Mapping somatosensory evoked potentials to finger stimulation at intervals of 450 to 4000 msec and the issue of habituation when assessing early cognitive components

Eh, ctroencephalography and clinical Neuropt~vsiologv, 1989, 74:347 358 Elsevier Scientific Publishers Ireland, Ltd.

347

EVOPOq[ 23100

Mapping somatosensory evoked potentials to finger stimulation at intervals of 450 to 4000 msec and the issue of habituation when assessing early cognitive components l Claude Tomberg, John E. Desmedt, Isamu Ozaki, T.H. Nguyen and Vincent Chalklin Brain Research Unit. Uniuersi(v of Bruss'el;, Brussels 1000 (Belgium)

(Accepted for publication: 16 May 1989)

SummaD Somatosensory evoked potentials (SEPs) to mild electric stimulation of two fingers of the left hand were studied tit regular interstimulus intervals (ISis) of 450, 800, 1400, 2500 and 4000 msec. Habituation was evaluated while the subject was reading a novel so as to virtually ignore the finger stimuli while maintaining steady vigilance levels. Brain SEPs recorded from 25 scalp electrodes were assessed by scatter displays, electronic subtraction, bit-mapped potential fields, and by calculating the Z estimator and dilation factor. Similar results were obtained with randomly varying ISis. The P14 farfield and cortical N20 did not change with ISis. The parietal P27-P45 decreased at ISis of 800 and 450 msec, but showed no significant habituation at ISis of 1400, 2500 or 4000 reset. This validated the control conditions used for assessing the early cognitive P30 and P40 to attended target stimuli. The frontal N30 also decremented at the shorter ISis but still habituated up to ISis of 2500 msec. The clear dissociation between frontal N3(1 and parietal P27 at the larger ISis suggests that they involve at least in part distinct neural generators. Key words: Somatosensory evoked potentials: Habituation: lnterstimulus intervals: Early cognitive components: Event-related potentials

T h e a v e r a g i n g of e v e n t - r e l a t e d p o t e n t i a l s ( E R P s ) involves repeated p r e s e n t a t i o n s of sensory stimuli and the interstimulus intervals (ISis) used ma y be a critical p a r a m e t e r when assessing responses to stimuli u n d e r different a tt e n ti o n task conditions. T h e cognitive c o m p o n e n t s of E R P s to a t t e n d e d target stimuli must be identified by c o m parison with control responses to physically identical stimuli to which the subject should c o m m i t no cognitive resources w h e r e b y the u n d e r l y i n g 'exogen o u s o b l i g a t o r y ' profile can be revealed. T h e p r e c e d i n g p a p e r addressed this crucial issue in

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 R P research by d o c u m e n t i n g the responses to h o m o g e n e o u s series of identical stimuli that are neglected by the subject as h e / s h e is reading a novel, and it was a r g u e d that such responses may closely a p p r o x i m a t e to the ' n e u t r a l ' c o n d i t i o n s searched for ( D e s m e d t and T o m b e r g 1989). H o w e v e r , it is not sufficient to disengage attention from the sensory stimuli u n d e r study to obtain valid co n t r o l responses. A second r e q u i r e m e n t is that the latter must disclose the full size of the e x o g e n o u s o b l i g a t o r y profile, and it is necessary to e n q u i r e w h e t h e r the I S i s used are a d e q u a t e to av o i d h a b i t u a t i o n or rate effects which could unduly r e d u c e the responses in the co n t r o l runs. In o r d er to d o c u m e n t a g e n u i n e e n h a n c e m e n t of c o m p o n e n t s in the E R P s to target stimuli, one must exclude any u n d e r e s t i m a t i o n of the size of the e x o g e n o u s o b l i g a t o r y profile. W e are interested in this issue in c o n j u n c t i o n with the study of the very early co g n i t i v e P30, P40 and P l 0 0 c o m p o n e n t s of

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

348

somatosensory evoked potentials (SEPs) (Desmedt et al. 1983). This paper analyzes the influence of ISis in the range of 450-4000 msec on the topographic features of SEPs to electric stimulation of fingers. An important feature is that the subject's attention was disengaged therefrom and steadily focused on a reading task in order to minimize changes in subject's attitude, shifts in vigilance level or involuntary cognitive commitment to the finger stimuli.

C. T O M B E R G ET AI..

afferent conduction times related to differences in arm length (Desmedt and Cheron 1981). This electronic manipulation did not change any other feature of the responses and improved grand averages across subjects by placing early SEP components in register. Bit-mapping by spline interpolation (Perrin et al. 1987) generated frozen maps (3200 pixels) of the brain potentials with an absolute scale coded in 13 color steps with different hues of red for negative and of blue for positive (Desmedt et al. 1987). Z and dilation factors were calculated to estimate differences in topographic patterns (Desmedt and Chalklin 1989).

Methods

Procedure

Subjects Twenty-four experiments were carried out in 21 normal adult humans (9 females, age 18-24 years) in good health, free from neurological disease or drug addiction. They were paid medical students and had given informed consent. Selection criteria involved lack of excessive alpha in EEG, ability to relax and consistency in following instructions.

Stimulation and recording Square electric pulses of 0.2 msec were delivered through flexible metal ring electrodes (cathode proximal) to the left index and medius. Current intensities were carefully adjusted at 2 - 3 times the subjective threshold which was defined by the method of limits. The stimuli were not obtrusive and could be virtually neglected by the subject when he was reading a novel (see Desmedt and Tomberg 1989 for details). Brain potentials were recorded with thin sterile stainless steel needles inserted into 25 scalp sites for topographic mapping, using the right earlobe as reference. Four transverse rows of 5 electrodes (at 7 cm from each other) were located 2 and 7 cm in front of the vertex Cz or 3 and 8 cm behind Cz respectively (Fig. 1C). EEGs were monitored on 18 SC501 Tektronix miniscopes. Amplification, A / D conversion, averaging, quality controls, programming and data processing were performed on microVaxII (Digital Equipment), as in the preceding paper. For each subject the latency of all responses was shifted, when necessary, along the time scale (by up to 5 msec) to compensate for differences in

The subject lay in a comfortable chair in a sound-proofed air conditioned room. Throughout the session the subject was asked to disregard the finger stimuli and to be fully involved in reading a novel by Georges Simenon which was presented in 4 columns of 7 cm width to minimize eye movements (Desmedt and Tomberg 1989). A typical recording session of 150 rain included about 30 runs of 170 stimuli delivered at regular ISis. The runs at each of the following ISis: 450, 800, 1400, 2500 or 4000 msec were presented in random order. In a number of experiments, runs at regular ISis of 1400 msec were compared to runs at ISis varying randomly between 1100 and 1700 msec. The microVax computer stored the data of each run in 5 different files for trials 1-10, 11-20, 21-70, 71 120 and 121-170 respectively. For each subject, the off-line average at each ISI included all (accepted) trials at that ISI. In addition, separate averages were done for groups of trials according to their rank in the run (Ritter et al. 1968; Roth and Kopell 1969) to evaluate the incidence of habituation.

Results

Regular ISis The effects of the different ISis on early SEP components are shown for grand averages of the 18 experiments (Fig. 1). No significant change (Table I) is noticed for the P14 farfield thought to reflect the medial lemniscus volley (Nakanishi et

ISis AND HABITUATION OF SEP

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I Fig. 1. Grand averages of SEPs recorded at the midfront (A) and right parietal (B) electrodes {circled in the figurine in C) in 18 experiments. Electric stimulation of left fingers I I - l l l at regular interstimulus intervals (ISis) of 450, 800, 1400, 2500, and 4000 msec as indicated. C: placement of the 25 recording scalp electrodes on a 2-dimensional head projection.

al. 1978; Desmedt and Cheron 1980; Anziska and Cracco 1981; Maugui6re et al. 1983b), nor for the parietal N20 and its frontal counterpart P20 ( D e -

smedt and Cheron 1981; kueders et al. 1983: Maugui6re et al. 1983a; Deiber et al. 1986; Desmedt et al. 1987; Rossini et al. 1987). The parietal P27 and P45 are quite similar for the ISis of 1400-4000 msec, but reduce markedly at 800 and 450 msec (Fig. 1B). The frontal N30 is largest for 4000 msec and appears to reduce as ISis become shorter (Fig. 1A). Scatter displays of the grand averages at the 25 scalp electrodes (Fig. 2) indicate with thicker lines the 2 traces of Fig. 1, which indeed have the largest potential peaks between 25 and 50 reset. The display size is wider between about 80 and 130 msec and tends to flatten out thereafter. At 800 and 450 msec all traces reduce consistently and no component seems to be increased (Fig. 2D E). A curious flattening appears between about 55 and 80 msec and at 450 msec (E). Electronic subtraction by pair of these grand averages for each electrode helped clarify these effects. We chose as standard the data for 1400 msec. For 2500 minus 1400 msec, the traces remain remarkably close to prestimulus baseline up to about 130 msec (Fig. 3B). For 4000 minus 1400 msec (Fig. 3A), a clear upward (negative) deviation of several frontal traces occurs between about 25 and 55 msec without any equivalent positive deflexion. This reflects the larger frontal N30 at 4000 msec. For 1400 minus 800 msec (Fig. 3C), the difference shows both negative and positive residues at these latencies, a trend which is accentuated further in the 1400 minus 450 msec subtraction (Fig. 3D). In Fig. 3C D we subtracted the smaller grand average from the 1400 msec data to avoid reversal of polarities in the resulting difference traces.

TABLE 1

P14 N20 P27 N30 P45 N60 P100 N140 P200

1 400 ,aV

2 500 ~V

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ANOVA P

0.34 0.44 1.75 -2.15 2.19 -0.39 1.42 -0.01 0.16

0.38 - 0.44 1.80 2.34 2.16 -0.39 1.46 0.43 0.21

0.32 - 0.44 1.84 -2.63 2.21 -0.52 1.41 -0.59 0.13

> > < > > > < >

0.2 < P < 0.25 0.25 0.25 0.00l 0.25 0.25 0.25 0.05 0.25

2 500-1 400 ~V

4 000 1 400 gV

0.04 0.00 0.05 0.18 0.03 0.00 0.04 -0.42 0.05

-0.02 0.00 0.09 0.48 0.02 -0.13 - 0.01 -0.58 -0.03

4 000-2 50(1 ja V 0.06 0.00 0.04 0.29 0.05 0.13 0.05 -0.16 0.08

95 % CI #V :+-0.09 + 0.11 :+ 0.23 :±0.33 ±0.27 +0.51 + 0.46 +0.50 ÷0.57

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s i g n i f i c a n t c h a n g e s f o r N 2 0 , P27, N 6 0 , P 1 0 0 a n d

( T a b l e I a n d F i g . 4). T h e f r o n t a l N 1 4 0 w a s i n c o n s i s t e n t w i t h a m e a n v o l t a g e o f - 0 . 0 1 /~V a t 1400

P200 (the latter 3 components were not identifi-

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P14 N20 P27 N30 P45 N60 P100 N140 P200

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450-800/LV

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0.35 -0.43 0.95 - 1.30 1.I 8 -0.17 0.78 0.06 0.34

0.26 -0.42 1.26 - 1.85 1.64 -0.46 0.84 -0.02 0.31

0.34 -0.44 1.74 - 2.15 2.19 -0.39 1.42 -0.01 0.16

0.2 < P < 0.25 > 0.25 < 0.001 < 0.001 < 0.001 <0.5 < 0.001 > 0.25 > 0.25

0.09 -0.007 - 0.31 0.55 - 0.47 0.29 - 0.06 0.08 0.03

-0.004 -0.005 0.79 0.85 1.01 -0.22 0.64 0.07 - 0.19

0.08 0.012 0.49 0.30 0.54 0.07 0.58 0.01 - 0.15

±0.14 +0.12 + 0.42 + 0.41 + 0.44 ±0.30 + ().41 +0.50 + 0.51

C. TOMBERG ET AL.

352 -3

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Fig. 4. Diagram of the mean voltage of SEP components at the different regular ISis.

nificant changes for P14 and N20, but clear reductions of P27, N30, P45, N60 and P100 as ISis shorten from 1400 to 800 and to 450 msec (Table II and Fig. 4).

Scalp mapping Bit-mapped grand averages are presented as frozen maps at 5 or 10 msec intervals starting at 20 msec (Fig. 5). The normal topographies of early SEP components (Desmedt and Nguyen 1984; Desmedt and Bourguet 1985; Deiber et al. 1986; Desmedt et al. 1987) are readily identified at each ISI, suggesting that the SEP generators can be either enhanced or reduced, but apparently not changed, for different ISis. A clear enhancement of the frontal N30 without any equivalent change in the concomitant parietal positivities is observed at 4000 msec (Fig. 5A) as compared to the other ISis. This is made even clearer by subtraction mapping (4000 minus 1400) at latencies of 25-40 msec whereby the excess frontal negativities show up as a red area while the posterior scalp does not show any residual positivity and remains close to zero (Fig. 5F). This result suggests a distinct ISI sensitivity for N30 and P27-P45 respectively. By contrast, subtraction mapping of the grand averages for 1400 minus 800 msec at these latencies shows both frontal negative and parietal positive residues (Fig. 5G).

Assessment of topographic patterns Differences in topographic patterns can be estimated quantitatively by the Z estimator which

takes into account the potential values at the 25 electrodes (Desmedt and Chalklin 1989). A Z value of I indicates similarity in the set of active equivalent dipoles for the 2 maps compared. This is the case for the maps at ISis of 4000 and 1400 msec, at latencies from 25 to 65 msec (Fig. 6A). When Z = 1, it is possible to calculate a dilation factor (DF) which shows a mean enhancement by a factor of 1.2-1.4 for the 25 electrodes. When Z and D F are calculated separately for the set of frontal (Fig. 6 C - D ) or right parietal ( E - F ) electrodes, the mean enhancement increases to a factor of 1.3-1.6 for the frontal electrodes, but there is no significant change at the right parietal electrodes ( D F = 1 at latencies from 27 to 48 msec). When the 2 sets of electrodes are assessed separately, Z values are closer to 1 and the standard deviations are smaller. This is taken as strong evidence for a separate enhancement of the frontal N30 which must reflect distinct neural generators with different ISI sensitivity as compared to the parietal P27-P45. A similar comparison of the maps at ISis 800 and 1400 msec shows Z close to 1 at latencies from 25 to 65 msec (Fig. 7A). The mean D F of about 1.3 indicates larger potential values at 1SI 1400 msec. Separate calculation of D F for the set of frontal (Fig. 7 C - D ) or right parietal (Fig. 7 E - F ) electrodes shows a rather similar increase at 1.3, thus substantiating the impression that the reduction of responses at ISis of 800 msec is widely distributed over the scalp.

Irregular ISis The effect of irregular stimulus presentation was tested in 12 experiments by comparing runs with ISis varying randomly from 1100 to 1700 msec with runs at regular ISis of 1400 msec. Each run involved homogeneous series of identical finger stimuli. The scatter displays of grand averages for 25 scalp electrodes look remarkably similar (Fig. 8 A - B ) and the difference traces obtained by electronic subtraction remain close to baseline (Fig. 8C). A N O V A discloses no significant differences for components ( P > 0.25 for P14, N20, P27, P45, N60, P100 and N140; P > 0.1 for N30). Both types of runs were indeed about equally neglected by the subject, under the reading conditions.

353

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Fig. 5. Bit-mapped grand averages presented as frozen maps at 5 msec (first row) or 10 msec (second row) intervals from 20 mscc to 130 msec latencies. Regular ISis of 4000 (A), 2500 (B), 1400 (C), 800 (D) and 450 (E) msec. F: subtraction mapping of 4000 minus 1400 msec at 30-45 msec showing the residual frontal negativity at 4000 msec. G: subtraction mapping of 1400 minus 800 reset.

C. T O M B E R G

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Habituation during runs at regular I S i s The separate averages for groups of trials 1-10, 11-20, 21-70, 71-120 and 121-170 in each run were superimposed for the midfrontal Fz (upper display) and right parietal electrodes (see Fig. 1C) respectively at the 5 different regular ISis (Figs. 9 and 10). The residual noise is much larger in the

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ISis AND HABITUATION OF SEP

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msec, but it is clearly smaller at 800 and 450 msec which suggests that some decrement must occur over the first 10 trials. The progressively increasing size of the N30 grand averages (all trials included) at larger ISis (Table I and Figs. 1-5) thus presumably results from a reducing rate of habituation with larger ISis. The parietal P27 and P45 virtually do not change with trial rank at 1400, 2500 or 4000 msec (Fig. 9) which suggests that the parietal P27 is less susceptible to habituation than the concomitant frontal N30. The paradoxically smaller P45 for the first 1 10 sample is no doubt related to the small signal-to-noise ratio (Fig. 9A).

At ISis 800 and 450 msec, the size of the 1-10 and 11-20 profiles of P27 are about equal to that for ISis of 1400 msec but P27 undergoes marked decrement in the subsequent profiles, while N20 size is preserved. 7 he parietal P45 also reduces markedly with ra'4k at 800 and 450 msec ISis. Furthermore, it is smaller than at 1400 msec even in the first profiles (Fig. 10). At longer latencies the traces show some increased variability without any consistent trend with rank, except that trials ] 10 and 11-20 at ISis of 4000 msec show a positivity at 80-120 msec which is difficult to interpret at this stage (Fig. 8C).

356

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1% Discussion

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Interactions between selective attention, the orienting reflex to novel stimuli (Sokolov 1963; Karrer et al. 1984; Rohrbaugh 1984) and habituation with repetition (Bogacz et al. 1962; Ritter et al. 1968; Roth and Kopell 1969; Fruhstorfer 1971; Callaway 1973; Picton et al. 1976; Woods and Courchesne 1986; Woods and Elmasian 1986; Simons et al. 1987) are important to consider in ERP research. However, it is difficult to disentangle interactions between habituation and the subject's shifting attention. On the other hand, stimulus novelty can only play a minor role when the subject is attending selectively to expected well-identified target stimuli in ERP oddball paradigms. There is an urgent need to reformulate these issues in conjunction with the acknowledged c o r n -

ISis A N D H A B I T U A T I O N OF SEP

plex multicomponent structure of ERPs. It is well known that the identification of early cognitive components to attended target stimuli requires comparison with the underlying 'exogenous obligatory' control profile. Any divergence between the target and control responses could result either from a genuine increase of the target response whereby a cognitive component is identified, or from an underestimation of the matched 'control' response which could be spuriously reduced by some factor like habituation. The validation of control responses is thus important, namely in the case of early cognitive somatosensory P30 and P40 components (Desmedt et al. 1983) which are thought to reflect an enhancement of the exogenous obligatory response in receiving parietal cortex (Desmedt and Tomberg 1989). The main concern of this study is to assess the incidence of habituation or rate effects for nonattended sensory stimuli. The experimental design attempted to avoid subject's changes in attitude (interest for stimuli, novelty or mismatch, uncertainty, boredom) or in vigilance by involving them thoroughly in reading a novel of interest to them. This contributed to maintain vigilance at a fairly constant level (as checked by the EEG) and to disengage attention from the finger stimuli. The latter were of small enough intensity to avoid intrusiveness and they could indeed be virtually ignored throughout the experimental session (Desmedt and Tomberg 1989). The interstimulus intervals (ISis) of 450 or more were large enough to avoid any sensory adaptation, receptor fatigue (see Thompson and Spencer 1966) or refractoriness in the afferent pathway, as documented by the stable voltage of the P14 farfield (reflecting the medial lemniscus volley) and of the early N20 cortical response (Figs. 1-5 and Tables I II). Habituation effects were marked for the parietal P27 and P45 at regular ISis of 800 or 450 msec, but they were absent at regular ISis of 1400 to 4000 msec or at ISis varying randomly from 1100 to 1700 msec. Randomly varying ISis are equally acceptable with respect to lack of habituation of the parietal early positivities, but they are preferred over regular ISis at the same mean frequency as ERP controls to avoid time-locking and anticipation effects between adjacent stimuli

357

(Desmedt and Debecker 1979). The results validate the control conditions used to titrate the early P30 and P40 somatosensory components to target finger stimuli. We conclude that there is no underestimation of the exogenous obligatory profile used so that the effect can be interpreted as a genuine increase of the early target profile. The frontal N30 complex also exhibited clear habituation at ISis of 450 and 800 msec, but this extended up to 2500 msec. The progressively increasing size of the N30 grand averages (all trials included) at larger ISis (Table I and Figs. 1 5) presumably results from a reducing rate of habituation with larger ISis. The sensitivity of the frontal N30 to stimulus rate up to ISis of about 2500 msec raises no problem in conjunction with the assessment of the target responses whose early frontal negativity shows no increase and does not deviate from the N30 in controls in the ERP paradigms tested so far (Desmedt and T o m b e r g 1989). This can be used as an argument for saying that the conditions of the present study seem more than adequate to reveal any decrement in control responses that could meaningfully affect the assessment of target responses. A by-product of this study is to show clear dissociations between the frontal N30 increasing in size with ISis from 1400 to 4000 msec while the concomitant parietal P27 and P45 are not changed (Figs. 1, 3A, 4 and 5). This finding is in line with others (Desmedt and Tomberg 1989) to suggest that these components reflect at least in part distinct neural generators in the frontal and parietal cortex respectively.

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