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Hyperexcitatory activity in visual cortex in homonymous hemianopia after stroke
Clinical Neurophysiology 112 (2001) 336±343
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Hyperexcitatory activity in visual cortex in homonymous hemianopia after stroke Christoph Braun a,*, JuÈrgen Weber a, Ulrich Schiefer b, Martin Skalej c, Traugott Dietrich b a
Institute of Medical Psychology and Behavioral Neurobiology, University of TuÈbingen, Otfried-MuÈller-Strasse 47, 72076 TuÈbingen, Germany Department of Pathophysiology of Vision and Neuroophthalmology, University Eye Hospital TuÈbingen, Schleichstrasse 12-16, 72076 TuÈbingen, Germany c Department of Neuroradiology, University of TuÈbingen, Hoppe-Seyler-Strasse 3, 72076 TuÈbingen, Germany
b
Accepted 16 October 2000
Abstract Objectives: Damage to and destruction of neural afferents result in a disruption of sensory input, which causes reduced activity in the corresponding cortical areas. Conversely, there is also evidence that lesions in the sensory pathway induce changes in the intracortical connectivity resulting in augmented cortical activity due to disinhibition. As disinhibition is assumed to be involved in the recon®guration of neural networks, its appearance after brain lesions might be relevant for the restitution of impaired brain functions. Methods: The effects of lesions in the visual pathway on the activity in visual cortex were studied using magnetoencephalography. In order to compare the neural activity affected by the lesion with the activity associated with intact visual processing, only patients with unilateral, post-chiasmatic lesions resulting in homonymous hemianopia were examined. Results: Stimulation within the scotoma resulted in reduced magnetic activity compared to the stimulation of the intact hemi®eld. Increased activity was observed when the border region of the scotoma was stimulated. Conclusions: It is concluded that the magnetic hyperactivity re¯ects cortical disinhibition induced by lesions in the visual system. Furthermore, the possible role of cortical disinhibition as a basis for cortical reorganization and as a precondition for the recovery of impaired visual functions is discussed. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Stroke; Cortical disinhibition; Magnetoencephalography; Visual cortex; Homonymous hemianiopia
1. Introduction Damage to and destruction of the afferent pathways cause changes in the activation patterns of the corresponding cerebral cortex regions. On the one hand, cortical activity is reduced due to the disruption of sensory input as has been shown by non-invasive functional brain imaging methods by Biersdorf et al. (1992) and Schiefer et al. (1998). On the other hand, animal studies reveal for both the visual and somatosensory modality that cortical deafferentation causes disinhibition of regions in the sensory cortices by modifying the intracortical connectivity. Ultimately, the disinhibition yields increased receptive ®eld size of cortical neurons and increased cortical activity (Eysel, 1992; Rosier et al., 1995; Florence et al., 1997; Sengpiel et al., 1997; Arckens et al., 1998; Kelly et al., 1999). In contrast to the effects of lesions in the periphery of the sensory pathway on the cortical activity patterns, much less * Corresponding author. Tel.: 149-7071-2987705; fax: 149-7071295706. E-mail address: [email protected] (C. Braun).
is known about how the cortical activity changes if cortical tissue itself is damaged. In particular, functional changes in areas adjacent to the affected cortical regions are of interest. From the few animal experiments that have been reported it may be concluded that small lesions in cortical tissue can initiate disinhibition mechanisms similar to those initiated in classical deafferentation experiments. Increased excitability in peri-lesion and remote brain structures that reached a maximum 5 days post-lesion and declined during the following months have been found by BuchkremerRatzmann and Witte (1997) in the rat. Also for the same species, Mittmann et al. (1994) reported NMDA-receptor hyperexcitability and diminished GABA-ergic inhibition in neighboring cortical tissue of such focal lesions. It is supposed that cortical disinhibition in conjunction with the enlargement of neural receptive ®elds is closely related to mechanisms of functional reorganization of the cortex after lesions that form the basis for the recovery of impaired brain functions (Jenkins and Merzenich, 1987; Buonomano and Merzenich, 1998; Weiller and Rijntjes, 1999). To our knowledge, however, there have been no
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C. Braun et al. / Clinical Neurophysiology 112 (2001) 336±343
studies so far that have tried to con®rm the appearance of cortical disinhibition in humans after lesions in the sensory pathway. Moreover, there exist no reports about the possible role of cortical disinhibition for the recovery of sensory functions as, for example, in patients after stroke. In the present study, magnetoencephalography (MEG) was used to verify non-invasively the effects of disinhibition after cortical lesions that were assumed to express themselves in speci®c hyperactivity of the cortex. The examination was performed in patients suffering from homonymous hemianopia which is caused by unilateral post-chiasmal lesions resulting in visual ®eld defects in the visual hemi®eld contralateral to the lesion. With homonymous hemianopia, changes in the activity pattern after stimulation of the affected hemi®eld, as opposed to defects resulting from prechiasmatical lesions, can be compared with the activity evoked by stimulating the intact hemi®eld within the same subject. Due to the large interindividual differences of brain physiological parameters, intraindividual comparisons are advantageous in studying differences in brain activity (Baseler et al., 1999). 2. Methods 2.1. Patients Nine patients with homonymous hemianopia due to occipital ischemic lesions restricted to one hemisphere participated in the study after giving informed consent. The study, being in accordance with the Declaration of Helsinki, had been approved by the local ethics committee. Patients were selected according to the ®ndings based on perimetry and anatomical magnetic resonance tomography (MRT). Only patients with lesions exclusively restricted to the visual pathway were included in the study in order to rule out that visual processing disorders were confounded by de®cits of other brain functions. In all patients, the lesions covered both the visual radiation and the visual cortex to a variable extent. Among the different patients, the size of the scotoma ranged from small scotomas located within the central 108 of the visual ®eld up to complete hemi®eld loss. 2.2. Procedure All 9 subjects were examined within the ®rst 2 weeks after stroke. In 5 patients, at least two additional followup examinations could be realized: the ®rst within 3±8 months and the second after 1 year. Each examination included automatic static perimetry (TuÈbingen Automated Perimeter, Oculus Inc., Dutenhofen, with suprathreshold strategy and high resolution within the central 308) and Goldmann manual kinetic perimetry in order to assess the location and size of the entire visual ®eld de®cits. Additionally, the location and size of the cerebral lesion was inferred by MRT (1.5 T Siemens Vision, Erlangen) using T1 and T2 weighted sequences. MRT was applied in order to document
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edema and parenchymatic defects. Finally, in each session the magnetic brain activity was measured by means of visual evoked magnetic ®elds (VEF) using a 151 channel whole-head MEG system (CTF Inc., Vancouver). 2.3. Perimetry The quanti®cation of changes in scotoma extension was based on the results of the TuÈbingen automated perimetry, scanning a visual ®eld of 308 eccentricity with 191 test points. In order to account for the cortical magni®cation of foveal vision, this method arranges test points more densely in the center of the visual ®eld than in the periphery. The number of points that were never seen within one single examination (i.e. absolute scotoma) or that were seen only at higher stimulus intensities than normal (i.e. relative scotoma) were added. Perimetric results of the kth followup sessions obtained in 5 of the 9 patients were compared to the results of the ®rst session n1 by calculating an index of visual defect n rk k n1 A value less than 1 indicated an enlargement of the visual ®eld and a value greater than 1 indicated a reduction of the visual ®eld size. 2.4. Stimulation and MEG examination During MEG measurements, patients were seated comfortably in a chair inside a magnetically shielded room. The chair was adjustable for height and position so that the subject's head could be placed optimally in the head mould of the MEG dewar. A screen 1.25 m wide and 1 m high on the back of which the visual stimuli were projected was mounted 1.25 m in front of the patient. The size of the screen enabled stimulation of the patient's visual ®eld up to an eccentricity of ^308 horizontally and up to ^258 vertically. Visual stimuli were generated on a computer outside the shielded room and projected by a video projector and a double mirror system onto the back of the screen. The luminance of the black elements within the dartboard stimuli ranged from 0.5 to 1.5 cd/m 2 depending on the position on the screen, whereas the white elements showed a luminance between 5 and 27 cd/m 2. Due to the inhomogeneity in luminance characteristics of the video projector with respect to different locations on the screen, the contrast between black and white elements of the stimuli ranged between 1:10 and 1:18 with a higher contrast in the center of the screen. The experiment consisted of at least two blocks with different stimulus conditions. Within a single block, 4 sector stimuli that were identical in size and shape and mirrorsymmetric to the horizontal and vertical meridian were presented, one in each of the 4 quadrants. The location and size of the stimuli in the different blocks were selected according to the position and extension of the scotoma. In one block the stimuli were chosen such that the stimulus that
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was applied to the impaired quadrant was exclusively within the scotoma. In the other block the corresponding stimulus was selected adjacent to the scotoma (Fig. 1a). The different stimuli within one block were presented in random sequence, each of them 200 times using an interstimulus interval of 1000 ms. Fifty trials without any stimulation were interspersed in the stimulus sequence serving as a control condition (Fig. 1b). Subjects were informed about the occurrence but not about the number of these dummy trials in order not to confuse them if they did not perceive any stimulus. After 15 trials, an acoustic beep of 200 ms duration indicated a short break of 2 s during which eye blinks were allowed. Additionally, the beep reminded the patients to refocus their attention on the ®xation cross in the middle of the screen. To control for artifacts, horizontal and vertical electrooculograms (EOG) were recorded to monitor eye movements and to detect eye blinks in the MEG data. MEG and EOG activity were sampled with 625 Hz using an anti-aliasing low-pass of 208 Hz. Epochs of 400 ms duration including a baseline of 40 ms were collected. Before and after each block, the head position was determined by locating 3 ®duciary positions (nasion, left and right pre-auricular point) with the MEG system in order to align the anatomical magnetic resonance imaging with the results obtained by MEG analysis. 2.5. Data analysis The ®rst step of the data analysis involved scanning of the EOG channels for artifacts. All trials with vertical or hori-
zontal EOG amplitudes larger than 70 mV were excluded from further analysis. To exclude trials with high alpha activity, trials were bandpass ®ltered between 7 and 14 Hz. Six parietal-occipital channels with high alpha power were selected. If any of the selected channels exceeded 1 pT in MEG amplitude, the corresponding trials were discarded. On average 15.4% of all trials were excluded due to artifacts. The remaining trials of each block were averaged according to stimulation conditions. For a single session, individual averages were obtained for stimulating a sector within the scotoma, another for stimulating a sector adjacent to the scotoma and the remaining for stimulating the mirror positions of both sectors in the remaining quadrants of the visual ®eld. Two further averages were obtained by averaging the trials without stimulation. To quantify the magnetic brain activity in a time window expanding from 60 to 150 ms after stimulus onset, the global ®eld activity a of all n channels for time points l to m was computed. v u m X n X u 1 b2 at m 2 l 1 1n i1 k1 ik where bik is the magnetic ®eld amplitude at the ith time point at the kth sensor. The temporal window applied for the calculation of the global ®eld activity covered the ®rst prominent peak of the visual evoked activity which is supposed to be identical with the P100m (Nakasato et al., 1996). In order to correct the mean activity of the `no stimulation' condition for the reduced number of trials contributing to the average (a quarter of the trial numbers of the other conditions) the global ®eld activity was divided by 2
Fig. 1. Dartboard-like stimuli were used in the study. During one experimental block, symmetric locations in the 4 quadrants of the visual ®eld were stimulated by mirror-symmetric sectors (b). Individual quadrants were stimulated on a trial-by-trial basis in random sequence. The position and size of the stimuli were selected according to the results of perimetry. For at least one block, stimuli were applied to the scotoma region of the visual ®eld (a, left). If possible, the visual area adjacent to the scotoma was stimulated in a further block (a, right). An interstimulus interval of 1000 ms was used. After 15 trials a beep indicated a break of 2 s in order to permit eye blinks and to remind the patients to focus on the cross in the middle of the screen.
C. Braun et al. / Clinical Neurophysiology 112 (2001) 336±343
(Bendat and Piersol, 1986). It was assumed that the observed activity is only noise which decreases with the square-root of the trial number by averaging. The `no stimulation' condition could then be used as a control condition to test whether the activity evoked by stimulating the scotoma deviates signi®cantly from zero activity. The statistical signi®cance of differences in brain activity according to the stimulation within the scotoma and contralateral to the scotoma was tested by an ANOVA with the repeated measurement factor `stimulation' comprising the 3 levels `no stimulation', and stimulation of the `ipsilateral' and `contralateral' hemi®eld referred to the location of the scotoma. For comparing the activities evoked by stimulating within the scotoma and adjacent to the scotoma, an additional ANOVA was calculated including the repeated measurement factor `stimulation site'. Only 7 subjects were included in this comparison because two patients suffering from complete hemianopia, involving one total visual hemi®eld, had to be excluded from the analysis since no stimulation adjacent to the scotoma could be performed. To quantify asymmetries between the activity evoked by stimulation inside the impaired hemi®eld aipsi and the activity evoked by stimulating the contralateral, intact hemi®eld acontra using the same stimulus mirrored at the vertical meridian, the ratio q was calculated as q
aipsi acontra
In healthy subjects equally high activation corresponding to a ratio q 1 can be assumed for stimulation of equivalent visual ®eld sectors on either hemi®eld. A value of q lower than 1 indicates reduced activation for stimulating a certain visual ®eld region in the impaired hemi®eld compared to stimulation of the equivalent region on the contralateral side. A value larger than 1 suggests increased activation.
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conducted. Over the 3 follow-up sessions no systematic tendency to either increase or decrease could be determined. Four out of the 5 patients revealed q ratios smaller than 1 indicating a reduced activity for stimulation inside the scotoma. The subject with a ratio larger than 1 (patient `01') revealed a mild cortical infarction but a severe lesion in the optic radiation close to the lateral geniculate nucleus (Fig. 2). In order to study the effects of disinhibition it was tested whether the stimulation of visual ®eld areas adjacent to the scotoma revealed altered activities compared to the activity in the contralateral, intact side (Fig. 3). The ANOVA with repeated measurements for the factors `stimulation' (ipsiand contralateral to the side of the subjectively perceived scotoma and as a control activity with `no stimulation') and `stimulation site' (inside the scotoma and adjacent to the scotoma) revealed a signi®cant main effect of `stimulation' (F 2; 6 13:371, P 0:0017, e 0:862) (Fig. 4) re¯ecting the low evoked activity for the `no stimulation' condition compared to ipsi- and contralateral stimulation and a signi®cant interaction between `stimulation' and `stimulation site' (F 2; 12 5:265, P 0:0396, e 0:720). A post-hoc test exhibited signi®cantly greater activity for the stimulation of the visual ®eld region close to the scotoma (40.23 ^ 6.88 fT) than for the corresponding stimulation in the intact hemi®eld (29.15 ^ 4.72 fT; F 1; 6 5:93, P 0:046). This result is surprising because both stimuli were identical in size and their position and shape were merely mirrored at the vertical meridian. The emergence of cortical hyperactivity after cortical
3. Results The statistical analysis of the magnetic activities evoked by stimulus presentation inside the individual scotoma (mean ^ standard error 21.95 ^ 3.56 fT), contralateral to the scotoma (39.15 ^ 7.46 fT) and without any stimulation (15.49 ^ 2.53 fT) revealed a signi®cant difference (F 2; 8 10:27, P 0:007, e 0:687). A post-hoc analysis showed less magnetic activity from stimulation inside the scotoma than from stimulation on the contralateral side (F 1; 8 10:132, P 0:016). The activity during stimulation inside the scotoma was not signi®cantly larger than the activity measured during trials without any stimulation (F 1; 8 1:44, P 0:23). In order to study whether the reduced activity is only transient, the activity ratio q between ipsi- and contralateral stimulation of the scotoma region was calculated for 5 patients for which follow-up measurements could be
Fig. 2. Axial MR-tomogram slice of patient `01' revealing a lesion in the optical radiation close to the lateral geniculate nucleus (arrow lgn) and a minor cortical lesion in the left hemisphere (arrow vc). Patient `01' was the only one showing hyperactivity throughout the scotoma, whereas other patients showed reduced activity at least in the central region of the scotoma. The left hemisphere is indicated by the letter `L'.
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4. Discussion
Fig. 3. Visual evoked magnetic activity for stimulation inside (a) and adjacent to the scotoma (b) and at the corresponding sites on the contralateral visual ®eld (c,d). The time course of the magnetic activity at all 151 MEG channels is overlaid. The time interval ranging from 60 to 150 ms was used for the analysis of the magnetic activity. In the maps, the topographical distribution of the magnetic activity at 92 ms after stimulus onset is presented. Positive amplitudes represent magnetic ¯ux going out of the head. In the maps in-going ¯ux is shaded gray.
infarction raises the question of whether these activities correlate somehow with the restitution of visual functions. In 4 patients with exclusively cortical lesions, the cortical activity evoked by stimulation inside and outside the scotoma correlated with the recovery of vision over time. In the initial perimetry examination two of the 4 patients suffered from hemianopia, affecting parts of both the upper and lower quadrants of the visual ®eld, whereas the other two revealed visual defects restricted to only one quadrant. As expressed by the visual defect index rk, the size of the scotoma diminished during the follow-up period in two patients, in one with complete hemianopia and in one with quadrantanopia (Figs. 5 and 6). In all 4 patients, due to the size and shape of the scotoma, different parts of the scotoma area could be stimulated in consecutive blocks of the MEG examination. In accordance with the results obtained by the group analysis, the stimulation in at least one part of the scotoma yielded a reduced magnetic activity. However, in two patients, regions within the scotoma were found in the ®rst examination where hyperactivity referring to the contralateral side could be evoked. It turned out that in both subjects these regions overlapped largely with the visual ®eld regions where recovery of vision occurred.
In the present experiment, stimulation within the scotoma in patients with homonymous hemianopia resulted in reduced magnetic activity as compared to the stimulation in the intact hemi®eld. Increased activity was observed when the border region of the scotoma was stimulated. Lesions in the sensory pathway cause deafferentation of cortical areas. Consequently, the deafferented regions cease to be active. In various studies using functional brain imaging methods a decrease in cortical activity after lesions has been demonstrated (Celesia et al., 1983; Biersdorf et al., 1992; Brecelj, 1992). For example, in a study by Biersdorf et al. (1992) the cortical activity in patients suffering from hemianopia has been reported to be abolished or at least reduced if stimulus presentation is restricted exclusively to the scotoma region. In the present study, stimulation inside the scotoma de®ned by perimetry did not totally eliminate the evoked magnetic activity in all patients. Moreover, the characteristic wave-shape of the evoked magnetic ®elds was maintained in some cases. It might be speculated that the visual ®eld defect is caused by edema that generally accompany infarctions. Edema might affect the functionality of afferent neurons without destroying them and might therefore be responsible for the reduction in cortical activity. However, according to Katzman et al. (1977) edema normally disappear after 2 weeks (3 months at the latest) after the infarction and should therefore have no effect on the cortical activity afterwards. In fact, in all 5 patients whose brain anatomy was examined repeatedly, the disap-
Fig. 4. Average global ®eld activity of 7 subjects evoked by stimulation inside the scotoma (white) and adjacent to the scotoma (gray). Stimulation inside the scotoma yielded reduced activity compared to the contralateral, intact side. The activity was larger, however, than brain activity without any stimulation, indicating that the stimulation within the scotoma activated visual cortex at least partially. Stimulation of regions adjacent to the scotoma evoked larger activities than did the contralateral stimulation. Error bars indicate standard errors of the mean values.
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Fig. 5. (Upper) Individual ratios of global ®eld activities (q) evoked by stimulation of visual ®eld regions within the scotoma and contralateral to the scotoma across the 1 year follow-up. The ®rst session was within the ®rst 2 weeks after infarction (1) (hollow diamonds and circles), the second was after 3±8 months (2), and the third was after 1 year (3) (solid diamonds and circles). Ipsilateral stimulation led to smaller activities compared to contralateral stimulation indicated by q , 1:0. In patients `05' and `06' both stimulation inside the scotoma (diamonds) and in the border region of the scotoma (circles) yielded reduced cortical activities. In patients `07' and `08' it was possible to identify in addition to a region causing reduced activity another region at the border of the scotoma (circles) that generated hyperactivity upon stimulation, at least during the ®rst session (hollow circles). (Lower) Patients `05' and `06' showed no improvement of visual ®eld defects (visual defect index r). However, patients `07' and `08' revealed a shrinkage of their scotoma mainly in that part of the visual ®eld from which the hyperactivity could be elicited. The results indicate that hyperactivity associated with stimulation in the border of the scotoma is associated with improvement of vision.
pearance of the edema within the ®rst 3 months after infarction could be con®rmed by magnetic resonance images. Therefore, it has to be concluded that the decreased cortical excitability that could still be observed even after 1 year cannot be caused by transitory effects of edema. A further explanation for the occurrence of the residual activity might be the retention of isles of intact vision within the scotoma that were not detected by perimetry. Alternatively, it has to be considered that visual information might arrive at the visual cortex without reaching consciousness, i.e. bypassing the thalamocortical tract by using alternative pathways, as is suggested for blind-sight (Stoerig and Cowey, 1997). It is well known that in partially blind patients the extension and shape of the scotoma depends on the perimetric techniques applied (Kolb et al., 1995; Schiefer et al., 1999). Different techniques sometimes yield diverging results, indicating that the boundary of a scotoma is not unambiguously de®ned. There are visual ®eld areas in which patients
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are capable of perceiving, for example, bright and large or moving stimuli, but not static ones (Riddoch, 1917). From these observations one may conclude that an infarction in the visual cortex may lead to cortical zones with necrotic neural tissue and to zones with impaired but retained connectivity and decreased or dysfunctional activity. The term ischemic penumbra as a region of viable tissue with functional impairments might re¯ect these psychophysical ®ndings in a neurological respect (Heiss and Graf, 1994). In the present experiment we examined the activity evoked by stimulation in the absolute scotoma, in the transition zone between the scotoma and the visual ®eld areas with normal function and in areas adjacent to the scotoma. The decreased magnetic responses that were found while stimulating inside the absolute scotoma re¯ected the impairment, the degeneration or even the necrosis of cortical tissue. Stimulation of the transition zone between the scotoma and the areas of normal vision or of visual ®eld areas adjacent to the scotoma elicited magnetic activities that were surprisingly larger on the affected side than on the intact hemisphere. An explanation for the observed hyperactivity is based on observations in animal studies. From studies in rats it is known that lesions in the visual pathway cause disinhibition of the affected cortical region (Schiene et al., 1996). Changes in the receptive ®eld size of cortical neurons in the deafferented visual cortex subsequent to cortical or subcortical lesions have been reported (Ciaramitaro et al., 1997; Eysel and Schweigart, 1999). It is supposed that neurons in the intact cortex exert an inhibitory effect on neighboring neurons and especially on long-range horizontal connections (Eysel, 1992), reducing the receptive ®eld size of individual neurons. By administering bicuculline, a GABA antagonist, the receptive ®eld size of single neurons in the intact visual cortex could be increased similarly, pointing to the GABA-ergic nature of the inhibiting process (Alloway and Burton, 1991). The increase in the receptive ®eld size after lesions may enable the deafferented cortical neurons to receive meaningful input again and might therefore be a ®rst stage in the functional reorganization of visual cortex and in the recovery of vision (Nudo et al., 1996). As MEG measures the overall cortical activity of some 10 000 neurons, it appears to be plausible that after the disinhibition of a larger cortical region, an increased activity can be observed due to changes in both the dentric membrane potentials and in the receptive ®eld size. According to our ®ndings the hyperactivity following infarction in the visual pathway, therefore, can be seen as the macroscopic equivalent to the disinhibition that has been demonstrated on a cellular level in animal studies. Concerning the functional role of the disinhibition, our data suggest that disinhibition generally accompanies lesions in the visual pathway. Disinhibition alone seems not to indicate the occurrence of cortical reorganization and restitution of sensory function, as could be concluded from the data of the 5 patients who have been studied over a
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Fig. 6. Results of TuÈbingen automated perimetry in patient `08' after 3 days (1), 8 months (2), and 1 year (3) following infarction. The time course reveals a reduction of the scotoma in the lower left quadrant of the visual ®eld. The positions of the test points are marked by dots. Test points detected at neither low nor high stimulus intensities are indicated by black squares (absolute scotoma). Test points detected only at high intensity levels are marked by white squares (relative scotoma).
year. Only the hyperactivity evoked by stimulation inside the scotoma may predict the consecutive recovery of visual functions in cases with cortical lesions. It might be concluded that the hyperactivity evoked by stimulating inside the scotoma indicates that the functionally impaired cortical tissue is still vital and retains the capacity to
recover. Additionally, the hyperactivity might re¯ect a neural mechanism that causes the rearrangement of cortical networks in order to regain proper functions (Safran and Landis, 1996). Further study of disinhibition in patients suffering from homonymous hemianopia may provide insight into the basic mechanisms of cortical reorganization
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Hyperexcitatory activity in visual cortex in homonymous hemianopia after stroke Christoph Braun a,*, JuÈrgen Weber a, Ulrich Schiefer b, Martin Skalej c, Traugott Dietrich b a
Institute of Medical Psychology and Behavioral Neurobiology, University of TuÈbingen, Otfried-MuÈller-Strasse 47, 72076 TuÈbingen, Germany Department of Pathophysiology of Vision and Neuroophthalmology, University Eye Hospital TuÈbingen, Schleichstrasse 12-16, 72076 TuÈbingen, Germany c Department of Neuroradiology, University of TuÈbingen, Hoppe-Seyler-Strasse 3, 72076 TuÈbingen, Germany
b
Accepted 16 October 2000
Abstract Objectives: Damage to and destruction of neural afferents result in a disruption of sensory input, which causes reduced activity in the corresponding cortical areas. Conversely, there is also evidence that lesions in the sensory pathway induce changes in the intracortical connectivity resulting in augmented cortical activity due to disinhibition. As disinhibition is assumed to be involved in the recon®guration of neural networks, its appearance after brain lesions might be relevant for the restitution of impaired brain functions. Methods: The effects of lesions in the visual pathway on the activity in visual cortex were studied using magnetoencephalography. In order to compare the neural activity affected by the lesion with the activity associated with intact visual processing, only patients with unilateral, post-chiasmatic lesions resulting in homonymous hemianopia were examined. Results: Stimulation within the scotoma resulted in reduced magnetic activity compared to the stimulation of the intact hemi®eld. Increased activity was observed when the border region of the scotoma was stimulated. Conclusions: It is concluded that the magnetic hyperactivity re¯ects cortical disinhibition induced by lesions in the visual system. Furthermore, the possible role of cortical disinhibition as a basis for cortical reorganization and as a precondition for the recovery of impaired visual functions is discussed. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Stroke; Cortical disinhibition; Magnetoencephalography; Visual cortex; Homonymous hemianiopia
1. Introduction Damage to and destruction of the afferent pathways cause changes in the activation patterns of the corresponding cerebral cortex regions. On the one hand, cortical activity is reduced due to the disruption of sensory input as has been shown by non-invasive functional brain imaging methods by Biersdorf et al. (1992) and Schiefer et al. (1998). On the other hand, animal studies reveal for both the visual and somatosensory modality that cortical deafferentation causes disinhibition of regions in the sensory cortices by modifying the intracortical connectivity. Ultimately, the disinhibition yields increased receptive ®eld size of cortical neurons and increased cortical activity (Eysel, 1992; Rosier et al., 1995; Florence et al., 1997; Sengpiel et al., 1997; Arckens et al., 1998; Kelly et al., 1999). In contrast to the effects of lesions in the periphery of the sensory pathway on the cortical activity patterns, much less * Corresponding author. Tel.: 149-7071-2987705; fax: 149-7071295706. E-mail address: [email protected] (C. Braun).
is known about how the cortical activity changes if cortical tissue itself is damaged. In particular, functional changes in areas adjacent to the affected cortical regions are of interest. From the few animal experiments that have been reported it may be concluded that small lesions in cortical tissue can initiate disinhibition mechanisms similar to those initiated in classical deafferentation experiments. Increased excitability in peri-lesion and remote brain structures that reached a maximum 5 days post-lesion and declined during the following months have been found by BuchkremerRatzmann and Witte (1997) in the rat. Also for the same species, Mittmann et al. (1994) reported NMDA-receptor hyperexcitability and diminished GABA-ergic inhibition in neighboring cortical tissue of such focal lesions. It is supposed that cortical disinhibition in conjunction with the enlargement of neural receptive ®elds is closely related to mechanisms of functional reorganization of the cortex after lesions that form the basis for the recovery of impaired brain functions (Jenkins and Merzenich, 1987; Buonomano and Merzenich, 1998; Weiller and Rijntjes, 1999). To our knowledge, however, there have been no
1388-2457/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(00)0050 8-3
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studies so far that have tried to con®rm the appearance of cortical disinhibition in humans after lesions in the sensory pathway. Moreover, there exist no reports about the possible role of cortical disinhibition for the recovery of sensory functions as, for example, in patients after stroke. In the present study, magnetoencephalography (MEG) was used to verify non-invasively the effects of disinhibition after cortical lesions that were assumed to express themselves in speci®c hyperactivity of the cortex. The examination was performed in patients suffering from homonymous hemianopia which is caused by unilateral post-chiasmal lesions resulting in visual ®eld defects in the visual hemi®eld contralateral to the lesion. With homonymous hemianopia, changes in the activity pattern after stimulation of the affected hemi®eld, as opposed to defects resulting from prechiasmatical lesions, can be compared with the activity evoked by stimulating the intact hemi®eld within the same subject. Due to the large interindividual differences of brain physiological parameters, intraindividual comparisons are advantageous in studying differences in brain activity (Baseler et al., 1999). 2. Methods 2.1. Patients Nine patients with homonymous hemianopia due to occipital ischemic lesions restricted to one hemisphere participated in the study after giving informed consent. The study, being in accordance with the Declaration of Helsinki, had been approved by the local ethics committee. Patients were selected according to the ®ndings based on perimetry and anatomical magnetic resonance tomography (MRT). Only patients with lesions exclusively restricted to the visual pathway were included in the study in order to rule out that visual processing disorders were confounded by de®cits of other brain functions. In all patients, the lesions covered both the visual radiation and the visual cortex to a variable extent. Among the different patients, the size of the scotoma ranged from small scotomas located within the central 108 of the visual ®eld up to complete hemi®eld loss. 2.2. Procedure All 9 subjects were examined within the ®rst 2 weeks after stroke. In 5 patients, at least two additional followup examinations could be realized: the ®rst within 3±8 months and the second after 1 year. Each examination included automatic static perimetry (TuÈbingen Automated Perimeter, Oculus Inc., Dutenhofen, with suprathreshold strategy and high resolution within the central 308) and Goldmann manual kinetic perimetry in order to assess the location and size of the entire visual ®eld de®cits. Additionally, the location and size of the cerebral lesion was inferred by MRT (1.5 T Siemens Vision, Erlangen) using T1 and T2 weighted sequences. MRT was applied in order to document
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edema and parenchymatic defects. Finally, in each session the magnetic brain activity was measured by means of visual evoked magnetic ®elds (VEF) using a 151 channel whole-head MEG system (CTF Inc., Vancouver). 2.3. Perimetry The quanti®cation of changes in scotoma extension was based on the results of the TuÈbingen automated perimetry, scanning a visual ®eld of 308 eccentricity with 191 test points. In order to account for the cortical magni®cation of foveal vision, this method arranges test points more densely in the center of the visual ®eld than in the periphery. The number of points that were never seen within one single examination (i.e. absolute scotoma) or that were seen only at higher stimulus intensities than normal (i.e. relative scotoma) were added. Perimetric results of the kth followup sessions obtained in 5 of the 9 patients were compared to the results of the ®rst session n1 by calculating an index of visual defect n rk k n1 A value less than 1 indicated an enlargement of the visual ®eld and a value greater than 1 indicated a reduction of the visual ®eld size. 2.4. Stimulation and MEG examination During MEG measurements, patients were seated comfortably in a chair inside a magnetically shielded room. The chair was adjustable for height and position so that the subject's head could be placed optimally in the head mould of the MEG dewar. A screen 1.25 m wide and 1 m high on the back of which the visual stimuli were projected was mounted 1.25 m in front of the patient. The size of the screen enabled stimulation of the patient's visual ®eld up to an eccentricity of ^308 horizontally and up to ^258 vertically. Visual stimuli were generated on a computer outside the shielded room and projected by a video projector and a double mirror system onto the back of the screen. The luminance of the black elements within the dartboard stimuli ranged from 0.5 to 1.5 cd/m 2 depending on the position on the screen, whereas the white elements showed a luminance between 5 and 27 cd/m 2. Due to the inhomogeneity in luminance characteristics of the video projector with respect to different locations on the screen, the contrast between black and white elements of the stimuli ranged between 1:10 and 1:18 with a higher contrast in the center of the screen. The experiment consisted of at least two blocks with different stimulus conditions. Within a single block, 4 sector stimuli that were identical in size and shape and mirrorsymmetric to the horizontal and vertical meridian were presented, one in each of the 4 quadrants. The location and size of the stimuli in the different blocks were selected according to the position and extension of the scotoma. In one block the stimuli were chosen such that the stimulus that
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was applied to the impaired quadrant was exclusively within the scotoma. In the other block the corresponding stimulus was selected adjacent to the scotoma (Fig. 1a). The different stimuli within one block were presented in random sequence, each of them 200 times using an interstimulus interval of 1000 ms. Fifty trials without any stimulation were interspersed in the stimulus sequence serving as a control condition (Fig. 1b). Subjects were informed about the occurrence but not about the number of these dummy trials in order not to confuse them if they did not perceive any stimulus. After 15 trials, an acoustic beep of 200 ms duration indicated a short break of 2 s during which eye blinks were allowed. Additionally, the beep reminded the patients to refocus their attention on the ®xation cross in the middle of the screen. To control for artifacts, horizontal and vertical electrooculograms (EOG) were recorded to monitor eye movements and to detect eye blinks in the MEG data. MEG and EOG activity were sampled with 625 Hz using an anti-aliasing low-pass of 208 Hz. Epochs of 400 ms duration including a baseline of 40 ms were collected. Before and after each block, the head position was determined by locating 3 ®duciary positions (nasion, left and right pre-auricular point) with the MEG system in order to align the anatomical magnetic resonance imaging with the results obtained by MEG analysis. 2.5. Data analysis The ®rst step of the data analysis involved scanning of the EOG channels for artifacts. All trials with vertical or hori-
zontal EOG amplitudes larger than 70 mV were excluded from further analysis. To exclude trials with high alpha activity, trials were bandpass ®ltered between 7 and 14 Hz. Six parietal-occipital channels with high alpha power were selected. If any of the selected channels exceeded 1 pT in MEG amplitude, the corresponding trials were discarded. On average 15.4% of all trials were excluded due to artifacts. The remaining trials of each block were averaged according to stimulation conditions. For a single session, individual averages were obtained for stimulating a sector within the scotoma, another for stimulating a sector adjacent to the scotoma and the remaining for stimulating the mirror positions of both sectors in the remaining quadrants of the visual ®eld. Two further averages were obtained by averaging the trials without stimulation. To quantify the magnetic brain activity in a time window expanding from 60 to 150 ms after stimulus onset, the global ®eld activity a of all n channels for time points l to m was computed. v u m X n X u 1 b2 at m 2 l 1 1n i1 k1 ik where bik is the magnetic ®eld amplitude at the ith time point at the kth sensor. The temporal window applied for the calculation of the global ®eld activity covered the ®rst prominent peak of the visual evoked activity which is supposed to be identical with the P100m (Nakasato et al., 1996). In order to correct the mean activity of the `no stimulation' condition for the reduced number of trials contributing to the average (a quarter of the trial numbers of the other conditions) the global ®eld activity was divided by 2
Fig. 1. Dartboard-like stimuli were used in the study. During one experimental block, symmetric locations in the 4 quadrants of the visual ®eld were stimulated by mirror-symmetric sectors (b). Individual quadrants were stimulated on a trial-by-trial basis in random sequence. The position and size of the stimuli were selected according to the results of perimetry. For at least one block, stimuli were applied to the scotoma region of the visual ®eld (a, left). If possible, the visual area adjacent to the scotoma was stimulated in a further block (a, right). An interstimulus interval of 1000 ms was used. After 15 trials a beep indicated a break of 2 s in order to permit eye blinks and to remind the patients to focus on the cross in the middle of the screen.
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(Bendat and Piersol, 1986). It was assumed that the observed activity is only noise which decreases with the square-root of the trial number by averaging. The `no stimulation' condition could then be used as a control condition to test whether the activity evoked by stimulating the scotoma deviates signi®cantly from zero activity. The statistical signi®cance of differences in brain activity according to the stimulation within the scotoma and contralateral to the scotoma was tested by an ANOVA with the repeated measurement factor `stimulation' comprising the 3 levels `no stimulation', and stimulation of the `ipsilateral' and `contralateral' hemi®eld referred to the location of the scotoma. For comparing the activities evoked by stimulating within the scotoma and adjacent to the scotoma, an additional ANOVA was calculated including the repeated measurement factor `stimulation site'. Only 7 subjects were included in this comparison because two patients suffering from complete hemianopia, involving one total visual hemi®eld, had to be excluded from the analysis since no stimulation adjacent to the scotoma could be performed. To quantify asymmetries between the activity evoked by stimulation inside the impaired hemi®eld aipsi and the activity evoked by stimulating the contralateral, intact hemi®eld acontra using the same stimulus mirrored at the vertical meridian, the ratio q was calculated as q
aipsi acontra
In healthy subjects equally high activation corresponding to a ratio q 1 can be assumed for stimulation of equivalent visual ®eld sectors on either hemi®eld. A value of q lower than 1 indicates reduced activation for stimulating a certain visual ®eld region in the impaired hemi®eld compared to stimulation of the equivalent region on the contralateral side. A value larger than 1 suggests increased activation.
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conducted. Over the 3 follow-up sessions no systematic tendency to either increase or decrease could be determined. Four out of the 5 patients revealed q ratios smaller than 1 indicating a reduced activity for stimulation inside the scotoma. The subject with a ratio larger than 1 (patient `01') revealed a mild cortical infarction but a severe lesion in the optic radiation close to the lateral geniculate nucleus (Fig. 2). In order to study the effects of disinhibition it was tested whether the stimulation of visual ®eld areas adjacent to the scotoma revealed altered activities compared to the activity in the contralateral, intact side (Fig. 3). The ANOVA with repeated measurements for the factors `stimulation' (ipsiand contralateral to the side of the subjectively perceived scotoma and as a control activity with `no stimulation') and `stimulation site' (inside the scotoma and adjacent to the scotoma) revealed a signi®cant main effect of `stimulation' (F 2; 6 13:371, P 0:0017, e 0:862) (Fig. 4) re¯ecting the low evoked activity for the `no stimulation' condition compared to ipsi- and contralateral stimulation and a signi®cant interaction between `stimulation' and `stimulation site' (F 2; 12 5:265, P 0:0396, e 0:720). A post-hoc test exhibited signi®cantly greater activity for the stimulation of the visual ®eld region close to the scotoma (40.23 ^ 6.88 fT) than for the corresponding stimulation in the intact hemi®eld (29.15 ^ 4.72 fT; F 1; 6 5:93, P 0:046). This result is surprising because both stimuli were identical in size and their position and shape were merely mirrored at the vertical meridian. The emergence of cortical hyperactivity after cortical
3. Results The statistical analysis of the magnetic activities evoked by stimulus presentation inside the individual scotoma (mean ^ standard error 21.95 ^ 3.56 fT), contralateral to the scotoma (39.15 ^ 7.46 fT) and without any stimulation (15.49 ^ 2.53 fT) revealed a signi®cant difference (F 2; 8 10:27, P 0:007, e 0:687). A post-hoc analysis showed less magnetic activity from stimulation inside the scotoma than from stimulation on the contralateral side (F 1; 8 10:132, P 0:016). The activity during stimulation inside the scotoma was not signi®cantly larger than the activity measured during trials without any stimulation (F 1; 8 1:44, P 0:23). In order to study whether the reduced activity is only transient, the activity ratio q between ipsi- and contralateral stimulation of the scotoma region was calculated for 5 patients for which follow-up measurements could be
Fig. 2. Axial MR-tomogram slice of patient `01' revealing a lesion in the optical radiation close to the lateral geniculate nucleus (arrow lgn) and a minor cortical lesion in the left hemisphere (arrow vc). Patient `01' was the only one showing hyperactivity throughout the scotoma, whereas other patients showed reduced activity at least in the central region of the scotoma. The left hemisphere is indicated by the letter `L'.
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4. Discussion
Fig. 3. Visual evoked magnetic activity for stimulation inside (a) and adjacent to the scotoma (b) and at the corresponding sites on the contralateral visual ®eld (c,d). The time course of the magnetic activity at all 151 MEG channels is overlaid. The time interval ranging from 60 to 150 ms was used for the analysis of the magnetic activity. In the maps, the topographical distribution of the magnetic activity at 92 ms after stimulus onset is presented. Positive amplitudes represent magnetic ¯ux going out of the head. In the maps in-going ¯ux is shaded gray.
infarction raises the question of whether these activities correlate somehow with the restitution of visual functions. In 4 patients with exclusively cortical lesions, the cortical activity evoked by stimulation inside and outside the scotoma correlated with the recovery of vision over time. In the initial perimetry examination two of the 4 patients suffered from hemianopia, affecting parts of both the upper and lower quadrants of the visual ®eld, whereas the other two revealed visual defects restricted to only one quadrant. As expressed by the visual defect index rk, the size of the scotoma diminished during the follow-up period in two patients, in one with complete hemianopia and in one with quadrantanopia (Figs. 5 and 6). In all 4 patients, due to the size and shape of the scotoma, different parts of the scotoma area could be stimulated in consecutive blocks of the MEG examination. In accordance with the results obtained by the group analysis, the stimulation in at least one part of the scotoma yielded a reduced magnetic activity. However, in two patients, regions within the scotoma were found in the ®rst examination where hyperactivity referring to the contralateral side could be evoked. It turned out that in both subjects these regions overlapped largely with the visual ®eld regions where recovery of vision occurred.
In the present experiment, stimulation within the scotoma in patients with homonymous hemianopia resulted in reduced magnetic activity as compared to the stimulation in the intact hemi®eld. Increased activity was observed when the border region of the scotoma was stimulated. Lesions in the sensory pathway cause deafferentation of cortical areas. Consequently, the deafferented regions cease to be active. In various studies using functional brain imaging methods a decrease in cortical activity after lesions has been demonstrated (Celesia et al., 1983; Biersdorf et al., 1992; Brecelj, 1992). For example, in a study by Biersdorf et al. (1992) the cortical activity in patients suffering from hemianopia has been reported to be abolished or at least reduced if stimulus presentation is restricted exclusively to the scotoma region. In the present study, stimulation inside the scotoma de®ned by perimetry did not totally eliminate the evoked magnetic activity in all patients. Moreover, the characteristic wave-shape of the evoked magnetic ®elds was maintained in some cases. It might be speculated that the visual ®eld defect is caused by edema that generally accompany infarctions. Edema might affect the functionality of afferent neurons without destroying them and might therefore be responsible for the reduction in cortical activity. However, according to Katzman et al. (1977) edema normally disappear after 2 weeks (3 months at the latest) after the infarction and should therefore have no effect on the cortical activity afterwards. In fact, in all 5 patients whose brain anatomy was examined repeatedly, the disap-
Fig. 4. Average global ®eld activity of 7 subjects evoked by stimulation inside the scotoma (white) and adjacent to the scotoma (gray). Stimulation inside the scotoma yielded reduced activity compared to the contralateral, intact side. The activity was larger, however, than brain activity without any stimulation, indicating that the stimulation within the scotoma activated visual cortex at least partially. Stimulation of regions adjacent to the scotoma evoked larger activities than did the contralateral stimulation. Error bars indicate standard errors of the mean values.
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Fig. 5. (Upper) Individual ratios of global ®eld activities (q) evoked by stimulation of visual ®eld regions within the scotoma and contralateral to the scotoma across the 1 year follow-up. The ®rst session was within the ®rst 2 weeks after infarction (1) (hollow diamonds and circles), the second was after 3±8 months (2), and the third was after 1 year (3) (solid diamonds and circles). Ipsilateral stimulation led to smaller activities compared to contralateral stimulation indicated by q , 1:0. In patients `05' and `06' both stimulation inside the scotoma (diamonds) and in the border region of the scotoma (circles) yielded reduced cortical activities. In patients `07' and `08' it was possible to identify in addition to a region causing reduced activity another region at the border of the scotoma (circles) that generated hyperactivity upon stimulation, at least during the ®rst session (hollow circles). (Lower) Patients `05' and `06' showed no improvement of visual ®eld defects (visual defect index r). However, patients `07' and `08' revealed a shrinkage of their scotoma mainly in that part of the visual ®eld from which the hyperactivity could be elicited. The results indicate that hyperactivity associated with stimulation in the border of the scotoma is associated with improvement of vision.
pearance of the edema within the ®rst 3 months after infarction could be con®rmed by magnetic resonance images. Therefore, it has to be concluded that the decreased cortical excitability that could still be observed even after 1 year cannot be caused by transitory effects of edema. A further explanation for the occurrence of the residual activity might be the retention of isles of intact vision within the scotoma that were not detected by perimetry. Alternatively, it has to be considered that visual information might arrive at the visual cortex without reaching consciousness, i.e. bypassing the thalamocortical tract by using alternative pathways, as is suggested for blind-sight (Stoerig and Cowey, 1997). It is well known that in partially blind patients the extension and shape of the scotoma depends on the perimetric techniques applied (Kolb et al., 1995; Schiefer et al., 1999). Different techniques sometimes yield diverging results, indicating that the boundary of a scotoma is not unambiguously de®ned. There are visual ®eld areas in which patients
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are capable of perceiving, for example, bright and large or moving stimuli, but not static ones (Riddoch, 1917). From these observations one may conclude that an infarction in the visual cortex may lead to cortical zones with necrotic neural tissue and to zones with impaired but retained connectivity and decreased or dysfunctional activity. The term ischemic penumbra as a region of viable tissue with functional impairments might re¯ect these psychophysical ®ndings in a neurological respect (Heiss and Graf, 1994). In the present experiment we examined the activity evoked by stimulation in the absolute scotoma, in the transition zone between the scotoma and the visual ®eld areas with normal function and in areas adjacent to the scotoma. The decreased magnetic responses that were found while stimulating inside the absolute scotoma re¯ected the impairment, the degeneration or even the necrosis of cortical tissue. Stimulation of the transition zone between the scotoma and the areas of normal vision or of visual ®eld areas adjacent to the scotoma elicited magnetic activities that were surprisingly larger on the affected side than on the intact hemisphere. An explanation for the observed hyperactivity is based on observations in animal studies. From studies in rats it is known that lesions in the visual pathway cause disinhibition of the affected cortical region (Schiene et al., 1996). Changes in the receptive ®eld size of cortical neurons in the deafferented visual cortex subsequent to cortical or subcortical lesions have been reported (Ciaramitaro et al., 1997; Eysel and Schweigart, 1999). It is supposed that neurons in the intact cortex exert an inhibitory effect on neighboring neurons and especially on long-range horizontal connections (Eysel, 1992), reducing the receptive ®eld size of individual neurons. By administering bicuculline, a GABA antagonist, the receptive ®eld size of single neurons in the intact visual cortex could be increased similarly, pointing to the GABA-ergic nature of the inhibiting process (Alloway and Burton, 1991). The increase in the receptive ®eld size after lesions may enable the deafferented cortical neurons to receive meaningful input again and might therefore be a ®rst stage in the functional reorganization of visual cortex and in the recovery of vision (Nudo et al., 1996). As MEG measures the overall cortical activity of some 10 000 neurons, it appears to be plausible that after the disinhibition of a larger cortical region, an increased activity can be observed due to changes in both the dentric membrane potentials and in the receptive ®eld size. According to our ®ndings the hyperactivity following infarction in the visual pathway, therefore, can be seen as the macroscopic equivalent to the disinhibition that has been demonstrated on a cellular level in animal studies. Concerning the functional role of the disinhibition, our data suggest that disinhibition generally accompanies lesions in the visual pathway. Disinhibition alone seems not to indicate the occurrence of cortical reorganization and restitution of sensory function, as could be concluded from the data of the 5 patients who have been studied over a
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Fig. 6. Results of TuÈbingen automated perimetry in patient `08' after 3 days (1), 8 months (2), and 1 year (3) following infarction. The time course reveals a reduction of the scotoma in the lower left quadrant of the visual ®eld. The positions of the test points are marked by dots. Test points detected at neither low nor high stimulus intensities are indicated by black squares (absolute scotoma). Test points detected only at high intensity levels are marked by white squares (relative scotoma).
year. Only the hyperactivity evoked by stimulation inside the scotoma may predict the consecutive recovery of visual functions in cases with cortical lesions. It might be concluded that the hyperactivity evoked by stimulating inside the scotoma indicates that the functionally impaired cortical tissue is still vital and retains the capacity to
recover. Additionally, the hyperactivity might re¯ect a neural mechanism that causes the rearrangement of cortical networks in order to regain proper functions (Safran and Landis, 1996). Further study of disinhibition in patients suffering from homonymous hemianopia may provide insight into the basic mechanisms of cortical reorganization
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