-invasive measurements of visual cortex function with functional MRI or PET are naturally restricted in blind persons, in whom sensory stimulation via visual input from the retina is absent. In contrast, electrical or magnetic stimulation of the occipital lobe is not hampered by such limitations and produces mainly simple phosphenes in the visual field (Brindley and Lewin, 1968; Brindley et al., 1972; Merton and Morton, 1980; Barker et al., 1985; Meyer et al., 1991; Brandt et al., 2001). It has been shown recently in healthy subjects transiently deprived of light sensation that analysis of transcranially elicited phosphenes can provide information about excitability changes in the human visual cortex (Boroojerdi et al., 2000a, b).
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Subjects
Following approval of the study by the ethics committee of the Charité, campus Virchow, stimulation mapping of the visual cortex was performed with informed consent in 10 healthy volunteers (five men, five women, aged 27 ± 2 years) and 35 registered blind subjects. The latter were investigated >10 years after the onset of lesions of different aetiology of the retina or the optic nerve, but without concomitant damage of postgeniculate visual pathways. The causes of blindness (Table 1) were optic nerve atrophy of different aetiologies (n = 10), glaucoma (n = 6), retinitis pigmentosa (n = 1), retinopathy of unknown cause (n = 2), cataract (n = 4), retinopathy of prematurity (n = 4), retinoblastoma (n = 2), cone cell dystrophy (n = 1), perinatal retinal ablation (n = 1), perinatal toxoplasmosis of the eye (n = 1), childhood optic neuritis (n = 1), meningioma of the optic nerve (n = 1) and pituitary tumour (n = 1). Blind subjects were assigned to three groups with different degrees of residual vision.
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Group 1 comprised 10 blind subjects with residual vision measurable with Snellen test charts as <20/400 (three men, seven women; mean age 18 ± 0.5 years; impaired vision for 10–19 years, mean 16 ± 4 years). Group 2 comprised 15 blind subjects whose residual visual function was not measurable with Snellen test charts but who were able to perceive light or movement (10 men, five women; age 18–65 years, mean age 39 ± 15 years; blind for 11–59 years, mean 28 ± 16 years). Group 3 comprised 10 blind subjects without any residual vision (no perception of movement or light) (eight men, two women; age 18–58 years, mean age 38 ± 15 years; blind for 12–48 years, mean 31 ± 11 years).
Twenty-five blind subjects of Groups 2 and 3 were interviewed regarding their Braille reading skills. Five subjects with relatively late onset of blindness could not read Braille. All other subjects were skilled Braille readers with more than 1 h of Braille reading activity every day for >10 years. In all except one of the Braille reading subjects, the right hand led during reading (Table 1, 2). Subjects with a history of migraine, seizures or other neurological or psychiatric disease were excluded from the study.
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In Table 3 we list information about the residual visual function of individual subjects, previous visual experience and the use of visual imagery and correlate it with the subjective visual experiences and other sensations elicited by TMS over the occiput.
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Stimulation mapping over the visual cortex
TMS was performed with biphasic pulses using a focal, figure-of-eight-shaped coil (radius of one half-coil, 6 cm) connected to a stimulator (Magpro; Dantec, Skovlunde, Denmark). For stimulation mapping of the visual cortex, the centre of the coil was placed over the intersections of a 1 x 1 cm skull surface grid drawn on a tightly fitting bathing cap. The grid was based on lines running parallel to lines connecting the inion and the two preauricular points and the inion and the nasion (Fig. 1). The position of the coil centre on the skull surface grid was described in centimetres left or right of the midline and in centimetres rostral to the inion. In the mapping procedure, rows of adjacent positions were stimulated following a mediolateral direction. To avoid serial order effects, the hemisphere that was stimulated first was randomized, as were the directions of stimulated columns on the stimulation grid (bottom-up or up-down).
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Stimulation was performed with seven consecutive 15 Hz stimuli with an intensity of 1.3 times the individual motor threshold (i.e. on average 54 ± 10% of maximum stimulator output); under such conditions phosphenes, defined as brief flashes of white or coloured patches of light, occur reliably (Ray et al., 1998
; Niehaus et al., 2000). Phosphene thresholds seem to be lower under repetitive stimulation, which is suggested by our own unpublished measurements with paired pulses using an interstimulus interval equivalent to stimulation at 15 Hz. Under this condition, the thresholds were reduced to 74 ± 10% of the threshold for single pulses (n = 10).
One stimulus train was applied over each intersection of the grid. Inter-train intervals were at least 10 s. As a control, randomly interspersed sham stimulation was performed with a special coil (type MC-B70; Dantec) at 
10% of the sites at which phosphenes had been reported for real stimulation. None of the subjects reported phosphenes for such sham stimulation. Sham stimulation also caused a tingling sensation on the scalp, so that subjects were not aware of the difference between real and sham stimulation.
All subjects were examined whilst sitting in a room 120 cm in front of a semicircular screen extending to 33° on each side. In the room the light was dimmed to such a degree that the investigators were still able to record the reports of the subjects and to direct the stimulation coil over the surface grid. With their eyes open, subjects were asked to report any visual or other subjective sensations during TMS. Subjects with residual vision indicated with a laser pointer the point on the screen where they had perceived the phosphenes. Subjects without residual visual function pointed with their arm in the direction of the perceived phosphenes. Phosphenes were classified as bilateral when they occurred in both halves of the visual field and outside the foveal 5° of visual angle. Phosphenes were classified as lateralized when they occurred in only one-half of the visual field. Phosphenes with an extent of 1–2° visual angle in the centre of the visual field were classified as foveal. Eye movements were not monitored.
Phosphene and motor thresholds
In all 25 blind subjects of Groups 2 and 3, the thresholds for eliciting phosphenes were compared with the individual motor thresholds. We also compared phosphene and motor thresholds with those measured in a second group of 26 healthy subjects with unimpaired vision (aged 15–38 years, mean 27 ± 11 years; 15 women, 11 men).
During the experiment, the subjects were examined in a dimly lit room and stimuli were applied to the lateral occiput at a site at which in normal subjects phosphenes could be elicited reliably (3 cm above the inion and 3 cm to the right or left of the midline).
The phosphene threshold was defined as the lowest stimulus intensity (as a percentage of the maximum stimulator output) at which phosphenes were perceived when trains of seven consecutive 15 Hz stimuli were applied. The phosphene threshold was calculated as the mean value of the thresholds determined by increasing and decreasing the stimulus intensity in a stepwise fashion by 1% of the maximum stimulator output. The motor threshold was defined as the percentage of the maximum stimulator output at which, in five of 10 single consecutive stimuli, motor responses of 0.05 mV occurred in the relaxed first dorsal interosseus muscle contralateral to the stimulated primary motor cortex. All 26 normal subjects were right-handed, as assessed with the Edinburgh Handedness Inventory (Oldfield, 1971).
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No adverse effects occurred during the study. TMS elicited phosphenes in all healthy subjects and in 21 of the 35 patients at a highly variable number of stimulation sites on the skull surface grid. The reported phosphenes were wedge-shaped and often tended to extend from foveal parts of the visual field into one visual hemifield and preferentially into the lower quadrants.
In all subjects with phosphene perception, stimulation over the left and right hemispheres elicited phosphenes at approximately the same number of stimulation points of the skull surface grid (P > 0.1; Table 4).
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Stimulation mapping
In normal subjects, the occurrence of phosphenes was reported for TMS over, on average, 39.5 ± 21.2 intersections on the skull surface grid. Stimulation was most effective at points located on both sides of the occipital skull between 3 and 7 cm rostral to the inion and 1–3 cm lateral to the midline. When stimulating with the coil centre placed
1 cm lateral to the midline and then pooling the data for effective stimulation sites over both hemispheres, phosphenes occurred in the contralateral visual hemifield in 54.2% of effective coil positions, in the ipsilateral hemifield in 22%, in both hemifields in 4.5% and in the foveal region in 13.9% (Table 4). Thus, phosphenes occurred more frequently in the contralateral than in the ipsilateral visual field (Mann–Whitney U-test, P = 0.066). Usually, the phosphenes were unstructured and white. Two of the normal subjects reported coloured (yellowish or greenish) phosphenes when being stimulated 4 cm rostral to the inion (Subject 1) or 4 cm rostral to the inion and 1 cm right of the midline (Subject 2).
Group 1
TMS elicited phosphenes in all blind subjects of this group. The number of effective stimulation sites and their spatial distribution on the skull surface grid was very similar to that in normal subjects (36.8 ± 29.2 versus 39.5 ± 21.2 in normal subjects) (Figs 2 and 3). In comparison with normal subjects, the phosphenes occurred less often exclusively in the contralateral visual field (Table 4), otherwise phosphenes did not differ in shape or other quality between normal and blind subjects in Group 1.
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Group 2
Sixty per cent of the blind subjects in this group perceived phosphenes in response to TMS (Fig. 3), but phosphenes occurred at fewer stimulation points than in normal subjects (29.7 ± 26.6 versus 39.5 ± 21.2, P < 0.05) (Fig. ). When stimulating 1 cm or more lateral to the midline and pooling the data from stimulation of both hemispheres, phosphenes occurred in the contralateral hemifield in 45.0% of effective coil positions, which was not significantly different from normal subjects (Table 4).
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Group 3
Only two of the blind subjects in this group (both with previous visual experience) reported phosphenes (Fig. ). They occurred at 15 (subject M.H.) or 34 (subject M.B.) points on the skull surface grid (Figs D and 4). In one of the two subjects (M.B.), phosphenes occurred exclusively in the central visual field. The other subject (M.H.) perceived phosphenes predominantly in the left lower visual field (Fig. 4). Another patient, who had been completely blind since birth, reproducibly reported the experience of a circumscribed, localized sensation of warmth (‘like a heating-lamp’) in the contralateral half of his ‘near-grasping space’.
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Generally, in subjects of Groups 2 and 3 the occurrence of phosphenes correlated negatively with the time since onset of blindness. The average time since the onset of blindness was 23 ± 12 years in subjects who perceived phosphenes, which is significantly shorter than the corresponding interval in subjects who did not perceive phosphenes (35 ± 13 years; P = 0.036). A statistically significant correlation between Braille reading activity or experience and phosphene thresholds was not present.
Phosphene and motor thresholds in normal subjects and blind patients
Hand motor thresholds and phosphene thresholds were determined in the blind subjects and in a group of 26 normal subjects. The sample of normal subjects was different from the control group investigated by stimulation mapping. Motor thresholds did not differ significantly between normally sighted and blind subjects and were the same for both hands (Table 5). Phosphene thresholds were not significantly different when normal subjects were compared with the nine (of a total of 15) blind subjects with residual vision in whom TMS elicited phosphenes. In two of the 10 blind subjects without residual vision who experienced phosphenes, the thresholds lay within the normal range (Table 5).
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Discussion |
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Repetitive TMS of the visual cortex was used to study visual cortex activation in subjects who had been visually deprived, by pregeniculate lesions, for many years, in many cases since birth or childhood. Phosphenes were elicited by direct visual stimulation of the cortex to bypass the retinogeniculate pathways. We assumed that susceptibility to phosphene induction could be used as an indicator of functional intactness of the visual cortex in human subjects.
Single TMS pulses can be used to suppress the perception of visual sensations (Amassian et al., 1989, 1998; Beckers and Hömberg, 1991; Kammer and Nusseck, 1998; Kastner et al., 1998; Kamitani and Shimojo, 1999) or to interfere with perceptual learning (Stewart et al., 1999). TMS may also elicit unstructured white or coloured phosphenes in the visual field (Barker et al., 1985; Meyer et al., 1991; Ray et al., 1998; Kammer, 1999; Cowey and Walsh, 2000; Stewart et al., 2001). Phosphenes reflect the activation of cortical cells and thus at least a rudimentary aspect of neuronal function in the visual cortex. This should be true irrespective of whether such transcranially elicited phosphenes are generated by subcortical activation of fibres targeting the visual cortex or by direct excitation of neurones within the visual cortex. Analysis of phosphenes elicited by TMS provides information about changes in excitability in the human visual cortex. This has been shown recently in patients with migraines (Afra et al., 1998; Aurora et al., 1998) and in healthy subjects transiently deprived of light sensations or whose visual cortex has been stimulated repetitively (Boroojerdi et al., 2000a, b).
TMS elicited phosphenes in all blind subjects of Group 1, i.e. the blind subjects with the highest degree of residual vision. The distribution of effective stimulation points on the skull surface grid was remarkably similar to that in normally sighted subjects. By contrast, phosphenes could be induced in only 60% of subjects in Group 2 (blind subjects with a low degree of residual vision) and in only 20% of subjects in Group 3 (blind subjects without residual vision). Interestingly, in all blind subjects of Groups 2 and 3 who perceived phosphenes, the thresholds lay within the normal range, but the area of coil positions from which phosphenes could be elicited was significantly reduced. In our sample of blind subjects, the occurrence of phosphenes decreased with increasing duration of blindness. These observations lead to the general conclusion that long-term visual deafferentation causes a reorganization of the visual system that reduces the ability of the blind subject to experience cortically elicited phosphenes. The calcarine part of the striate cortex (Meyer et al., 1991), the dorsal extrastriate areas V2/V3 (Brindley and Lewin, 1968; Brindley et al.,1972; Kastner et al., 1998) and the geniculostriate fibres (Brandt et al., 2001) have all been discussed as potential sites at which phosphenes might be elicited by brain stimulation. Each of these structures or secondary processes engaged in bringing the effects of cortex stimulation to consciousness might be altered in blind subjects. It may be hypothesized that blind subjects who perceive phosphenes but who have smaller response maps have reduced excitability of the visual cortex at marginal stimulation sites, i.e. in secondary visual areas projecting to the primary visual cortex. In the severely deafferented subjects who do not perceive phosphenes, the excitability is probably also reduced in primary visual areas lying under the central coil positions. This assumption is supported by recently reported findings in one peripherally blind subject who, in response to TMS, experienced normal phosphenes that were concentrated in the centre of the visual field (Cowey and Walsh, 2000). Qualitatively, we made a very similar observation in one of the totally blind subjects (M.B.). Brindley and Lewin (1968) and Cowey and Walsh (2000) obtained good localization of phosphenes by asking their peripherally blinded subjects to touch a fixation point with a fingertip of one hand and to fixate this fingertip effectively. In blind subjects, one has to take into account the less exact localization of phosphenes. This is due to the poor ability of blind subjects to localize the phosphenes in their visual world or grasping space and their poor ability to fixate the eye position at a given reference point in space. It remains unclear which reorganizational processes underlie the observed changes in phosphene perception in blind patients and what their functional relevance is. This lack of understanding is due to the elementary nature of the phosphenes elicited artificially by TMS and our ignorance of whether they are produced by a system that overlaps with that engaged in higher visual functions. Furthermore, most other studies of visual deafferentation in animals and humans have addressed aspects of cross-modal plasticity but do not supply information about the function of the visual cortex for processing visual inputs (Hyvärinen and Hyvärinen, 1983; Uhl et al., 1991; Sadato et al., 1996; Cohen et al., 1997; Büchel et al., 1998).
In animal studies in which the eyelids of both eyes were sutured for several months, a proportion of cells in the visual cortex was found to have abnormal function or was completely unresponsive. When the eyes were reopened, the animals appeared to be blind (Hyvärinen et al., 1981). While no histomorphological changes have been found in the retina or the cortex, cell atrophy occurred in all layers of the geniculate body (Wiesel and Hubel, 1965). Under similar conditions, the development of corticocortical connections originating from area 17 was reduced (Zufferey et al., 1999). Experiments in which cats were reared in darkness for 3–12 weeks resulted in suppression of the development of visual responsiveness and specific receptive field properties in areas 17 and 18 (Blakemore and Price, 1987). In general terms, such results may be interpreted to suggest that visual deprivation leads to reduced function and excitability of the visual cortex.
Humans deprived of vision at an early age, e.g. owing to cataracts, face great difficulties in visual perception if they regain sight late in life (Senden, 1932; Ackroyd et al., 1974; Hyvärinen et al., 1981). Such observations remind us of kittens being functionally blind when they open their eyes after a period of visual deprivation (Wiesel and Hubel, 1965) and hint at reduced function of the visual cortex. This is generally compatible with our finding of reduced ability of blind subjects to experience phosphenes during TMS of the visual cortex. This is different in human subjects after short-term periods of light deprivation. Forty-five minutes after onset of light deprivation, the thresholds of TMS-induced phosphenes decreased, indicating increased excitability of the visual cortex (Boroojerdi et al., 2000a).
If we assume that the decreased ability of the blind patients in our study to perceive phosphenes reflects a reduced excitability of the visual cortex, this finding seems to be in contrast to observations in traumatic limb amputation and in other states of sensory deprivation in humans. In limb amputees, the excitability of the sensorimotor cortex is increased, which is probably related to the occurrence of phantom limb pain (Cohen et al., 1991; Kew et al., 1994; Röricht et al., 1999). However, long-standing, complete blindness due to cataract or retinal degeneration might have as a consequence the absence of all inputs to the visual cortex from the retina, especially because, after bilateral visual deprivation, the cells in the geniculate body have been found to degenerate (Wiesel and Hubel, 1965). In limb amputation, the situation is different in two respects. First, ectopic spontaneous nerve firing occurs in mechanosensitive neuromas reacting to adhesions, oedema or muscle spasms (Devor, 1997). Such nerve activity sends abnormal patterns of afferents to the cortical representation of the lost limb. Secondly, limb amputation leads to partial deafferentation of only the somatosensory cortex, since afferents from the stump may still reach the cortical representation of the lost limb (Knecht et al., 1998).
Studies of the functional consequences of visual deprivation in humans have disclosed correlates of cross-modal plasticity, with a role for the visual cortex in tactile processes (Uhl et al., 1991; Sadato et al., 1996; Cohen et al., 1997; Büchel et al., 1998). Such reorganizational changes were beyond the scope of our study, but it can be stated that at least no changes in motor cortex excitability occurred in the blind subjects. In our study, we did not find a correlation between the occurrence of phosphenes and Braille reading skill. One patient reported a sensation of warmth in his face contralaterally to the stimulated visual cortex. This phenomenon may be related to the concept of cross-modal plasticity that has been called ‘facial vision’ (Supa et al., 1944), which describes a synaesthetic process of ‘seeing with tactile senses’. In general, one must bear in mind that congenitally blind subjects may lack the terminology and experience in conceptualizing the perception of light. However, in our sample only two subjects with absolute blindness (Group 3) had no previous visual experience.
While blind people of Group 1 perceived phosphenes elicited by TMS as often as normal subjects, phosphenes were significantly less often located within the visual field contralateral to stimulation. This might be explained by a loss of stimulus selectivity of deafferented cortical neurones, as has been described for dark-reared kittens (Blakemore and Price, 1987). The assumption that early visual deprivation leads to suppression of the development of the visual cortex is supported by the finding that only blind subjects with prior visual experience were able to perceive phosphenes. Generally speaking, blindness with the highest degree of residual vision seems to lead to qualitative changes in visual cortex function, while complete blindness or blindness with a low degree of residual vision seems to lead to changes in visual cortex excitability. Therefore, TMS of the visual cortex might be a useful tool to test preoperatively for residual functions of the visual cortex in blind people who subject themselves to cortex stimulation with so-called visual prostheses, which use phosphenes to generate mental pictures (Hambrecht, 1995; Schmidt et al., 1996).
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