New method for titrating differences in scalp topographic patterns in brain evoked potential mapping

Electroencephalography and clinical Neurophysiology, 1989, 74:359-366

359

Elsevier Scientific Publishers Ireland, Ltd. EVOPOT 02311

New method for titrating differences in scalp topographic patterns in brain evoked potential mapping ~ John E. Desmedt and Vincent Chalklin Brain Research Unit, University of Brussels, Brussels 1000 (Belgium)

(Accepted for publication: 16 May 1989)

Summary A method is described for computing a Z estimator for the quantitative comparison of topographical patterns m 2 maps. Z can assume values between 1 and - 1 . The procedure is illustrated on a 3-shell head model for different configurations of current dipoles in the head space. The sensitivity of Z estimation can be adjusted by different weighting procedures or by using an average reference. When Z = I indicates identity of the set of active dipoles in the 2 maps compared, a dilation factor can be computed to estimate the enhanced or reduced activity of these generators. Key words: Mapping; Comparison of topographic patterns; Average reference; Somatosensory evoked potentials

W h e n assessing b i t - m a p p e d scalp p o t e n t i a l s acquired u n d e r different c o n d i t i o n s (say in p a tients vs. n o r m a i s ; left o r right s t i m u l a t i o n ; d r u g o r a t t e n t i o n effects), a m a j o r q u e s t i o n is w h e t h e r a n y given c o m p o n e n t b e i n g c o m p a r e d in the different m a p s m a y a c t u a l l y reflect similar or different sets of neural g e n e r a t o r s ( L e h m a n n 1972; D a r c e y et al. 1980; C o p p o l a et al. 1982; D e s m e d t a n d N g u y e n 1984; G e v i n s 1984; D e s m e d t a n d Bourguet 1985; G i a r d et al. 1985; D e i b e r et al. 1986; D e s m e d t et al. 1987a; Perrin et al. 1987). T h e reason for d o i n g d e t a i l e d scalp m a p p i n g is o b v i o u s l y to e n h a n c e the c a p a c i t y for revealing characteristic t o p o g r a p h i c signatures of the underlying neural generators. Evoked p o t e n t i a l profiles involve m a n y c o m p o nents (Picton 1988) a n d their reliable a s s e s s m e n t in p r a c t i c a l studies is an urgent issue that c a n n o t wait until a c o m p r e h e n s i v e m o d e l i n g of the

i This research has been supported by the Fonds de la Recherche Scientifique M6dicale, Belgium. Correspondence to: Prof. John E. Desmedt, Brain Research Unit, 115 Boulevard de Waterloo, Brussels 1000 (Belgium).

e q u i v a l e n t d i p o l e sources has been c o m p l e t e d . T h e wealth of t o p o g r a p h i c i n f o r m a t i o n a v a i l a b l e in scalp m a p s c a n n o t b e fully assessed by mere visual i n s p e c t i o n b u t requires q u a n t i t a t i v e i n s t r u m e n t s which are still wanting. O n e a t t e m p t in this direction is the l o c a t i o n of m a x i m u m a n d m i n i m u m values of p o t e n t i a l fields ( L e h m a n n a n d S k r a n d i e s 1980, 1984) to d e f i n e e p o c h s of stable spatial c o n f i g u r a t i o n s but this a p p e a r s i n a d e q u a t e for assessing c o m p l e x p o t e n t i a l fields. This p a p e r describes a numerical e s t i m a t o r Z c a l c u l a t e d on p a i r e d p o t e n t i a l values at all scalp l o c a t i o n s at each chosen time. It expresses the i n s t a n t a n e o u s t o p o g r a p h i c congruities of 2 m a p s b y a n u m b e r b e t w e e n 1 and 1 that can be followed a l o n g time. Z = 1 when the 2 topog r a p h i c p a t t e r n s are identical, even though their a b s o l u t e voltages might differ by a dilation factor which will be e s t i m a t e d . Z = 1 when the 2 m a p s have reverse or m i r r o r t o p o g r a p h i c patterns. The Z values b e t w e e n 1 a n d - 1 titrate the difference in t o p o g r a p h i c p a t t e r n s between the m a p s at the time c o n s i d e r e d . T h e m e t h o d will be d o c u m e n t e d b y c a l c u l a t e d p o t e n t i a l d i s t r i b u t i o n in a 3-shell h e a d m o d e l ( R u s h and Driscoll 1968) for different d i p o l e generators.

0168-5597//89/$03.50 © 1989 Elsevier Scientific Publishers Ireland, Ltd.

360

Methods In this article we wish to describe the Z estimator and show some of its features independently of effects resulting from the number and position of electrodes or from errors in measuring electrical potential, hence the use of a theoretical model of the head as a sphere with 3 concentric shell structures consisting of a homogeneous sphere of neural tissue surrounded by 2 spherical shells representing the skull of low conductivity and the scalp of similar conductivity as the inner sphere. The outer medium (air) has zero conductivity. With this model and the knowledge of the dipole char-

J.E. DESMEDT, V. CHALKLIN

acteristics, the electromagnetic theory gives the possibility to determine the electrical potential at all points in space (Rush and Driscoll 1968; Kavanagh et al. 1978; Ary et al. 1981; Nunez 1981; De Munck et al. 1988). Electrical potential values were computed at 45 'electrode' sites spread uniformly on a 2-dimensional radial projection of the upper half head surface. This number is adequate to delienate topographic details of the model and avoids long computation delays. One or more dipoles were inserted in the head space. They are described by their polar coordinates: r 1 (radius times eccentricity), 01 (vector angle from the vertical), and q~l (vector angle from the transverse vertical plane), while the orientation is defined by polar angles (02, if2) in a local coordinate system such that 02 = 90 ° for a tangential dipole and 0z = 0 ° for a radial dipole (Fig. 1).

Results and discussion

Fig. 1. Coordinate system for defining dipoles position and orientation in the spherical head model.

The search for an estimator was guided by a few simple requirements, such as to have a convenient range of values (between 1 and - 1). Each set of potential measures at the n electrodes of a m a p was interpreted as a resultant vector in a space with n dimensions (see Appendix). The sets of potential measures of 2 maps were compared by calculating the cosine of the angle between the 2 corresponding vectors in that space. The angle between the 2 vectors reflects differences in the number, locations a n d / o r orientations of the generators involved but not the size of the resultant vectors.

Fig. 2. A-B: topographic maps based on 4800 pixels calculated for different positions and intensities of a tangential dipole (A) or dipoles of different characteristics (B) as defined in Table I. C: Z estimations (ordinate) for comparisons of dipoles A1-A6 with dipole A1. D: Z for comparisons of dipoles B7-B12 with dipole A1. Fig. 4. A: topographic maps for 6 different orientations of a tangential dipole rotating through 360 ×. B-D: Z estimations (ordinate) for comparisons of the dipoles with the first, using uniform (B), product (C) or inverse product (D) weighting. Fig. 7. A: topographic maps (distant reference) resulting from the same dipole shown in Fig. 4A with addition of a 5 times stronger deep radial dipole. B-D: Z estimations (ordinate) for comparisons of the dipoles with the first, using an average reference. E-G: same estimations using a distant reference. The weightings used are uniform (B, E), product (C, F) or inverse product (D, G).

COMPARISON OF SCALP TOPOGRAPHIC PATTERNS

36

FIGURE 2

================================= ..................................

........ ':::i::i .......... ...........

FIGURE 4

.......... O"

60"

/-i

20"

8"

240"

30 °

:

:

:

:

O"

....... ......

60"

120"

180"

240"

:

:

"

:

3OO"

*

300"

O"

FIGURE 7

-1 B

C

:l;y ............... -NI?

2;---2:-2--o......

D

:

:

:

:

:

.......-.......

Y-22-2Z; :--i.

362

J.E. D E S M E D T , V C H A L K L I N

The following weighting procedures will be considered: Uniform p i = l . 0 V i = l . . . . . n.

TABLE I C h a r a c t e r i s t i c s of dipoles in Fig. 2. Dip.

Ampl.

Ecc.

O]

~]

~b2

02

A1

1

0.6

0°

0°

90 °

0°

A2 A3

2 0.5

0.6 0.6

0° 0o

0° 0o

90 ° 90 o

0° 0o

A4

-1

0.6

0°

0°

90 °

0°

A5

-2

0.6

0°

0°

90 °

0°

A6

-0.5

0.6

0°

0°

90 °

0°

B7

- 1

0.6

45 °

0o

90 o

0o

B8 B9

1 1

0.6 0.7

45 ° 45 o

0° 225 o

0° 90 o

0° 0o

B10 B11

1 1

0.2 0.6

0° 60 o

0° 90 o

0° 90 °

0° 90 o

B12

1

0.6

45 °

135 °

90 °

90 °

Product Pi = ] f i ' g i I Vi = 1 . . . . . n. Inverse product p i = l . 0 / l f i ' g i l iflfi .gil >~ 0.1; Pi = 10.0 if I f i ' g i I < 0.1. In order to incorporate the weights, formula (1) must be changed into rl

Y'. Pifigi Z =

i=t E Pifi 2 i=l

A

Basic" formula L figi

:t
(l)

=

Pig~ i=l

electrodes xa

z

(2)

xd

,,+

•1

ex

2•

2

%

n) are the 2 measures to

compare such that ( ~

fi2) 1/2 • 0 and ( ~

13

i=l

n

"2

s

3

i=l

Weights of electrodes The sensitivity of the Z estimator to certain differences in topographic patterns may be enhanced by changing the weights of the electrodes.

3

.2 Pi

z

5

Pi'fi.g~

B "2

gi2)b~2

• 0, and n is the number of electrodes (45 in this paper). The sensitivity of Z to topographic patterns but not to amplitude is illustrated by comparisons of maps produced by tangential dipoles of 0.6 eccentricity (Fig. 2Al-A6). Z = 1 (Fig. 2C) when the maps compared to A] are generated by a dipole with double (A2) or half (A3) amplitude. Z = - 1 when maps generated by tangential dipoles of reverse polarity, irrespective whether the amplitude is equal (Fig. 2A4), double (As) or half (A6) are compared with A v Z values range between 1 and - 1 (Fig. 212)) when for comparing with A] a series of maps produced by dipoles of amplitude = 1 but with various characteristics as those defined in Table I.

5"

1

5 WEIGHTS

where fi, gi (i = 1 . . . . .

potential 2 (g,)

potential 1 (f,)

bx

1

UNIFORM

1+

.a

t

C PRODUCT

*2

.2

+. 10.

II~

9 35

;.5

o"1

3~

35.

1oo"

35.

,o

1O"

4

82 ~22s

D INVERSE PRODUCT

o.5

0~1

I

0.0e29

21 0.0.29

I

,i

to

Fig. 3. W e i g h t i n g p r o c e d u r e s a p p l i e d to a simple set of 7 electrodes (labeled a - g ) with p o t e n t i a l values s h o w n for 2 m a p s to be c o m p a r e d (A). B: u n i f o r m weighting. C: p r o d u c t weighting. D: inverse p r o d u c t weighting. T h e d a t a in the c o l u m n on the right side show the c o n t r i b u t i o n of each of tile 7 electrodes to the n u m e r a t o r of the Z e q u a t i o n w h e n a p p l y i n g the d i f f e r e n t weights.

COMPARISON OF SCALP T O P O G R A P H I C PATTERNS

363

where p, are n non-negative real numbers such t h a t ( Y'. ° pifi2)I/2 e: 0 and ( i=l

L

DISTANT

pig,)l/2 #: 0.

Z=0.8

~ e)ect rode 2

I

i=]

In a simple example (Fig. 3), the maps to be compared are represented by 2 sets of 7 electrodes

M-25YR$

REFERENCE

A MESURE MEAN

1 1.5

b

NC REF

N,.4163

i

electrode 1

~y FINGERS l-If AVERAGE

REFERENCE

[]

Z=-I

/IX i

2o

i

,

I

p.22/.

\

I

MESURE

I[ I

d",, i

!

~e5

MESURE

2

I

05

- -1W--' -0.

1

-05 '

I I I I

Fig. 6. Effect of an average reference on Z illustrated by comparing maps represented by only 2 electrodes with a positive potential value• A: distant reference, potential values of 1 and 2 in the first map and of 2 and 1 in the second map. B: with the average reference the potential values change to 0.5 and - 0 . 5 while Z changes from 0.8 to - 1, [ R~. PARIETAL

•

,

,

;

,.

,

,

,

,

.

D L~ PARIETAL

/

= R~ P REROL

I,.

~

I

do,, \ v

I~

X

I

I

'

,

Fig. 5. Somatosensory evoked potentials to electric stimulation of left fingers 1-I1 recorded with a non-cephalic ( A - C ) or with an average (D F) reference based on the 2"I electrodes recorded (data from Desmedt et al. 1987a). The subcortically generated P14 farfield and N18 prolonged negativity' seen with non-cephalic reference recording are eliminated by average reference recording. A new positive wave with peak at 33 msec appears in the ipsilateral parietal trace (D).

for whom arbitrary potential values are indicated (Fig. 3A). The m a x i m u m potential (7) occurs at electrode g in map 1 and e in map 2. When a uniform weight is given to the electrodes, the product of the potential at each electrode in maps 1 and 2. multiplied by the weight of that electrode. gives values varying from 2 to 35. A uniform weight thus favors in eqn. (2) the electrodes where the potential product is larger. When the weight given to each electrode is defined by the product of the absolute value at that electrode in the 2 maps. the results range from 4 to 1225 (Fig. 2C) and the electrode weights are considerably en'aanced for those with a larger potential value (right side). The relative contribution to numerator of eqn. (2) between electrodes e and b increases from 3.5 (B) to 12.25 (C). When the weight given to each electrode is defined by the inverse product of the absolute potential value at each electrode m the 2 maps. the contribution of each electrode to the numerator of eqn. (2) stays at 1 which considerably reduces the influence of electrodes with a large potential in the

364 Z equation. The maximum weight is set at 10 to avoid giving an excessive value to very small potentials. The outcome is to enhance the search for small relevant potential patterns when the latter would otherwise be obliterated by an overwhelming focal potential field. The use of different weighting procedures gives the opportunity to adapt the Z sensitivity to specific changes of the dipole parameters. A set of tangential dipoles (Fig. 4) of eccentricity = 0.6. 0~ = 60 ° were compared for the variations of ~: from 0 ° to 360°. The Z values are given for the uniform (B), product (C) and inverse product (D) weighting procedure. With uniform weighting, the Z sensitivity is proportional to the angle between the tangential dipoles (B). It is larger for the larger angles between dipoles with the product weighting (C) and for the smaller angles with the inverse product method (D). Another application of the weights is to select easily for analysis a brain region where electrogenesis is expected to be interesting, for example to study focal dipoles active in this region with reduced interference from focal dipoles located in other regions. This is achieved by drastically reducing the weight for electrodes outside the region to be analyzed in detail. Finally the weighting procedure can be used to adapt the Z sensitivity to signal-to-noise ratio. The product weight is the less sensitive to noise while the inverse product is the most sensitive to noise. A t,erage refi, rence

Using an average reference (Lehmann and Skrandies 1980; Bertrand et al. 1985; Brandeis and Lehmann 1986) introduces definite changes in the mapping condition if the mean value of the electrode potentials was different from zero when recording with another reference. For example, mapping somatosensory evoked potentials with a non-cephalic reference discloses, before the cortical P20-N20, P22, P27 and N30 responses, widespread far-field potentials such as the brief P14 or the prolonged negative N18 which are generated subcortically (Desmedt and Cheron 1981; Maugui&e et al. 1983; Desmedt et al. 1987a) (Fig. 5 A - ( ' ) . Applying the average reference to such

J.E DESMEDT, V. CHALKL1N data removes the widespread potentials and also introduces some distortion in the focally generated components. For example while the size and profile of N20, P20 and P22 are virtually not changed, the frontal N30 is somewhat reduced while the parietal P27 is increased (Fig. 5E-F). A spurious positivity appears at the ipsilateral parietal scalp (D). The explanation for these distortions is that frontal N30 field is larger than the concomitant P27 field. Taking the average potential as reference admittedly does not affect the potential differences between field extrema (P27-N30), but it changes the absolute values of potential field by a shift of the baseline at these latencies. Moreover, this negative shift fabricates a positive component at the ipsilateral parietal site where no generator is active at these latencies (Fig. 5D). The fact that an average reference can modify topographical analyses is illustrated by a simple model involving only 2 electrodes to facilitate the display of the resulting vector. With respect to a distant reference, the positive potential values are 1 and 2 and Z = 0.8 (Fig. 6A). When applying an average reference that will be at 1.5, the potential values become - 0 . 5 and + 0.5 unit respectively, giving a Z=-1 (Fig. 6B) which would imply a quite different interpretation of the same maps. These problems arise when a relevant widespread component is involved. On the other hand, the average reference may be useful when such widespread components may be disregarded in order to focus on small superficial generators which may be hidden by a larger uniform potential component. Fig. 7 includes the same set of dipoles as Fig. 4 but with the addition of a 5 times stronger radial dipole located in the lower half of the head at 0.75 eccentricity. The variations of Z values with changes of the tangential dipole are virtually obliterated irrespective of the weighting procedure used (Fig. 7 E - G ) , but they are largely recovered by applying the average reference (Fig. 7B D). Dilation f a c t o r

When comparing seemingly different maps, Z estimates the amount of difference in the underlying set of dipoles, but can also reveal that they are in fact similar ( Z = I or - 1 ) . In this case it is

C O M P A R I S O N OF SCALP T O P O G R A P H I C P A T T E R N S

useful to c o m p u t e the dilation factor ( D F ) defined as the arithmetical mean of the ratio of potential values at each electrode in the 2 maps. The D F is not applicable when Z is different from 1 for the whole map but it can be used for a selected set of electrodes to test whether focal neural generators are enhanced (Tomberg et al. 1989).

365

Therefore f = +a2g(e~¢R0)¢=~ Z =

-F1

(A 2 )

and (~a~R.

suchthat

¢ = +_a-~g)~

l
+1 (A~)

Weights Conclusion The Z estimator is easy to c o m p u t e and provides a sensitive measure of the a m o u n t of difference in topographic patterns between 2 maps. Z is quite sensitive to changes in location of extrema, even in the case of complex patterns, and can thus be expected to enlarge the range of applications of the segmentation of brain microstates along time ( L e h m a n n et al. 1987). Z can also identify widespread focal similarities in the set of generators involved in which case D F can be c o m p u t e d to estimate the enhanced or reduced activity of these generators.

Appendix Notations R R" ( (f~ . . . . . (. ~,

= set of the real numbers. = vectorial space on R with n dimensions. = a vector in R". fn) = ( represented by its c o m p o n e n t s in a basis of R n. = scalar product of ( and g; (. ~, = o

= ~ f,gi. i--1

]l f ]I R,,

= norm of f; IIf]] = (('()L~z. = R\{O}.

Basic fi)rmula Let f and g be 2 vectors of R n with I1( II ~ 0 and IIg II ~ O. W e can set

z

-

fg

- cos 0

Ilfll'llgll

where 0 is the angle in R" between f and g.

(A,)

The use of eqn. (2) instead of eqn. (1) preserves ( A z ) and (A3). Indeed it is possible to see the change from (1) to (2) as the effect of geometrical transformations (dilation of a basis vector or projection into a hyperplane). These transformations preserve (=

+ a2g

with

~-" 4= 0

if (1) p, > 0 and (2) [[f'][ : # 0 a n d Ilg'll 4 - 0 w h e r e f ' denotes the vector transformed from f.

References Ary, J.P., Klein, S.A. and Fender, D.H. Location of sources of evoked scalp potentials: corrections for skull and scalp thicknesses. IEEE Trans. Biomed. Eng., 1981. BME-28: 447 452. Bertrand, O., Perrin, F. and Pernier, J. A theoretical justification of the average reference in topographic evoked potential studies. Electroenceph. olin. Neurophysiol., 1985. 62: 462 464. Brandeis. D. and Lehmann, D. Event-related potentials of the brain and cognitive processes: approaches and applications. Neuropsychologia, 1986. 24: 151-168. Coppola, R.. Buchsbaum. M.S. and Rigal. F. Computer generation of surface distribution maps of measures of brain activity. Comput. Biol. Med., 1982, 12: 191-199. Darcey, T.M., Ary. J.P. and Fender, D.H. Methods for the localisation of electrical sources in the h u m a n brain. Prog. Brain Res.. 1980, 54: 128-134. Deiber, M.P., Giard, M.H and Maugui6re, F. Separate generatars with distinct o,:entations for N20 and P22 samarasensory evoked pol,,ntials to finger stimulation. Electroenceph. clin. Neuroph>siol., 1986.65:321 334. De Munck, J.C., Van Dijk. B.W. and Spekreijse, H. Mathematical dipoles are adequate to describe realistic generators of h u m a n brain activity. IEEE Trans. Biomed. Eng., 1988, BME-35: 960-966. Desmedt, J.E. and Bourguet. M. Color imaging of scalp topography of parietal and frontal components of somatosensory evoked potentials to stimulation of median or posterior tibial nerve in man. Electroenceph. clin. Neurophysiol., 1985, 62:1 17.

366 Desmedt, J.E. and Cheron, G. Non-cephalic reference recording of early somatosensory potentials to finger stimulation in adult or aging man: differentiation of widespread N18 and contralateral N20 from the prerolandic P22 and N30 components. Electroenceph. clin. Neurophysiol., 1981, 52: 553-570. Desmedt. J.E. and Nguyen, T.H. Bit-mapped colour imaging of the potential fields of propagated and segmental subcortical components of somatosensory evoked potentials in man. Electroenceph. clin. Neurophysiol., 1984, 58: 481-497. Desmedt, J.E., Nguyen, T.H. and Bourguet, M. Color imaging of h u m a n evoked potentials with reference to the N20, P22, P27 and N30 somatosensory response. Electroenceph. clin. Neurophysiol., 1987a, 68:1 22. l)esmedt, J.E., Tomberg. C., Zhu, Y. and Nguyen, T.H. Bitmapped scalp field topographies of early and late cognitive components to somatosensory (finger) target stimuli. In: R. Johnson, Jr., J.W. Rohrbaugh and R. Parasuraman (Eds.), Current Trends in Event-Related Potential Research. Electroenceph, clin. Neurophysiol., Suppl. 40, Elsevier, Amsterdam, 1987b: 170 177. Gevins, A. Analysis of the electromagnetic signals of the h u m a n brain: milestones, obstacles and goals. IEEE Trans. Biomed. Eng., 1984, BME-31: 833-850. Giard, M.H., Peronnet. F., Pernier, J., Maugui&e, F. and Bertrand. O. Sequential colour mapping system of brain potentials. Comput. Meth. Prog. Biomed., 1985, 20: 9-16. Kavanagh, R.N., Darcey, T.M., Lehmann, D. and Fender, D.H. Evaluation of methods for three-dimensional localization of electrical sources in the h u m a n brain. IEEE Trans. Biomed. Eng., 1978, BME-25: 421-429. l.ehmann, D. H u m a n scalp EEG fields: evoked, alpha, sleep, and spike-wave patterns. In: H. Petsche and M. Brazier (Eds.), Synchronization of EEG Activity in Epilepsies. Springer, New York, 1972:301 325.

J.E. DESMEDT. V. C H A L K L I N k e h m a n n , D. and Skrandies, W. Reference-free identification of c o m p o n e n t s of checkerboard-evoked multichannel potential fields. Electroenceph. clin. Neurophysiol., 1980. 48: 609-621. k e h m a n n , D. and Skrandies, W. Spatial analysis of evoked potentials in m a n - - a review. Prog. Neurobiol., 1984, 23: 227-250. Lehmann, D., Ozaki, H. and Pal, 1. EEG alpha map series: brain micro-states by space-oriented adaptative segmentation. Electroenceph. clin. Ncurophysiol., 1987, 67:271 288. Maugui6re, F., Desmedt, J.E. and Courjon, J. Neural generators of N18 and P14 far-field somatosensory ew)ked potentials studied in patients with lesion of thalamus or thalamo-cortical radiations. Electroenceph. clin. Neurophysiol., 1983, 56:283 292. Nunez, P.L. Electric Fields of the Brain: the Neurophysics of EEG. Oxford University Press, New York. 1981. Perrin, F.. Bertrand, O. and Pernier, J. Scalp current density mapping: value and estimation from potential data. IEEE Trans. Biomed. Eng., 1987, BME-34: 283-288. Picton, T.W. (Ed.). H u m a n Event-Related Potentials. Handbook of Electroencephalography and Clinical Neurophysiology. Revised Set. Vol. 3. Elsevier, Amsterdam, 1988. Rush. S. and Driscoll, D.A. Current distribution in the brain from surface electrodes. Anesth. Analg. Curr. Res.. 1968, 47: 717-723. Tomberg, C., Desmedt, J.E., Ozaki, I., Nguyen, T.H. and Chalklin. V. Mapping somatosensory evoked potentials to finger stimulation at interwlls of 450 to 4000 msec and the issue of habituation when assessing early cognitive components. Electroenceph. olin. Neurophysiol.. 1989, 74: 347-358.