Suppression of visual perception by transcranial magnetic stimulation — experimental findings in healthy subjects and patients with optic neuritis

Electroencephalography and clinicalNeurophysiology, 86 (1993) 259-267

259

© 1993 Elsevier Scientific Publishers Ireland, Ltd. 0013-4649/93/$06.00

EEG 92537

Suppression of visual perception by transcranial magnetic stimulation experimental findings in healthy subjects and patients with optic neuritis H. Masur, K. Papke and C. Oberwittler Department of Neurology, University of Miinster, Miinster (Germany) (Accepted for publication: 2 December 1992)

Summary The influence of noninvasive magnetic brain stimulation by a magnetic coil (MC) placed over the occiput on perception and correct reporting of a briefly presented set of 3 letters of the alphabet was examined in 15 patients with prolonged VEP latencies due to neuritis of the optic nerve. The results derived from observing these patients were compared to the results obtained from an age-matched control group of 20 healthy voluntary subjects examined under the same experimental conditions. In both groups it was possible to demonstrate that transcranial magnetic stimulation is able to suppress recognition of the letters if applied with a certain delay time after a brief presentation of the visual stimulus. The groups were compared to each other with regard to the delay with which it was possible to demonstrate the most effective suppression. In the healthy subjects, this delay was found between 60 and 100 msec. In the patients, it was prolonged to 80-140 msec. This prolongation was closely related to the VEP latency (P100). Furthermore, visual suppression and the influence on it by different parameters were studied in detail in healthy subjects; the visual suppression depends on visual (e.g., brightness, duration) and magnetic (e.g., intensity) stimulus conditions. The method described seems to be of considerable value in the investigation of basic mechanisms of visual perception. This includes pathophysiological changes caused by optic neuritis and possibly other disorders affecting the visual system. Key words: Visual perception; Transcranial magnetic stimulation; Optic neuritis; Human occipital cortex

Noninvasive transcranial magnetic stimulation of the m o t o r c o r t e x was i n t r o d u c e d in 1985 by B a r k e r et al. P r i o r to this time, noninvasive s t i m u l a t i o n of t h e m o t o r c o r t e x in m a n was p e r f o r m e d electrically a f t e r first b e i n g d e s c r i b e d by M e r t o n a n d M o r t o n (1980). N o n i n vasive s t i m u l a t i o n o f t h e b r a i n p r o v e d to play an imp o r t a n t role in n e u r o l o g i c a l diagnosis, for e x a m p l e in m u l t i p l e sclerosis ( H e s s et al. 1987; I n g r a m et al. 1988; B r i t t o n et al. 1991), cervical spinal stenosis ( M a s u r et al. 1989) a n d a m y o t r o p h i c l a t e r a l sclerosis ( B e r a r d e l l i et al. 1987; S c h r i e f e r et al. 1989).. F u r t h e r m o r e , this m e t h o d t u r n e d o u t to b e a u n i q u e p r o b e in analysing c e r t a i n physiological p h e n o m e n a like facilitation o r i n h i b i t i o n o f m o t o r e v o k e d p o t e n tials (Claus et al. 1988), m o t o r f u n c t i o n o f cranial nerves ( B e n e c k e et al. 1988), t h e e x e c u t i o n of v o l u n t a r y m o v e m e n t s ( D a y et al. 1989) a n d t h e s e l e c t i o n o f m o t o r p r o g r a m m e s ( A m m o n a n d G a n d e v i a 1990). O n l y a few studies have b e e n p e r f o r m e d with t h e

Correspondence to: PD Dr. H. Masur, Department of Neurology, University of Miinster, Albert-Schweitzer-Str. 33, D-4400 Miinster (Germany). Tel.: (0)251/838190; Fax: (0)251/838181.

a t t e m p t to s t i m u l a t e cortical a r e a s o t h e r t h a n the m o tor cortex. H o w e v e r , i n t e r e s t i n g findings have b e e n r e p o r t e d c o n c e r n i n g t h e i n f l u e n c e of m a g n e t i c b r a i n s t i m u l a t i o n on visual p e r c e p t i o n ( A m a s s i a n et al. 1989). In this study t h e a u t h o r s d e m o n s t r a t e d s u p p r e s s i o n of t h e r e c o g n i t i o n of briefly p r e s e n t e d visual stimuli d u e to m a g n e t i c s t i m u l a t i o n over the o c c i p u t in 4 persons. In c o n t r a s t to t h e s e inhibitory effects on visual p e r c e p tion, excitatory p h e n o m e n a have also b e e n r e p o r t e d . T h e elicitation of p h o s p h e n e s following noninvasive m a g n e t i c s t i m u l a t i o n o f t h e r e t i n a a n d visual c o r t e x has b e e n r e v i e w e d by M a r g (1991). It was t h e aim of this study to d e v e l o p an experim e n t a l s c h e m e which m a k e s it p o s s i b l e to e x a m i n e in d e t a i l t h e i n f l u e n c e o f t h e m a g n e t i c s t i m u l a t i o n on visual p e r c e p t i o n in h e a l t h y v o l u n t e e r s a n d to d e t e c t p a t h o l o g i c a l c h a n g e s in p a t i e n t s suffering from n e u r i t i s o f t h e optic nerve.

Material and methods T w e n t y h e a l t h y v o l u n t e e r s a g e d 2 0 - 3 4 y e a r s (10 males, 10 f e m a l e s ) served as a c o n t r o l g r o u p (cf., T a b l e

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1). All subjects were free of evident neurological or metabolic diseases. Fifteen patients aged 19-38 with prolonged VEP latencies were tested. They were selected for participation in the study if the VEP (P100) was longer than 110 msec. This was usually due to optic neuritis as a manifestation of a probable or definite multiple sclerosis (cf., Table II). The criteria for the diagnosis of MS were those set out by Poser et al. (1983). Pattern reversal visual evoked potentials were recorded bilaterally in all patients. The visual stimulus was presented on a TV screen with a contrast of 82% and a spatial frequency of 0.34 c / d e g . Electrodes were placed 3 cm above the inion and referred to a midfrontal electrode (Fz). The pattern reversal frequency was 1 Hz; signals were averaged 100 times. A filtering bandpass from 1 to 100 Hz was used. The reproduced latencies (P100) were compared with normative data established in our laboratory. Both patients and healthy volunteers gave informed consent after detailed explanation of the procedure; subjects with contraindications (epilepsy, cardiac pacemaker or other implanted electronic devices, metal implants) were excluded.

Experimental conditions Prior to testing healthy subjects and patients under standardized conditions, evaluation of different experimental parameters was necessary in pilot experiments, including size and distance of the letters presented, duration, brightness and contrast of the visual stimulus, coil placement, orientation of the magnetic current and the magnetic stimulus intensity.

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60 770 80 90 100 110 120 130 140 Delay time [ms] to=67 ms Fig. 1. Illustration of the method designed to describe the key attribute of the suppression interval. The calculated value of t o characterizes the delay at which the minimum of visual perception ( = most effective suppression) is observed. Subject: K.P., 25 years, male. Right eye. 30

40

50

Among these factors, some turned out to be of critical importance for the results and were subjected to systematic investigation in additional experiments discussed below; these experiments also served to verify the intraindividual reproducibility of the method. The standard protocol used to examine patients and the control group was as follows. Presentation of the visual stimulus. The subjects were placed 50 cm in front of a screen (20 × 30 cm) and presented slides showing a random set of 3 letters. Character sets forming words, syllables or common abbreviations were excluded because perception of such combinations might be supported by different neuronal strategies, making recognition easier. Presentation of more (e.g., 4 or 5) letters in one slide would allow better separation between normal and suppressed perception with fewer magnetic stimuli; in that case, however, the results become more and more dependent on other factors like concentration and short memory. For that reason, we retained the presentation of 3 letters in 1 slide. The letters appeared white on a dark background and were 4 mm tall on the screen, thus subtending a visual angle of 0°36'; the visual angle between the left and right letters was 4042 '. After measuring the luminance of the illuminated letters and the surrounding dark screen with a luxmeter, the contrast was calculated according to the formula C = (Imax - Imin)//(Imax "+-Imin). In our experimental setting, the contrast was 95%. To aid fixation of the letters, a small arrow painted on the screen pointed to the middle letter. A tachistoscope was used to present the slides for a duration of 1 msec which was verified by recording the emitted light signal with a phototransistor and displaying it on an oscilloscope. Given the described experimental conditions, all healthy subjects were able to report the letters correctly, producing only occasional errors. In some patients, however, a longer presentation of the visual stimulus was required. Magnetic stimulation. The visual stimulus was followed by transcranial magnetic stimulation using a Novametrix Magstim, 1.5 Tesla maximum output. The round magnetic coil (14 cm outer diameter) was placed over the occiput in a tangential and flat position, symmetrically according to the midline. To achieve visual suppression, the center of the coil had to be placed approximately 5 - 7 cm above the inion. As the inhibitory effect turned out to require high magnetic stimulus intensities (70-100%), 100% output was used throughout. The delay between the visual and magnetic stimuli was precisely determined. Immediately after presentation of one slide, the subjects were asked to report the letters they had seen. Right and left eyes were tested separately, varying the

VISUAL SUPPRESSION BY M A G N E T I C S T I M U L A T I O N

261

delay from 20 to 140 msec (up to 180 msec in some patients) in steps of 10 msec in randomized order. Three slides were presented for each delay, resulting in 0 - 9 correct answers. The number of correct answers was plotted against the delay. Mathematical evaluation. To determine the delay with which suppression of visual perception was most effective, the original suppression curve was approximated by the following mathematical function: fit) = 9 - 1/(m(t - to) 2 - n). In this function, which imitates the relevant attributes of the original suppression curve, t represents the delay, f(t) the number of correctly reported letters, and m, n and to are parame-

Results

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ters that were successively modified to approximate the function to the original results. The parameter t o is of special interest as it determines the location of the minimum of the resulting approximation curve with regard to the time axis, thus characterizing the delay appropriate for the best suppression. An illustration of the method is given in Fig. 1. To determine the correlation between two parameters, the simple linear regression test was used. The U test for unpaired samples (Wilcoxon-Mann-Whitney) was used to compare the results of the patients with the control group.

50

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Fig. 2. Results derived from normal subjects using the standard protocol. Upper part: complete suppression of letter recognition at delays between 60 and 80 msec in both eyes; t o (right)= 76 msec, t o (left)= 77 msec. Subject: S.R., 24 years, male. Lower part: partial suppression of visual perception at later delays between 80 and 110 msec in both eyes; t o (right) = 100 msec, t o (left) = 94 msec. Subject: S.H., 24 years, female.

Controls In 4 cases out of 20 volunteers visual perception was not significantly affected by transcranial magnetic stimulation. In all other cases, a clear-cut suppression interval was detectable with either complete or partial suppression of the ability to report the letters correctly, depending upon the chosen delay. Representative plots of the results of 2 control subjects are shown in Fig. 2. The illustrations demonstrate two different types of visual suppression: in 10 subjects, complete suppression of visual perception could be demonstrated in association with t o of 64-83 msec (cf., Fig. 2, upper part). In the other subjects, suppression was incomplete (cf., Fig. 2, bottom part), associated with longer t o of 77-106 msec (cf., Table I). Definition of complete and partial suppression was based on the number of letters reported correctly at the minimum of visual perception. A subject was allocated to the group with complete suppression if the number of correctly reported letters was zero in at least one eye. We are aware that this definition is relative and depends upon several experimental parameters; however, it shows that the extent of suppression is related to the delay time at which suppression was most effective: the later most effective suppression occurred, the more letters were still reported correctly at the minimum of visual perception; this is reflected by the high positive correlation (r = 0.75) between the minimum number of correctly reported letters and t o (cf., Fig. 3). The subjective impressions of the subjects strongly depended upon the chosen delay time; if complete suppression was achieved in a subject with delay times around 70 msec, usually nothing or a blur was seen. In association with delay times of 100-120 msec the subjects often claimed they had seen the letters but not exactly remembered them. Delays of 120 and 130 msec often made the subjects feel that they had seen the letters twice, once before and once during or shortly after the magnetic stimulus. If this occurred, the letters were usually reported correctly; the subjects had the

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TABLE I

Minimum of correct answers

Results: healthy subjects. The results of the control subjects are subdivided into group a with complete suppression of visual percep-

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tion and group b with only partial inhibition; a and b differ with regard to the delay which provokes most effective suppression. Abbreviations: t 0, parameter indicating the delay of best suppression; minimum, number of letters reported correctly at the minimum of the suppression curve; n.d., not detectable. Name

Age

Sex

t o (msec) Left

23 25 20 23 24 22 22 24 25 23

Mean S.D.

22.1 3.5

Right

Left

Right

25 22 22 34 23 25 22 24 24 23

f m f m m f f m m m

Mean S.D.

24.4 3.6

f m m m f m f f f f

32-

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1 67 64 80 70 72 78 79 77 82 66

68 67 79 71 75 78 83 76 78 65

0 0 0 0 0 1 0 0 0 0

0 1 1 2 0 0 1 0 0 0

73.5 6.5

74.0 5.95

0.1 0.32

0.5 0.71

3 9 4 9 1 3 7 6 3 8

4 8 3 8 3 3 8 6 3 8

(b) Partial suppression C.B. F.K. G.W. H.M. I.P. M.B. S.A. S.H. S.N. S.Re.

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(a) Comp&te suppression H.P. K.P. K.S. O.K. S.K. S.Ka. S.L. S.R. U.H. U.S.

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Fig. 3. Each dot represents the experimental result of one eye of the control group with regard to t o (x-axis) and to the minimum number of letters still reported correctly at the minimum of the suppression curve (y-axis). The later most effective suppression occurs, the more letters are still recognized correctly at the minimum of visual perception (r = 0.75).

In 4 subjects the experiment was additionally performed with both eyes open; as expected, the parameter t o was not influenced by this change. However, the extent of suppression as defined by the number of errors made in reproducing the letters was reduced, resulting in flattened suppression curves. This effect might be caused by higher redundancy of the visual

to[mS]; right eye

94.2 10.7

92.0 8.2

5.6 3.2

5.6 2.7

110

81.25 13.05

80.75 11.17

2.85 3.57

3.05 3.24

100

Entire control group (a and b) Mean S.D.

23.75 2.75

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impression that they clearly recognized the letters when appearing for the second time. This impression was often spontaneously reported by the subjects. Upon closer investigation, nearly all subjects reported this observation. Both illustrations of Fig. 2 show 2 different suppression curves, reflecting the separate testing of the left and right eyes of each subject. The considerable congruence of the curves observed in all healthy subjects is also expressed by the very high intraindividual correlation (r --- 0.9) of the t o values calculated for the left and right sides (cf., Fig. 4). The intraindividual reproducibility of the method was also confirmed by the repeated examination and calculation of t o of 3 eyes by different examiners on different dates. The results were as follows: subject K.P., right eye, t o = 6 7 / 7 2 / 6 9 msec, left eye, t o = 6 4 / 7 1 msec; subject U.S., left eye, t o = 6 6 / 6 9 msec.

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t0[ms]; left e y e Fig. 4. The dot plot demonstrates the very high (r = 0.9) correlation between the t o values obtained from the left and the right eye of each control subject; each dot represents one subject and indicates the t o value calculated for the left and the right side.

VISUAL SUPPRESSION BY MAGNETIC STIMULATION i n f o r m a t i o n , e.g., by s p a t i a l l y a n d t e m p o r a l l y e x t e n d e d r e p r e s e n t a t i o n of t h e visual i n f o r m a t i o n in t h e visual cortex. It is p r o b a b l e t h a t a h i g h e r m a g n e t i c stimulus intensity is n e c e s s a r y to extinguish t h e i n f o r m a t i o n t r a n s m i t t e d by two eyes r a t h e r t h a n by one. T o d e t e r m i n e to w h a t e x t e n t t h e i n t e r i n d i v i d u a l d i f f e r e n c e s c o n c e r n i n g t h e e x t e n t of s u p p r e s s i o n a n d t o a r e r e l a t e d to e x p e r i m e n t a l conditions, we r e t e s t e d 2 subjects with early c o m p l e t e s u p p r e s s i o n , successively r e d u c i n g the m a g n e t i c stimulus intensity. R e d u c t i o n from 100 to 90% led to i n c o m p l e t e s u p p r e s s i o n a n d to a s u d d e n shift o f t 0 f r o m 69 to 86 msec. F u r t h e r r e d u c t i o n to 80%, however, d i d n o t result in f u r t h e r i n c r e a s e o f t o . A t 75% stimulus intensity, no d e t e c t a b l e effect r e m a i n e d . A m o n g v a r i o u s factors t e s t e d in p i l o t e x p e r i m e n t s for t h e i r i n f l u e n c e o n t h e results, t h e b r i g h t n e s s o f t h e visual stimulus p r e s e n t e d t u r n e d o u t to b e critical for the d e l a y of m o s t effective s u p p r e s s i o n . This o b s e r v a tion was e x a m i n e d f u r t h e r in 2 h e a l t h y subjects: the b r i g h t n e s s o f the l e t t e r s was r e d u c e d by inserting a grey filter into the t a c h i s t o s c o p e . T h e r e d u c t i o n o f t h e b r i g h t n e s s o f the l e t t e r s alone, however, w o u l d dec r e a s e t h e c o n t r a s t o f t h e visual stimulus with a consecutive inability o f the subjects to r e c o g n i z e t h e tachistoscopic letters; thus t h e b a c k g r o u n d i l l u m i n a t i o n o f the s c r e e n was r e d u c e d s i m u l t a n e o u s l y to k e e p the contrast constant; t h e c o n t r a s t was m e a s u r e d as d e s c r i b e d above. G i v e n t h e s e c h a n g e s o f t h e visual stimulus, t h e ability o f the subjects to r e p o r t t h e visual stimulus without magnetic stimulation remained unaltered. H o w e v e r , the m a x i m u m o f visual s u p p r e s s i o n was shifted to c o n s i d e r a b l y l a t e r times. In o n e subject (H.P., 23 years, f e m a l e , right eye), t 0 was p r o l o n g e d f r o m 68 to 94 msec. In the o t h e r subject t e s t e d this way (S.L., 22 years, f e m a l e , left eye), t h e p r o l o n g a t i o n of t o was f r o m 79 to 93 msec. In an a d d i t i o n a l e x p e r i m e n t t h e i n f l u e n c e o f t h e d u r a t i o n o f t h e visual stimulus was e x a m i n e d . F o r t h a t p u r p o s e , its d u r a t i o n was successively p r o l o n g e d u p to 100 m s e c using the d e l a y t i m e t h a t h a d p r o v o k e d o p t i m u m s u p p r e s s i o n in the subjects. Successive p r o l o n g a t i o n o f visual p r e s e n t a t i o n led to a g r a d u a l l y d e c r e a s i n g n u m b e r of e r r o r s in r e p r o d u c i n g the letters. T h e longest d u r a t i o n o f t h e visual stimulus was d e t e r m i n e d that c o u l d still b e c o m p l e t e l y s u p p r e s s e d . G i v e n the e x p e r i m e n t a l c o n d i t i o n s d e s c r i b e d above, this d u r a tion was f o u n d b e t w e e n 1 a n d 4 m s e c in t h e 4 subjects tested. Visual stimulus p r e s e n t a t i o n for l o n g e r t h a n 4 m s e c m a y i n d u c e n e u r o n a l activity in l a r g e r cortical a r e a s for a l o n g e r p e r i o d o f time. Thus, t h e s u p p r e s sion of visual p e r c e p t i o n by a single m a g n e t i c stimulus can fail for 2 reasons: t h e s p a t i a l e x t e n s i o n o f the stimulus m i g h t b e t o o small or its d u r a t i o n t o o short. W i t h i n a r a n g e f r o m 5 to 100 m s e c o f visual p r e s e n t a -

263 tion, m a g n e t i c s t i m u l a t i o n still e x h i b i t e d an effect which was i n c o m p l e t e ; in o n e subject, w h o was very susceptib l e to t h e m a g n e t i c stimulus, p a r t i a l s u p p r e s s i o n was still o b s e r v e d at 100 m s e c d u r a t i o n . Owing to t h e large n u m b e r of stimuli r e q u i r e d to prove the significance o f a slightly i n c r e a s e d e r r o r rate, we r e s t r i c t e d o u r experim e n t s to d e t e r m i n e the d u r a t i o n o f p r e s e n t a t i o n t h a t c o u l d b e totally s u p p r e s s e d .

Patients T h e 15 p a t i e n t s e x a m i n e d in this study s h o w e d diff e r e n t p a t h o l o g i c a l c o n d i t i o n s of t h e i r visual p e r c e p tion as follows. (1) C o m p l e t e inability to r e a d the l e t t e r s even if p r e s e n t e d for i n d e f i n i t e d u r a t i o n w i t h o u t s u b s e q u e n t m a g n e t i c stimulation. This was possibly, e.g., owing to loss o f visual acuity or d u e to a visual field defect. (2) Inability to r e c o g n i z e the letters without s u b s e q u e n t m a g n e t i c s t i m u l a t i o n if p r e s e n t e d for a t a c h i s t o s c o p i c d u r a t i o n . In t h e s e cases we d e t e r m i n e d the m i n i m u m d u r a t i o n of p r e s e n t a t i o n which was necessary to m a k e t h e r e c o g n i t i o n of the l e t t e r s possible. V a r y i n g interindividually, this d u r a t i o n was f o u n d to be TABLE II Results: patients. The table shows the results of the patients with regard to the VEP latency (P100) and the approximated delay of maximum visual suppression (to). The prolongation of t o is closely correlated to the VEP latencies. Abbreviations: MS, diagnosis of MS, according to the diagnostic criteria of Poser (1983); p., probable; d., definite; to, approximated value of the delay of best suppression; n.d., not detectable. Name

Age

Sex

MS

A.E. A.N. A.P. G.L. H.A. H.K. H.Ko. H.P. K.R. K.S. M.O. O.T. S.K. N.A.H. P.T.

34 22 26 30 25 21 19 38 24 23 27 26 37 27 35

m f m f f m f m f m f m f f m

p. d. d. d. p. p. p. p. p. p. p. p. d. d. d.

Mean S.D.

27.6 5.9

VEP (Pl00)

t o (msec)

Left

Right

Left

Right

105 118 132 142 148 135 135 118 131 102 112 127 149 n.d. 4 n.d. 4

114 133 141 n.d. 4 107 117 123 108 118 123 144 n.d. 4 152 130 125

73 83 n.d. 2 141 n.d. 2 100 89 n.d. 3 128 99 79 87 132 88 n.d. 1

95 121 129 n.d. n.d. 3 84 94 n.d. 3 114 99 n.d. 2 89 129 103 n.d. 2

127.2 15.3

125.8 13.8

99.9 23.2

105.7 16.5

1 Unable to read the letters even if presented for indefinite duration without subsequent magnetic stimulation (e.g., owing to a scotoma or loss of visual acuity). 2 Unable to recognize the letters if presented for a duration shorter than 300-600 msec without magnetic stimulation. 3 High error rate in reporting the letters with subsequent magnetic stimulus over a wide range of delays; no clearcut suppression interval detectable. 4 Deformed potentials.

264

H. M A S U R E T AL.

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.

Fig. 5. These plots demonstrate the results of 2 patients in whom t o could be calculated for both eyes. U p p e r part: patient H.K., 21 years, male. t o (left)= 100 msec, t o ( r i g h t ) = 8 4 msec. The suppression interval seems to be extended over a wider range of delays than in the healthy subjects. Lower part; patient S.K., 37 years, female, t o (left) = 132 msec, t o (right) = 129 msec.

in healthy subjects. Fig. 5 illustrates the suppression curves of 2 patients. To verify the statistical significance of this observation, the group of patients was compared with the control group. To build up the sample of the patient group, t o of one eye of each patient was chosen as follows: for the comparison we took into account t 0 of the clinically affected eye; when both eyes were clinically affected, the more affected eye (with respect to the VEP) was chosen for the comparison. This sample was compared with 3 different control samples built up as follows: (1) the left eyes of all control subjects with a detectable t o (mean: 81.25 msec); (2) the left eye of each control subject of the subgroup with complete suppression (mean: 73.5 msec); (3) the left eyes of the subjects with partial suppression and a detectable t o (mean: 94.2 msec). The mean of the patient sample (111 msec) exceeds the mean of all control samples described; the difference is statistically significant when comparing the patient sample with the whole control group 1 ( P < 0.01) (cf., Fig. 7) or the subgroup with complete visual suppression 2 ( P < 0.01). The difference between patients and subgroup with incomplete suppression 3 is not significant (probably due to the small number) but shows a clear tendency. The result was the same when the patient sample was compared with control samples built up with the right eyes of the control subjects. Furthermore, the values of t o were compared with the VEP latency (P100) recorded from the corresponding eye of the patient. In 2 eyes with a detectable t o it was not possible to determine a VEP latency due to deformed potentials. Thus the simple linear regression analysis was performed with 19 pairs of t o vs. VEP

to[mS] 150 140

between 300 and 600 msec. (3) High background failure to report the letters correctly when tested with subsequent transcranial magnetic stimulation resulting in the lack of a clearcut suppression interval (cf., Table II). In some patients, the pathological condition of visual perception varied considerably from side to side. Thus the right and left eyes of the patients had to be regarded separately. Out of 30 eyes investigated, 2 eyes fell into category 1, 4 into category 2, and 3 into category 3, so we were not able to determine the parameter t o in 9 eyes. The resulting values of t o of the remaining 21 eyes were compared with the t o of the healthy subjects. In 7 eyes, t o exceeded the highest value detected in a healthy subject. This indicates that in the patients with prolonged VEP latencies, the delay to achieve maximum visual suppression is longer than

130 120 110 100 9O 8O 7O 100

110

120

130

140

l

150 160 VEP (P 100) [ms]

Fig. 6. Each dot represents one eye of a patient in whom VEP (Pl00) and t o could be determined; the line demonstrates the linear regression. The value of t o correlates with the VEP latency of an eye (r = 0.74). T h u s the neuritis of the optic nerve not only provokes a VEP prolongation but also leads to an increase of the delay of best suppression as detected by the experiment described in this study.

VISUAL SUPPRESSION BY MAGNETIC STIMULATION [ms] 140130 120 110 100 9O 80 7O 6O Patients (n=11)

Controls (n=16)

Fig. 7. Comparison between the t o values (delay of maximum suppression) of the right eye in healthy volunteers and the affected eye in patients with neuritis of the optic nerve. Box-and-Whisker plot representing the median (horizontal line), lower and upper quartile (box), and the range (vertical line) of the distribution. Significant difference P < 0.01.

latency (Fig. 6). The value of t o proved to be closely related to the pathological V E P prolongation of the patients (r = 0.74). In contrast to the prolongation of t 0, reflecting a later maximum of suppression in the patients, the onset of visual suppression in some patients seems to resemble that observed in healthy subjects (cf., Fig. 5, u p p e r part). A late maximum of visual suppression associated with normal onset is characterized by a suppression interval which seems to extend over a wider range of delays than in the healthy subjects.

Discussion As previously shown by Amassian et al. (1989), this study confirmed that transcranial magnetic stimulation can interfere with visual perception if applied after a visual stimulus of short duration, depending upon the delay between visual presentation and magnetic stimulus. As a result of the observation that the localization of the suppressed letter is related to the exact MC location over the occiput, Amassian concluded that there was an effect on the calcarine cortex and its projection system. By the investigation of different parameters influencing visual perception and its suppression by MC stimulation and by studying changes in visual suppression in patients with optic neuritis, we can confirm and extend the findings of Amassian et al. (1989). We found that the suppression of visual perception depends upon visual (e.g., brightness, duration) and mag-

265 netic (e.g., intensity) stimulus conditions. Compared to the normal subjects, the delay necessary to achieve maximum suppression was significantly prolonged in the group of patients. This prolongation closely correlated with the V E P latency (P100) of the patients. The mathematical method, and especially the formula we have chosen to describe the results, may appear arbitrary; we are aware that it does not provide a full characterization of the results. It was rather our major concern to extract the key p a r a m e t e r - - the delay time t o - - from the raw data according to a reproducible algorithm. This should make it possible to compare the results obtained from different subjects a n d / o r under different conditions. The function chosen to approximate the results shares the relevant attributes of the original curve. These are: (1) convergence to 9 ( = maximum number of correct answers) for very short and very long delays; (2) presence of a minimum whose depth, width and location with regard to the time axis are determined by 3 parameters which are adjusted to obtain the best possible adaptation of the approximation curve to the original data. The approximation function was adapted to the original suppression curve by minimizing the mean square deviation from the corresponding data. Under these conditions the particular approximation formula is not critical for the resulting value of t o. A major advantage of the method described is that all raw data influence the resulting value of to; in addition, the method fulfils the requirement of being more sensitive to the data close to the minimum than to single outlyers, especially if they are located far from the minimum. As in the study of Amassian et al. (1989), our subjects reported contractions of facial, masticatory and neck muscles as undesirable effects of the magnetic stimulation. Furthermore, orbicularis contractions and involuntary eye movements might occur as a result of the magnetic stimulus. However, we do not think that these possible side effects might interfere with our results: given a visual presentation of 1 msec and a delay time of 70-100 msec before the magnetic stimulus is applied, eye movements or orbicularis contractions (e.g., blink reflex) elicited by the MC cannot be expected to occur earlier than 80-110 msec after receiving the letters. By then, the retinal processing and transmission of the visual stimulus to the cortex should be mostly completed. Our findings differ from the results of Amassian et al. (1989) with respect to the delay that is required to obtain most effective suppression. We have demonstrated that reducing the luminance of the visual stimulus while maintaining its contrast induces an increase of t o. This observation is in analogy with the fact that

266 reducing the brightness of the visual stimulus in VEP measurements leads to increasing P100 latencies. It might be interpreted as a consequence of a summation process at the retinal synaptic level: higher stimulus intensity leads to faster summation at the single synapses and thus faster transmission. Furthermore, it is in accordance with the fact that luminance-dependent retino-calcarine channels propagate faster than the contrast-dependent ones: when reducing the luminance of the visual stimulus, the rapid luminance-dependent channels cannot come into effect, and the more slowly acting contrast-dependent channels have to play the main part in the transmission of the stimulus to the visual cortex. These considerations must be taken into account when one compares results derived under different visual stimulus conditions and might explain the above-mentioned difference of our results from those of Amassian et al. (1989). Furthermore, based on the interindividually different results in the healthy subjects and on the intraindividual influence of the magnetic stimulus intensity, we distinguished between early and late visual suppression. These results and also the described reports of the subjects hint at the inhibition of the visual process at at least two different levels, representing early and late processing of visual information. Early complete suppression of visual perception - - if at all achieved in a subject - - requires high stimulus intensity, thus pointing to a deep localization of the involved anatomical structure with regard to the head surface. Incomplete suppression at longer delays seems to reflect stimulation of a site which is related to the cognitive processing of the visual stimulus and to be more susceptible to the magnetic pulse, possibly due to its being located more superficially. A dual process was also suspected by Amassian et al. (1989), taking into account the subjective reports of his subjects. Our data confirm and verify this assumption. In 4 out of 20 healthy subjects, no visual suppression could be elicited by the magnetic stimulus. To explain this observation, anatomical reasons appear most likely to us. According to anatomical textbooks (e.g., Zille 1987), the localization and size (20-45 cm 2) of the primary visual cortex (area 17) vary considerably, due to the evolution of the brain during which ontogenetically new areas expand at the expense of more primitive functional structures. Concerning the visual system, most of the primary visual cortex has been shifted to the medial surface of the occipital lobe by associative areas like areas 18 and 19. Hence only a small, interindividually variable part of area 17 is situated on the occipital surface of the hemisphere close to the head surface; its major part is located far from the stimulating coil and is also orientated orthogonally with respect to it. Both reasons

H. MASUR ET AL. might contribute to a low, but interindividually variable noninvasive responsiveness of this structure. A similar situation is found in the magnetic stimulation of the motor cortex: eliciting an MEP response in the lower limbs, whose cortical representation is known to be situated on the medial surface of the hemisphere, requires higher stimulus intensities than MEP responses in the upper limbs. Among the pathological changes observed in the patients, the prolongation of the delay which is required to obtain the most effective suppression seems to be most remarkable; the correlation of t o with the prolonged VEP of the patients (Fig. 6) leads to the conclusion that both methods detect the same or a similar parameter which is related to the conduction time of the visual pathways. Our findings agree very well with the hypothesis that the neuritis of the optic nerve produces a delay and a desynchronization of nerve action potentials in the damaged or altered conducting nerve fibres and demonstrate that these pathological changes can be detected by the method described in this paper. Given the different conduction speeds of affected and unaffected fibres, the transmission of a visual stimulus extends over a longer period of time; hence the normal onset of visual suppression in some patients might reflect suppression of information transmitted by normal, unaffected fibres. In patients with late onset of suppression, the ratio of unaffected to affected fibres might be too low to transmit an early suppressible signal. Thus it may be presumed that the delayed conduction of the affected fibres causes the shift of the suppression interval to a longer delay whereas the desynchronization is responsible for the increased width of the suppression interval. Examination of the patients was made more difficult by the restricted ability of some patients to recognize the visual stimulus; on the other hand, in two cases the experiment led to interpretable results whereas the VEP latency could not be recorded owing to highly deformed potentials. Four patients were able to read the letters if presented for indefinite duration but failed to report them correctly if they were shown tachistoscopically for 1 msec, even without subsequent magnetic stimulation. In 3 eyes we were able to determine the critical duration of presentation that was necessary to allow correct recognition of at least 7 out of 9 letters. In patient P.T. (right eye), this duration was 600 msec, in patient A.P. (left eye) 500 msec and in patient M.O. (right eye) 300 msec. Possibly the reduced ability to recognize brief visual stimuli even without subsequent magnetic stimulation is attributable to the desynchronization of the visual information caused by the optic neuritis. Furthermore, with fewer fibres operating, temporal might have to replace spatial coding in order to extract the appropriate signal/noise ratio. In

VISUAL SUPPRESSION BY MAGNETIC STIMULATION

some cases, however, it might also be the result of reduced visual acuity or a scotoma so that the individual has to perform several eye movements to receive all letters. Further investigations should be performed to answer the question of how far the observed pathological changes correlate with the process of the disease, as defined by the corresponding clinical and neurophysiological parameters. We do not expect that the experimental principle described will replace the VEP examination in clinical routine use; however, a parallel examination of visual acuity, visual field, VEP latencies and the suppression of visual perception by transcranial magnetic stimulation several times during the course of the disease might be useful to clarify the underlying pathophysiological mechanism of the disorder; up to now it remains unclear why in some cases the clinical symptoms subside whereas the VEP latencies remain prolonged (and vice versa). One cannot necessarily expect that the VEP (P100), visual acuity and t o of visual suppression will correlate throughout the course of the disease. These investigations might contribute to a solution of the problem as to whether the experiment described provides an additional parameter to monitor the course of the neuritis of the optic nerve. Apart from these clinical aspects, transcranial magnetic stimulation seems to be of considerable value in the examination of different basic mechanisms of visual perception. We would like to thank Dipl. Phys. U. Nierste, Department of Physics, University of Wiirzburg, and Dr. A. Heinecke, Institute of Biomathematics, University of MOnster, for constructive contributions to the mathematical method described in this paper. We are grateful for the linguistic advice of Dr. D.L. Simpson, Department of English, University of Miinster.

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