International Journal of Psychophysiology, 12 (1992) 155-163 0 1992 Elsevier Science Publishers B-V. All rights reserved Q167-8760/92/$05.00

INTPSY 00370

155

mine 2, Jack C. Sipe ‘, aung Aung 2 onald J. Dalessio 2

’ Departnmt of Neuropharmacology, The Scripps Research Institute, La Jolla, CA (U.S.A.) and “ Dir*is:’ -7 of IVetrrology, Scripps Clinic and Research Foundation, La Jolic, CA (U.S.A.)

(Accepted 26 September 1991)

Kq words: P300; Multiple sclerosis; Visual evoked potential

The P3OO component of the event-related brain potential (ERP) elicited with auditory stimuli and pattern-shift visual evoked potentials (VEPs) was obtained from 16 patients with multiple sclerosis (MS) and 16 matched control subjects. P3QO latency was significantly longer and component ar:plitude relatively depressed in the MS patients compared to control subjects. The PlOO potential of the VEP also was delayed for lxth full-field and half-fieizl stimulus conditions in the patients compared to control subjects. The findings suggest that the P300 ERP may reflect the cognitive decline associated with MS.

I[NTRODUCTIQN

Although electrophysiological assessment of sensory processing with evoked potential tech- niques is now a routine procedure in the clinical diagnosis of multiple sclerosis or MS (Halliday, 1978; Starr, 1978; Chiappa, 1983; Rao et al., 1984), application of cognitive event-related po- tentials (ERPs) for the evaluation of the mental1 deficits associated with this disorder has received little attention (Newton et al., 1989; Schroeder et al., 1991; Towle et al., 1991). In particular, the

300 or P3 component of the ERP may provide a useful measure of the cognitive disturbances as- sociated with S (Ivnik, 1978; Peyser et al., 198Oa,b; Qalso et al., 1983; Rao et al., 1985; Joffe et al., 19871, since it has been applied previously to characterize impaired mental function in a variety of neurological disorders (Go~AI et al.,

Correspondertce: !. Polich, Dept. of Neuropharmacology (BCXY,)), The Scripps Research Institute, 10666 N. Torrey Pines Road, La Jolla, CA 92037, U.S.A.

1978a, 1983; Pfefferbaum et al., 1984b; O’Don- nell et al., i987; Polich et al., 1986, 1990) and to evaluate individual differences in normals (Lai et al., 1983; Howard and Polich, 1985; Polich and Martin, in press; Polich, 1986). Despite some debate over the nature of the kxental changes which accompany MS (Marsh, 1980; McKhann, 1982), a number of studies have suggested that a major characteristic of the cognitive dysfunction associated with this neurological disorder stems from difficulty in maintaining items in immediate memory (Jambor, 1969; Beatty and Gange, 1977; Carrol et al., 1984; Rao et al., 1984; Lyon-Caen et al., 1986; Van den Burg et al., 1987) which may be manifested even during the early stages of the diso,ase (Grant et al., 1984). Thus, because those aspects of human cognition associated with work- ing memory are reflected by the. P3 ERP (John- son et al., 1985; Neville et al., 1986; Meador et al., 1987; Donchin and Coles, 1988), this cognitive brain potential may provide a means of evaluat- ing the mental decline in MS.

The present study was designed to assess this possibility in a preliminary fashion by evaluating

156

S patient ERP data in comparison to matched control subjects. In addLion, pattern-shift visual evoked potentials (VEPs), which are sensitive to the demyelinating aspects of S on the visual pathways -(Aminoff, 1985; ammond and ‘-dian- nikas, I986; Anderson et al., 19871, also were obtained to: (I) demonstrate the clinical differ- ences between the patient vs. control groups; and (2) provide a means for comparing the possible cognitive decline reflected by the P3 to the sen- sory deficits indexed by the VEP data.

Subjects tal of 16 patients (14 fe ales)

were solicited from the patient popula- tion of the Neurology ivision at Scri AI1 patients were diagnosed as having least 2 years (mean = 5.4 years), were between the ages of 20 and 45 years, and were free of any other disorders. Fourteen of the patients criteria for clinically definite S, with the re- maining two classified as c ically probable (Poser, 1983). Each patient was matched with a disease-free control subject on sex, age (36.1 vs. 36.2 years), educational (15.4 vs. 15.4 years), and occupation level. Informed consent was o from all patients and controls; all subjects were paid for their partici

auditory stimuli recording procedures Electroencephalog~~phic EECJ activity

recorded at the I% and Ps electrode sites of IO-20 system using gold-plated electrodes affixed with electrode paste and tape, referred to linked earlobes with a forehead ground and impedance

octave/ slope). The EG was digitized at 1.5 ms per point for 700

with a 100 ms prestimulu

ceeded +45 I_CV were rejected automatically, with most subjects demonstrating very few artifact tri- als across conditions. 1 experimental conditions

were recorded with eyes closed. Rest periods were provided between task conditions if the subject requested a break.

every 2 s, and the subject was ask mental count of the number of hi sented. The subject was as ber of target tones count

creases in target stimulus probability in the same as unaffected control subjects (

The VEP was recor

creen from a distance I” visual angle) check

PV were rejected as artifact. ects were tested in the sa t was instructed to fixate on a 7 m

red dot located in the center of the screen, and the stimulus and signal

were recorded fi an occluding eye patch covering the unstimulate

A total of 200 artifact-free stimulus presenta- s were averaged for each trial block. This

process was replicated for each of the three (full- field, left half-field, right half-field) stimulus con- ditions to ensure accurate component identifica- tion. The full-field stimulus was presented first, with the left and right half-field stimulus pre-

second for each subject. The half-field ons were collected simultaneously by dif-

ferentially reversing the checkerboard pattern on the left and right side of the screen and recording the different VEPs to each lateral stimulus pre- sentation separately (Rowe, 1981).

measurements Performance for the P3 counting task was vir-

tually perfect for both the S and control sub-

157

jects, with 97.6% of the target tones correctly counted. No differences in the number of errors between subject groups, probability conditions, or the interaction of these two factors were obtained (F < 1, P > 0.90 in all cases). Hence, all subjects performed the auditory discrimination task equally well across all experimental conditions.

The target stimulus ERP waveforms from all subjects and each probability condition were ana- lyzed in the same fashion: the largest positive- going peak occurring at the Fz and Pz electrode sites after the M-P242 complex between 250 and 500 ms was designated as the P3 component. Amplitude was measured relative to the prestim- ulus baseline with peak latency defined as the time point of maximum positive amplitude. All subjects yielded waveforms which could be as- sessed, although the normal variability inherent

10%

P3

Nl

30%

0 200 400 600

50%

Latency (msec)

Fig. 1. Grand averaged event-related potential target stimuli waveforms (n = 16) from MS patients and matched control subjects for each probability and electrode site.

158

was observed in both groups 986). The amplitudes and latencies of 2, and N2 components also were ob-

tained from each target stimulus wavefor applying similar procedures to latency windows of 60-150, W-220, and MO-3 These measure highly accurat component values in a van- ety of studies s their sensi and reliability in normals (Polich, 1986, 1989, press) as well as demonstrating excellent utility previous clinical studies (Polich et al., 1986, ~99~~. All analyses of variance were performe p!oying Geisser-Greenhouse PTOCCdUitS tt3 COi-

rect for violations of the sp which can occur with repeate Only the probability values application of these corrections are reporte

P3 latency. The grand average waveforms for the target stimuli ERPs from each electrode site and probability condition for each subject group are presented in Fig. 1, with the mean ( + 1 stan- dard error) values for P3 latency and amplitude illustrated in Fig. a 7 for each condition. As is clear from the figures, t P3 component of the E occurs later for th S patients compared to normal controls a s somewhat smaller. espe- cially at the Fz electrode site. A 3-factor (gro x probability x electrode) analysis of varian was applied to the latency datd obtained fr each subject under eat E condition.

patients produced significantly longer tcncics ~c~~t~vc to t

= 7.5, P < 0.01, with reliable effects obtaked. delayed reliably for the pati control subject group.

amplitude. The same 3-factor analysis of variance was applied to the amplitude tained from each subject

ent condition. No over group was obtained ( usual significant decrease i increases in probability 26.2, P<O.OOL as was t crease from the frontal to the parietal portions of the scalp, FU,30) = 5.1; P < 0.05.

Nl, P2, N2 potentiah The component values

Fig. 2. Mean ( + 1 standard e

values as a function

error) values for

ost positive peak

159

02

3yv Ti. _I ,_I 50 100 150 200 250 50 100 150 200 250 50 100 150 200 250

Latenqi (msec)

Fig. 3. Grand averaged 01 = 16) pattern-shift visual evoked potentials from MS patients and matched control subjects for each

stimulus presentation condition.

between 80-200 ms (Pl), and the most negative eak between 120-240 ms (N2). The latency for

each component was measured at that portion of the waveform which s maximally positive or negative for both V replications. Amplitude

easures for the PI onent were obtained by calculating the difference in PV between the Nl and Pl peaks. Preliminary analyses revealed no

atic effects for the eye factor, and this variable was eliminated by collapsing the laten- ties and amplitudes over the left and right eye

ent conditions for the subsequent anal- yses.

Full-field. The iatencies from each component (Nl, Pl, N2) at each electrode site (Oz, 01, 02)

analysis of variance. At the Oz electrode site, all three components demonstrated significantly longer latencies for the MS patients relative to the controls (P < 0.001 in all cases). At the 01 and 02 electrode sites, the Nl and Pl compo- nents from the MS patients again produced sig- nificantly longer latencies than the controls (P < 0.03 in all cases), with the N2 component yielding marginally significant effects (P < 0.10). No sig- nificant amplitude differences were obtamed for the full-field measurement conditions at any elec- trode site, as indicated by the mean amplitude values portrayed in Fig. 4. The waveform differ- ences illustrated in Fig. 3 resulted from the large latency variability in the MS patients compared to

were analyzed with a l-factor (subject group) the controls.

(mm)

Full held left Half Ffetd Right H&If Field

150

140

130

120 2

110

100

150

140

130

120

110

100

FuMiefd 1 e f t Half &Id Right Half IreId

'Or

10

8

6

10

8

6

4

2

0 i

Fig. 4. Mean (+ 1 standard error) PI latency and amplitude values from each stimulus condition for MS patients and matched con t t-ok

of the two lat analyzed with a 3-factor (subject gro field side x electrode) analysis of varian

S patients demonstrated significantly longer component latencies than the control subjects for each component (P < O.QOl in all cases), wit other significant effects obtained except fo N2 peak which yielded a compl x interaction between group and electrode (P < .O I ). Analysis of the amplitude data in a similar f shim did not obtain any differences etween the groups as was observed for the full-field VEPs, but did yield a significant interaction between half-field side of stimulation and electrode site (P < 0.85) in a

fashion consistent with previous applications of ese procedures.

3 latencics and amplitudes (0.10 proba- bility condition, FL electrode) for each

ntrol are presente 5, along with the individual res

easured at Oz presente

trated to the i

butions for both the P3 and Pl potentials demon- strate overlap between the S patient and con- trol populations, they also are both similar in the

P:! ERP 500

r

Pl VEP

50-

40 -

30 -

20 -

10 -

I MS Pamnrs

0 Controls

0

0

0

8i 00

08 8 I 0

y

000 SI ”

Fig. 5. Latency and amplitude distributions from all MS patients and control subjects for the P3 ERP (Pz electrode, 10% condition) and PI VEP (Oz electrode, full-field condi- tion). The mean + 1 standard deviation are illustrated to the

immediate right of each distribution.

degree to which the distributions are shifted. Thus, longer latencies and somewhat smaller am- plitudes can be observed for both the P3 and Pl potentials from MS patients compared to those obtained from the control subjects.

ISCUSSION

Peak latency of the P3 component elicited with a simple auditory discrimination task was delayed in MS patients relative to matched control sub- jects. plitude of the P3 was diminished some- what but not reliably, although MS patients tended to have smaller amplitudes than controls at the frontal recording site. Sensory pathway deficits indicated by delayed latencies of pattern-

161

shift VEPs also were obtained (Aminoff, 1985; Hammond and Yiannikas, 1986; Anderson et al., 1987). These ERP results confirm and extend previous reports (Newton et al., 1989; Schroeder et al., 1991; Towle et al., 1991) and further sug- gest that the neuropsychological observations of cognitive (Ivnik, 1978; Peyser et al., 1980a,b; Dalso et al., 1983; Rao et al., 1985; Joffe et al., 1987) and memory deficits (Jambor, 1969; Beatty and Gange, 1977; Carrol et al., 1984; Rao et al., 1984; Lyon-Caen et al., 1986; Van den Burg et al., 1987) found in MS patients are reflected by in- creased P3 latency. Although standard neuropsy- chological testing was not available for the pre- sent subjects, it is reasonable to conclude that the significant increase in P3 latency observed for the l%lS compared to normal subjects reflects the cognitive decline associated with MS as has been found in other dementing neurological disorders (Goodin et al., 1978a, 1983; Pfefferbaum et al., 1984a,b; O’Donnell et al., 1987; Polich et al., 1986, 1990). Thus, MS appears to produce alter- ations in electrophysiological measures of cogni- tion as well as visual system function.

The present findings imply that the P3 compo- nent may contribute diagnostically for MS as has been suggested by previous ERP studies of other cognitive disorders. However, application of these procedures to clinical populations requires con- sideration of a number of factors. First, the sub- ject’s age must be taken into account to provide the zppropriate control values since P3 latency is known to increase as adults become older (Goodin et al., 1978b; Pfefferbaum et al., 1984a; Picton et

ol;ch et al. 1985). Second, the premor- bid mental level also can affect P3 latency since at least some aspects of cognitive capability are inversely related to P3 latency (Lai et al., 1983; Koward and Polich, 1985; O’Donnell et al., 1987; Prlich et al., 19901, as well as the degree of intellectual decline originating from the disorder (Goodin et a!., 1978a; Pfefferbaum et al., 1984b; Polich et al. 1986; O’Donnell et al., 1987). Third, body temperature and recency of food consump- tion also must be considered since several recent studies have found that both of these factors will affect P3 measures considerably (Geisler and Polich, 1990, in press). Hence, even with the

162

simple auditory task employed in the present study, evaluation of several subject-related vari- ables is required before meaningful intercreta- tion of P3 values from MS patients can be as- sumed.

ACKNOWLEDGEMENTS

This work was supported by the Armstrong McDonald Foundation and a Biomedical tie- search Grant from the University of California, San Diego. Its publication number 5313 IS

from the Research Institute of the Scripps Clinic.

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