Electroencephalography and clinical Neurophysiology, 84 (1992) 332-343 © 1992 Elsevier Scientific Publishers Ireland, Ltd. 0168-5597/92/$05.00

332

EVOPOT 91601

Event-related EEG potentials in mild dementia of the Alzheimer type Rolf Verlcgcr, Dctlcf K6mpf and Winfricd Ncuk~iter Klinik fi~r Neurologie, Medizinische Universitiit zu Liibeck, D 2400 Li~beck (F.R.G.) (Accepted for publication: 2 February 1992)

Summary Most studies on event-related EEG potentials in dementia have focussed on the P3 component and used auditory stimuli only. In the present study, N2b was analysed in the usual auditory oddball task in addition to P3, and a visual task was employed ("Push"/"Wait"), with recordings including an occipital scalp site. Seven Alzheimer-type patients, with their mean IQ still in the normal range, were compared to age-matched normal controls. In the oddball task, P3 did not differ between groups but the patients' N2b was delayed. The main difference in the Push/Wait task was in an occipital P270, which component was distinctly larger in the patients. It is suggested that both differences reflect the desintegration of patients' cognition: stimuli are perceived in a normal way but then a gap arises due to uncertainty what to do with the perceived event. Key words: Event-related potentials; EEG; Dementia; Alzheimer-type dementia

Event-related potential studies on demented patients have focussed on the P3 component in the auditory oddball task. In this task, two tones are repeated in random order. One of the tones is presented less frequently than the other and is designated the target tone that has to be counted or to be responded to by pressing a button. The target tones evoke a P3 component (see Donchin and Coles 1988 and Verleger 1988 for reviews). Goodin et al. (1978) had found that P3 latency is prolonged in demented patients compared to healthy elderly subjects. Since that first report, this finding has been repeated in several studies, above all in moderately demented patients (see the review by Polich 1991 and the discussion led by Goodin 1990, and Pfefferbaum et al. 1990). A number of questions remain, some of which were pursued in the present study. First, it is not clear whether P3 is also delayed in mild dementia. Polich et al. (1986) found that only those patients who had high scores on a Global Deterioration Rating Scale had delayed P3s. Similarly, Patterson et al. (1988) found that only 2 out of 15 patients had conspicuously prolonged P3s, having included 5 mildly demented patients in their sample. Likewise, the 4 mildly demented patients included in the sample of Neshige et al. (1988, Fig. 3: IQs between 75 and 95) had normal P3s (their Fig. 2). Finally, Kraiuhin et al. (1990) found that P3 latencies did not differ between

Correspondence to: Rolf Verleger, Klinik fiir Neurologie, Medizinische Universit~it zu Liibeck, Ratzeburger Allee 160, 2400 Liibeck 1 (F.R.G.).

mildly to moderately demented Alzheimer patients and control subjects. On the other hand, Ball et al. (1989) and Polich et al. (1990) found P3s to be prolonged in mildly demented patients. However, the degree of dementia is not clear from these reports, since Polich et al. (1990) did not report results of clinical or psychometric tests and Ball et al. (1989) did not report results of the neuropsychological tests. In the latter study, the Mini-Mental State examination (MMS) scores ranged between 22 and 27, but MMS scores might not clearly reflect the patients' cognitive abilities (Galasko et al. 1990). In view of this conflicting evidence, the P3s of mildly demented patients were compared to normal controls in the present study, using the usual auditory oddball task. Both patients and controls underwent detailed neurological and psychometric testing to assess their degree of cognitive functioning. A second open question concerns the N2 complex. In the auditory oddball task, at least two other endogenous components may be measured besides P3 (Novak et al. 1990): the mismatch negativity (MMN) and N2b. Both components can best be seen in the difference curve formed by subtracting the non-target potentials from the target potentials. N2b is the large negative peak of that difference curve, at about 200 msec, MMN appears as a smaller peak before N2b (see N~i~it~inen 1986 and 1990 for reviews). These two components usually combine to form the N2 complex. N2 was reliably delayed in many studies on demented patients, including the ones quoted above, e.g., Neshige et al. (1988), Patterson et al. (1988), Ball et al. (1989), Polich et al. (1990). Even the grand means of Kraiuhin

E V E N T - R E L A T E D P O T E N T I A L S IN M I L D D E M E N T I A

333

et al. (1990; their Fig. 3) show N2 to be delayed in the patients whereas the subsequent P3 component was not. Therefore, the present study investigated whether the N2 delay in mild dementia is due to a delay of both MMN and N2b. Thus, it was hoped to get a deeper understanding of the problems demented patients encounter in this task. Because MMN is usually overlapped by the onset of N2b, it is best measured in an "ignore" condition where subjects do not pay attention to the tones, usually reading some text of their choice (e.g., Paavilainen et al. 1991). We considered it unlikely that patients would be both relaxed and compliant enough to behave according to such an "ignore" protocol and, therefore, tried to measure the MMN directly in the oddball task, defining it as the negative peak preceding N2b in the difference waves. This peak may indeed be part of the MMN proper. Alternatively, it may reflect enhancement of the N1 component (cf., the discussion in Paavilainen et al. 1991). Thirdly, it is of interest whether findings made in the auditory oddball task generalize to other tasks. Therefore, the present study added the "Push/Wait" task introduced by Pfefferbaum et al. (1985). This formed a visual analogue of the auditory oddball task: subjects had to press a button when the word "Push" appeared on a screen and to withhold the response with the word "Wait." The task was more difficult than the oddball since there were more targets ("Push" had a probability of 50%), and because 50% of all stimuli were presented at a dim intensity. It was of special interest whether the demented patients' problems would become more obvious in this more difficult task

and whether group differences could be found that were specific to the visual modality. For this reason, records were made from the occipital scalp, in addition to the Fz, Cz, and Pz records reported by Pfefferbaum et al. (1985) and Pfefferbaum and Ford (1988) for healthy subjects performing this task.

Methods

Subjects Control group Twenty elderly healthy adults (12 women, 8 men) were recruited from the community. Their ages ranged from 55 to 87 years (median and mean 67 years, standard deviation 7 years) and none of them had experience with psychophysiological experiments. Before participating, the subjects were screened for health problems. First, their medical history was taken, with special emphasis on previous neurological or psychiatric disease, general conditions possibly affecting brain function, and current drug intake. Second, all subjects underwent clinical EEG recording and a neurological examination, including a brief evaluation of mental state and cognitive abilities. These screening procedures led us to exclude 7 subjects out of the original pool of 27 volunteers from the study. Reasons for excluding these subjects were a history of depression (3), organic mental syndrome suspected (2), Sj6gren syndrome (1), and a history of transitory ischemic attacks (1). At the time of testing, all subjects were in a condition of good health but inevitably some of the 20

TABLE I Results of psychometric tests. In the top half, the 7 patients' individual results are compiled. In the bottom half, m e a n s and standard deviations of the individual results are given, together with m e a n s and standard deviations of the control group. The group m e a n s were compared by t tests, and the resulting (2-sided) probabilities are displayed: n.s. not significant; ** P < 0.01; *** P < 0.001. The tests are: IN, SI, PC, BD: subtests information, similarities, picture completion, and block design of the WAIS (raw scores); IQ age-standardized intelligence quotient (WAIS), DSF and DSB digit span forward and backward (WAIS, raw scores), AVLT1 n u m b e r of words recalled at the first presentation of the list (AVLT, raw score), A V L T 5 - 1 increase in words recalled after the fifth presentation compared to the first one (AVLT, raw score), R C W read grey color words (Stroop; seconds needed to read the list), N C L name colored lines (Stroop; relation of the time needed to the time needed in RCW), N C W n a m e the color of colored words (Stroop; relation of the time needed to the time needed in NCL). Patient (no.)

IN

SI

PC

BD

IQ

DSF

DSB

1 2 3 4 5 6 7

12 1 15 3 6 4 8

13 2 8 4 12 5 13

12 3 7 7 7 8 9

23 0 0 9 13 15 15

109 65 90 83 91 81 92

3 7 5 5 7 6 6

3 2 3 2 4 3 5

Mean S.D.

7 (5) ***

8 (5) ***

8 (3) ***

11 (9) ***

87 (13) ***

6 (1) n.s.

Mean of controls S.D.

16 (4)

18 (3)

12 (2)

24 (6)

120 (10)

6 (3)

AVLT1

AVLT5-1

RCW

NCL

NCW

0 2 1 3 5 1 5

0 3 1 1 0 - 1 4

3 (1) n.s.

2 (2) ***

4 (2)

6 (1)

Age

59 111 84 48 38 44 27

2.2 0.9 1.5 1.6 1.9 2.7 1.3

4.6 2.7 2.8 3.0 3.6 2.0 2.0

67 69 64 74 71 64 75

1 (2) ***

59 (30) **

1.7 (0.6) n.s.

2.9 (0.9) ***

69 (4) n.s.

6 (2)

33 (7)

1.5 (0.3)

1.9 (0.4)

67 (7)

334 subjects included in this study had a history of diseases not interfering with brain function, above all coronary heart disease (n = 6) and hypertension (n = 3). Patients

The data of 7 patients (6 women, 1 man) will be reported. Their ages ranged from 64 to 75 years (median and mean 69 years, standard deviation 4 years). Originally, 24 patients were studied, being admitted to the clinic for a thorough 5 day medical examination of their suspected dementia. The 7 subjects are those patients who were finally diagnosed as suffering from dementia of the Alzheimer type and who performed adequately during recording of the event-related E E G potentials. The diagnosis of dementia was based on clinical interviews and psychometric tests (see below), that of the Alzheimer type was based on excluding possible other causes by means of blood tests, ECG, lumbar puncture, clinical E E G and EP recording, CT scans and SPECT. Two of the 24 patients were diagnosed as being healthy, 11 patients were excluded due to possible other causes of their dementing process: vascular (6), amyotrophic lateral sclerosis (1), mitochondrial myopathy (1), cerebellar atrophy (1), depression (1), unknown (a 39-year-old woman). Of the remaining 11 Alzheimer patients, 3 were excluded because they could not adequately perform the oddball task, another patient had to be excluded because her records were contaminated by artifacts. The subjects were psychometrically tested with 4 subtests o'f the German version of the WAIS: information, similarities, picture completion, block design. German norms are available for the sum of these 4 subtests, allowing an estimate of the IQ (Dahl 1972). In addition, 3 other tests were applied: the subtest digit span of the WAIS, a German version of the Auditory Verbal Learning Test (adapted from Lezak 1983) and the German version of the Stroop test (B~iumler 1985). Results are compiled in Table I: in the top half, the patients' individual test results are given, in the bottom half means (and standard deviations) of the patients are compared to the control group results. Since both groups were equally old, raw scores are used throughout in the table, except for the IQ, which is by definition age-standardized. Results of the RCW (read color words) subtest of the Stroop test are given in seconds, i.e., the time needed to read the list. In correspondence to the way the Stroop test is scored, the NCL and NCW results are given as ratios: NCL (name colored lines) is the ratio of time needed to name the lines versus the time needed for RCW. NCW (name color words) is the ratio of time needed to name the color of words printed in conflicting colors versus the time needed for NCL. It is evident from the table that patients performed worse than controls on all tests except for DSF (digit span forward), DSB (digit span

R. VERLEGER ET AL. backward) and for NCL (the increase of time needed for naming relative to reading). Their mean IQ was 87, so according to this global measure, patients were still as intelligent as the lower range of the average population. Most important for diagnosing dementia from these tests was the Auditory Verbal Learning Test (AVLT). Dementia patients were generally not able to recall more items on the fifth presentation of the 15-word list than they did on the first. Patient no. 7 was an exception insofar as dementia was obvious from her problems in daily routines and from her mental functions declining according to collateral informants but could not be clearly assessed by the psychometric tests. This is a notorious problem in dementia research (cf., Storandt and Hill 1989; Morris et al. 1991). Stimuli

In the oddball task, tones were generated by a Commodore Amiga 2000 and presented via earphones (Sony MDR-V2). Their intensity was 65 dB SPL, their duration was 60 msec, and they were presented in intervals of 1.5 sec. Sound intensity was measured by a Brfiel-Kjaer sound-intensity meter at a point midway between the earphones while the Amiga produced steady tones. Onset and offset was not gated because AmigaBasic unfortunately does not support this feature. 216 (86%) "non-target" tones were presented, with their frequency set to 1000 Hz, and 34 (14%) target tones with a frequency of 2000 Hz. The same predetermined random series was used for all subjects to exclude different sequential effects (Squires et al. 1976). In the P u s h / W a i t task, the German words driicken (push) or warten (wait) were flashed for 200 msec on the screen of the Amiga 2000 in light grey on a constant dark-grey background (luminance 2.2 cd/mZ). The words were either bright (26.3 c d / m 2) or dim (4.5 cd/m2). The interstimulus interval was 2 sec. Single letters were 1.3 cm high and 0.7 cm wide, so driicken subtended a visual angle of 2.2 ° × .6°, warten of 1.9 ° × .6° since subjects looked at the screen from approximately 1.2 m. 120 stimuli were presented in a predetermined random series with equal probabilities for each of the 4 different stimuli and also with each sequence of 2 stimuli in a row being equally probable in order to keep sequential effects constant. Procedure

After electrodes were applied, subjects put on the earphones, the oddball task was explained, and a practice block of 35 stimuli including 5 target tones was given. Subjects were instructed to press the left mouse-button of the Amiga 2000 with their preferred hand as fast as possible with each target tone. This

EVENT-RELATED POTENTIALS IN MILD DEMENTIA

button was marked by a red dot. The oddball task proper lasted for 6 min 15 sec. Then earphones were removed and 36 practice trials of the P u s h / W a i t task were given. Subjects were instructed to press the left mouse-button with every "Push," no matter whether the words were bright or dim. The task proper lasted for 4 rain. In both tasks, many patients did not show adequate performance after the first practice block. In these cases, the practice blocks were repeated until patients mastered the task.

335 milliseconds

800

Overt.Responses

700

600

Recording and data processing Sintered A g / A g C l electrodes (Picker-Schwarzer) were affixed at Fz, Cz, Pz, Oz, at both mastoids, and above and below the right eye. Grass EC-2 cream was used throughout. Mastoids were shunted via a 5 kY2 resistor and served as references for Fz, Cz, Pz, and Oz, whereas the vertical E O G was recorded bipolarly. E E G and E O G were amplified and filtered by a Nihon-Kohden 4421 amplifier, frequency limits being set to 0.16 Hz (1 sec time constant) and 30 Hz. The Commodore Amiga 2000 controlled the experiment and sent impulses with every stimulus and with subjects' responses via its parallel output, which impulses were stored together with the digitized physiological data. The data were digitized (12 bit) at 100 Hz, from 0.1 sec before to 1.0 sec after stimulus onset, using an AT-compatible microcomputer. Button presses were measured not only during the 1.0 sec but during the whole interval until the next stimulus (1.5 sec in the oddball, 2.0 sec in the Push/Wait). The E E G data were screened for artifacts with a program adapted from Berg (1986) that looked for blinks, zero lines, out-of-scale values, and fast shifts larger than 100 IzV. The transmission of blinks into the E E G was estimated by linear regression with a modified version of Berg's (1986) "median method" (Verleger 1991). EEGs were then corrected for blinks by subtracting the blinks as measured in the E O G weighted by the transmission coefficient. These edited data were averaged separately for target and non-target tones in the oddball task and for the 4 kinds of stimulus in the P u s h / W a i t task (Push and Wait/bright and dim). Trials containing artifacts other than blinks were excluded from averaging, as were " G o " trials (oddball targets, "Push") in which subjects did not respond and "No-go" trials (oddball non-targets and "Wait") in which subjects erroneously responded. Methods for defining the components in these averaged data will be described in the Results section. Amplitudes were always measured against the mean level of the 100 msec prestimulus period ("baseline"). Analyses of variance were computed with SPSS (PC version), defining group (patients/controls) as between-subjects factor and other variables as within-sub-

500

400

300

patients

controls

Fig. 1. Response times for pressing the button in the oddball task (bottom) and in the Push/Wait task (middle and top). The vertical bars mark 1 S.D.

jects factors. Whenever appropriate, degrees of freedom were corrected by the conservative GreenhouseGeisser estimate.

Results

Oddball task OL~ert responses For analysis of reaction times, each subject's median value of the response times to target tones was determined. Mean values of both groups are displayed in Fig. 1 (bottom line). In spite of the large interindividual differences in both groups (also displayed in Fig. 1), the patients reliably responded more slowly than the control subjects (x = 457 msec _+ 147 vs. 364 msec + 60, t (25) = 2.3, P < 0.05). Missing responses to targets did not differ between groups: all but 4 subjects (2 patients, 2 controls) had no omissions at all; two patients missed 1 and 7 out of 34 targets. Erroneous responses to non-targets (generally 1 or 2) occurred in 4 of the 7 patients (at most 13 out of 216 non-targets) and 14 of the 20 control subjects when they did not lift their fingers from the button after a target had occurred. In sum, errors were negligible but all these incorrect response trials were excluded from averaging. Response times and total number of errors tended to correlate negatively in the control group (r (19)= - 0 . 4 2 , P < 0.07), i.e., the fast responders tended to

336

R. VERLEGER ET AL.

make more mistakes. No such tendency was obtained in the patient group (r ( 6 ) = -0.04).

Event-related potentials G r a n d averages over the target and non-target tones are displayed in Fig. 2, with the potentials of the two groups overlaid. Mean values of the P3, " M M N " and N2b components, to be discussed in the following, are compiled in Table II, as are the F values obtained from 2-way analyses of variance (2 groups X 3 records) on amplitudes and latencies of these components. P3. In Fig. 2 hardly any difference is visible between groups for the P3 time range. This impression was confirmed by the A N O V A s on P3 amplitudes and latencies. P3 was measured as the most positive peak in the 250-500 msec time range. P3s had the same amplitudes in patients and controls ( F ( 1 / 2 5 ) = 0.0) and also the scalp topography of the amplitudes did not differ between groups (group x recording: F (2/50) =

1.0). Overall, P3s were largest at Pz, and of equal size at Fz and Cz (recording: F ( 2 / 5 0 ) = 18.6, • = 1.0, P < 0.001). Nor was there a main effect of group ( F (1/25) = 1.3) or an interaction of group x recording ( F (2/50) = 0.1) on P3 latency. Comparing the latencies between groups in single records, in spite of the lacking group x recording interaction, showed no group difference at Cz and Pz ( F (1/25) = 0.6 and 0.6) and a weak tendency at Fz for P3s being later in the patients ( F (1/25) = 2.0, P < 0.17). Whereas no differences were obtained for the P3 component, Fig. 2 illustrates a group difference in the 200 msec time range. In particular, with target tones it appears that the P2 component was larger in the patients, presumably because in the control group P2s were reduced by overlapping negative components. In order to examine these negative components, the difference curves (target minus non-target) were formed. From the grand mean of these differences (Fig. 3), it

Oddball targets: grand average

Oddball nontargets: grand average

controls patients ............. .,.-

controls patients

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

..

50 uV

,ouvT-

..'

.,

4-

""'" r.

lOu-+V

'_~

...,

Oz 0

200

400

600

milliseconds

800

1000

I

I

I

I

I

I

0

200

400

600

800

1000

milliseconds

Fig. 2. Grand means of the potentials recorded in the oddball task. Data from 7 patients and 20 control subjects.

EVENT-RELATED POTENTIALS IN MILD DEMENTIA

337

differences (target-nontarget)

c o n s t r a i n t in mind, t h e s e i m p r e s s i o n s w e r e t e s t e d by analyses o f v a r i a n c e on t h e a m p l i t u d e s a n d l a t e n c i e s o f " M M N " a n d N2b. "MMN" was q u a n t i f i e d as t h e largest n e g a t i v e p e a k p r e c e d i n g N2b, in t h e t i m e r a n g e 9 0 - 1 6 0 msec. Its a m p l i t u d e did n o t differ b e t w e e n t h e g r o u p s ( F ( 1 / 2 5 ) = 0.0; cf., T a b l e II) a n d t h e i n t e r a c t i o n of g r o u p s X r e c o r d i n g failed to r e a c h significance ( F ( 2 / 5 0 ) = 2.9, E = 0.74). N o r was t h e r e a significant d i f f e r e n c e b e t w e e n g r o u p s in " M M N " l a t e n c y a l t h o u g h t h e m e a n values t e n d e d to b e l a r g e r in t h e p a t i e n t s t h a n in t h e c o n t r o l s at Cz a n d Pz (see T a b l e II). N2b was q u a n t i f i e d as t h e largest n e g a t i v e p e a k in t h e t i m e r a n g e 170-300 msec. It was l a r g e r at Cz t h a n at Fz, a n d s m a l l e s t at Pz (effect o f r e c o r d i n g on N2b a m p l i t u d e s : F ( 2 / 5 0 ) = 16.2, • = 0.91, P < 0.001), a n d it p e a k e d e a r l i e r at Cz a n d Pz t h a n at Fz (effect o f r e c o r d i n g on N2b latencies: F ( 2 / 5 0 ) = 6.6, • = 0.67, P < 0.01). T h e a p p a r e n t r e d u c t i o n o f N 2 b a m p l i t u d e s in t h e p a t i e n t s , as s u g g e s t e d by Fig. 3, was n o t r e l i a b l e (the effect o f g r o u p s y i e l d e d an F ( 1 / 2 5 ) value o f 2.5 only, P < 0.13). H o w e v e r , N 2 b was significantly del a y e d in t h e p a t i e n t s (effect o f g r o u p s on N 2 b latency: F ( 1 / 2 5 ) = 5.5, P < 0.05). In sum, t h e m a i n d i f f e r e n c e b e t w e e n g r o u p s in the o d d b a l l t a s k was in the 2 0 0 - 2 5 0 m s e c t i m e r a n g e a n d c o u l d b e q u a n t i f i e d as a delay of N2b's peak in the p a t i e n t s ' d i f f e r e n c e waves. It m a y b e n o t e d t h a t this d i f f e r e n c e c o u l d also b e q u a n t i f i e d as a d i f f e r e n c e o f P2 amplitudes in the u n s u b t r a c t e d t a r g e t p o t e n t i a l s (which w e r e d e p i c t e d in Fig. 2): A t Fz, p a t i e n t s ' P2s w e r e l a r g e r in t h e p a t i e n t s t h a n in the controls.

FZ

10 uV +

"

0

200

controls

'

400

patients

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

600

800

1000

milliseconds Fig. 3. Grand means of the difference potentials, obtained by subtracting the potentials evoked by non-targets from the potentials evoked by targets. The arrow points to the time range in which mismatch negativity ( M M N ) was measured; the large negative peak is N2b.

a p p e a r s t h a t N2b was b o t h r e d u c e d a n d d e l a y e d in the p a t i e n t s while an e a r l i e r negativity t h a t might c o r r e s p o n d to M M N s e e m e d to have e q u a l a m p l i t u d e in b o t h groups. T h e p r o b l e m with this " M M N " is t h a t it is c e r t a i n l y o v e r l a p p e d in p a r t by N2b in the p r e s e n t d a t a (cf., I n t r o d u c t i o n ) such t h a t this early p e a k is p e r h a p s not an a d e q u a t e r e f l e c t i o n o f M M N . W i t h this

Push / Wait task Overt responses A s in t h e o d d b a l l task, t h e m e d i a n o f e a c h subject's c o r r e c t r e s p o n s e s to " P u s h " was d e t e r m i n e d . M e a n

TABLE II ERP parameters in the oddball task. Entries in the top half are means (and standard deviations) of the parameters for each group. Unit for amplitudes is microvolts, for latencies milliseconds. Entries in the bottom half are the F values obtained from 2-way analyses of variance on the parameters (Rec, = recording; G x R = group x recording).

Fz Cz Pz Group Rec. Gx R

P3 amplitude

P3 latency

"MMN" amplitude

"MMN" latency

N2b amplitude

N2b latency

Pat.

Cont.

Pat.

Cont.

Pat.

Cont.

Pat.

Cont.

Pat.

Cont.

Pat.

Cont.

8 (4) 10 (4) 16 (3)

10 (6) 10 (8) 14 (6)

360 (55) 369 (41) 367 (47)

333 (40) 351 (56) 348 (57)

-3 (4) - 4 (5) - 2 (5)

-4 (4) - 3 (4) - 2 (3)

129 (16) 129 (16) 131 (20)

127 (18) 123 (20) 121 (17)

-6 (9) -8 (8) - 3 (7)

- 10 (7) - 15 (10) - 7 (6)

249 (36) 227 (26) 227 (24)

221 (24) 212 (18) 211 (20)

0.0 18.6 ** 1.0

* P < 0.05; ** P < 0.01.

1.3 1.0 0.1

0.0 6.5 * 2.9

0.8 0.2 0.8

2.5 16.2 ** 1.0

5.5 * 6.6 * 1.1

338

R. V E R L E G E R ET AL.

response times of both groups (and standard deviations) are displayed in Fig. 1 (middle and top lines) and were evaluated by a group x brightness A N O V A . As in the oddball, the patients responded more slowly than the controls ( F (1/25) = 30.0, P < 0.001). Bright stimuli were responded to more quickly than dim ones ( F (1/25) = 18.7, P < 0.01). Mean values for bright and dim stimuli were 679 msec + 180 and 721 msec + 113 in the patients and 470 msec + 45 and 532 msec + 60 in the control group. " P u s h " was never missed by the control subjects when it was bright and 0.4 times on the average when it was dim, but 3.9 times by the patients when bright and 6.7 times when dim. Erroneous responses to " W a i t " were given 1.8 times by the control subjects when it was bright and 1.4 times when it was dim, by the patients 3.9 times when bright and 5.0 times when dim. An analysis of variance on these errors showed that the patients made more errors than the controls ( F (1/25) = 17.1, P < 0.001) and in particular that the patients made more errors with dim stimuli than with bright ones (brightness: F (1/25) = 10.1, P < 0.01; brightness x group: F (1/25) = 11.1, P < 0.01; simple effect of brightness for the patients: F ( 1 / 6 ) = 5.7, P < 0.06; for the control group: F ( 1 / 1 9 ) = 0.1, n.s.). There were large differences among the patients: the total number of errors for each of the 7 patients was 2, 4, 5, 17, 30, 36 and 42 (120 errors were possible, 60 errors would mean completely random responding). The total number of errors and the response time tended to correlate in the patient group (r (6) = 0.56, P = 0.19), i.e., those patients who made more mistakes also tended to make their correct responses more slowly. No such tendency was obtained for the control group (r ( 1 9 ) = -0.22).

PushWait: grand average • -:

.

.

.

.

.,..

..

. ..

j,*" __

...

u~I ~

"

EOG

controls

patients ............... ..... I

0

200

I

I

I

400

600

800

Fig. 4. Grand averages of the two groups in the Push/Wait task. Data were averaged over bright and dim "Push" and "Wait" stimuli to focus on the group differences.

TABLE III P3 latencies and amplitudes in the Push/Wait task. Entries are means (and standard deviations) of either group. Unit is milliseconds for latencies (rounded to the nearest 10) and microvolts for amplitudes. Within each cell the left column is from bright stimuli, the right column from dim ones. Patients

Control group

Push P3 latencies

Fz Cz Pz

P3 amplitudes

Fz Cz Pz

Wait

Push

Wait

440 (29) 440 (53) 440 (64)

480 (42) 470 (41) 380 (81)

480 (41) 480 (37) 410 (68)

480 (49) 460 (53) 430 (68)

400 (50) 410 (51) 420 (39)

420 (44) 420 (49) 430 (61)

440 (43) 460 (41) 450 (56)

460 (48) 470 (43) 460 (55)

11 (8) 13 (8) 15 (9)

8 (7) 8 (5) 10 (5)

11 (5) 10 (6) 10 (7)

8 (4) 10 (5) 10 (5)

13

13

16

13

(5)

(5)

(6)

(5)

14 (8) 17

12 (7) 14

17 (9) 14

16 (7) 12

(7)

(5)

(7)

(6)

E V E N T - R E L A T E D P O T E N T I A L S IN M I L D D E M E N T I A

339

T A B L E IV

P3 latencies

F values obtained in the analyses of variance on P3 latency and P3 amplitude in the P u s h / W a i t task. The left side within each column displays the effects that do not involve the group factor and the right side displays the effects involving the group factor. T h e top value on the right side of each column is the main effect of group. Degrees of freedom were 1 / 2 5 for the effects not including recordings. Effects including recordings had 2 / 5 0 dr, but probabilities are shown for Greenhouse-Geisser reduced degrees of freedom.

In the patients, P3s peaked latest at Fz. In contrast, there was no difference between recording sites in the control group (recording: F (2/50) = 6.5, • = 0.81, P < 0.01; recording x group: F (2/50) = 9.4, • = 0.81, P < 0.001; simple effect of recording in the patients: F (2/12) = 5.4, • = 0.66, P < 0.05; simple effect of recording in the controls: F ( 2 / 3 8 ) = 1.2, n.s.). Therefore, Fz latencies were earlier in the control group than in the patients: the simple effect of group was at Fz F (1/25) = 7.2, P < 0.05; at Cz: F (1/25) = 2.6, n.s. At Pz, P3s tended to peak earlier in the patients than in the control group but not significantly so, the simple effect of group at Pz being F ( 1 / 2 5 ) = 1.7, n.s. The patients' early Pz peak was especially marked with dim stimuli and least marked with bright " P u s h " (see Table III). These relations made the effects of brightness X meaning X recording x group ( F (2/50) = 6.9, E = 0.90, P < 0.01) as well as of brightness x meaning x recording significant ( F (2/50) = 6.6, • = 0.90, P < 0.01). Further effects on P3 latency were a general delay of "Wait"-P3s relative to "Push"-P3s (main effect of meaning: F (1/25) = 12.8, P < 0.01) and a delay with dim stimuli compared to bright ones at Fz (brightness x recording: F (2/50) = 5.0, • = 0.83, P < 0.05; simple effect of brightness at Fz: F (1/25) = 7.1, P < 0.05; at Cz: F (1/25) = 1.1; at Pz: F (1/25) = 0.8).

Brightness Meaning BxM Recording Bx R MxR B×MxR

P3 latency

P3 amplitude

Effect

Effect x g r o u p

Effect

Effect × g r o u p

0.8 12.8 0.0 6.5 5.0 1.6 6.6

1.0 1.5 2.4 0.1 9.4 *** 1.6 0.3 6.9 **

29.4 *** 0.0 2.4 0.7 0.0 14.1 *** 13.5 ***

2.3 0.7 0.6 2.6 0.6 0.5 4.5 * 1,3

** ** * **

* P < 0.05; ** P < 0.01; *** P < 0.001.

Event-related potentials As in the oddball task, only correct-response trials were included in the averages. Grand averages over all stimuli (i.e., averaged over both "Push" and "Wait", both bright and dim) are displayed in Fig. 4, separately for patients and control group (overlaid) for the EOG, Fz, Cz, Pz, and Oz records (from top to bottom). Different from the oddball task, the groups apparently differed in their P3 components. But the group differences seemed to vary with the recording site: P3 amplitudes seemed to be larger at Fz, Cz and Pz in the control group than in the patients and P3 peaks seemed to be earlier at Fz and Cz in the control group than in the patients. However, at Pz, and in particular at Oz, an earlier positivity emerged, above all in the patients. This occipital P270 seemed to be a component of its own.

In order to quantify these impressions, P3 was measured as the most positive peak 280-600 msec poststimulus at Fz, Cz, and Pz. P3 latencies and amplitudes (compiled in Table III) were tested by analyses of variance with the factors group (patients/controls), recording site ( F z / C z / P z ) , meaning (Push/Wait), and brightness (bright/dim), the latter 3 factors being repeated-measurement factors. The F values obtained in these ANOVAs are compiled in Table IV. Further, the occipital P270 was measured as the most positive peak 200-350 msec poststimulus at Oz and its amplitude was tested by an analysis of variance with the factors group (patients/controls), meaning (Push/Wait) and brightness (bright/dim). Results will be reported in detail in the following sections.

P3 amplitudes Contrary to the impression suggested by the grand means, P3s were not reliably larger in the control group than in the patients: there was neither a significant main effect of group ( F ( 1 / 2 5 ) = 2.3, P < 0.15) nor a significant group x r e c o r d i n g interaction ( F (2/50) = 0.6). However, the patients lacked the topographical differentiation between "Push" and "Wait" that was evident in the control subjects (Table III) whose P3s were largest at Pz with "Push," at Cz with "Wait." (Meaning X recording: F ( 2 / 5 0 ) = 14.1, e = 0.97, P < 0.001; meaning x recording x group: F (2/50) = 4.5, E = 0.97, P < 0.05; simple effect of meaning x recording in the control subjects: F (2/38) --- 29.8, E - 0.90, P < 0.001; simple effect of meaning x recording in the patients: F (2/12) = 1.4, E = 0.65, n.s.) Apart from group effects, bright stimuli elicited larger P3s than dim ones (brightness: F ( 1 / 2 5 ) = 29.4, P < 0.001), in particular bright " P u s h " at Pz (brightness x meaning x recording: F (2/50) = 13.5, E = 0.93, P < 0.001; simple effect of brightness x meaning at Fz: F (1/25) = 1.1; at Cz: F (1/25) = 4.1, P < 0.06; at Pz: F (1/25) = 9.3, P < 0.01).

Occipital P270 The occipital P270 ranged in latency from 220 to 320 msec. It could be easily distinguished in all patients

340 and in many control subjects. In the other control subjects it rode on the beginning parietal P3 wave but could still be discerned. Its amplitudes were submitted to an analysis of variance with the factors group, meaning, and brightness, the latter two factors being defined as repeated measurements. The main effects of these 3 factors were significant. Occipital P270 was indeed larger for the patients than for the control group ( F (1/25) = 11.3, P < 0.01) as suggested by Fig. 4. Further, this component was larger for bright stimuli than for dim ones ( F (1/25) = 9.2, P < 0.01) and was larger with " P u s h " than with " W a i t " ( F ( 1 / 2 5 ) = 5.5, P < 0.05). There were no significant interactions.

P2 and N2 Since the grand means displayed in Fig. 4 suggest that P2 amplitudes (at about 200 msec) were larger in the patients, this component was analyzed. P2 was defined as the most positive peak between 130 and 250 msec at Fz, Cz, and Pz, and submitted to the same A N O V A as P3. However, no effect involving the group factor became significant, either for P2 amplitude or for P2 latency. Similarly, N2 was defined as the most negative peak between 170 and 370 msec at Fz, Cz, and Pz, and submitted to the A N O V A . Again, no effect of the group factor became significant, while there were marked effects of brightness and of meaning both on P2 and N2 latencies and amplitudes. In sum, 3 effects distinguished the patients from the control group in this task. First, the patients' P3s measured at Fz were delayed whereas no difference was found at Cz and Pz where P3 is usually measured. Second, the P3 component did not change its topographical focus from " P u s h " to " W a i t " in the patients as it did in the control subjects. Third, the occipital P270 was distinctly larger in the patients than in the control group.

Discussion Event-related E E G potentials were recorded from 7 mildly demented patients suffering from dementia of the Alzheimer type and from 20 age-matched healthy control subjects. In agreement with previous studies it was found that P3 latency was not reliably delayed in the patients whereas auditory N2 was. Two new findings were made in the present study: the delay of auditory N2 was specifically due to a delay of its N2b component, not of the preceding M M N (as far as M M N could be measured in the present data, cf., Introduction); second, in the visual P u s h / W a i t task, an occipital positive component at 270 msec was larger in the patients than in the control subjects. These results will be discussed in the following.

R. VERLEGER ET AL.

P3 latency The lack of a delay was predicted in the Introduction, since P3s have so far been found to be delayed above all in more severely demented individuals, not so in mildly demented patients (Polich et al. 1986; Neshige et al. 1988; Patterson et al. 1988; Kraiuhin et al. 1990). In spite of the reasonably good agreement of the present P3 results with previous studies, some methodological objections might be made and will therefore be discussed. The lack of a delay was not due to the control group having very late P3s, thus diminishing the possible additional delay due to dementia. The P3s of the present control group were actually prolonged by 40 msec when compared to young healthy subjects (Verleger et al. 1991), resulting in an average increase of 0.94 m s e c / y e a r (average age of the present control group was 67 years, and that of the young group was 24 years) which is near the lower boundary of the age increases found (cf., the review by Polich 1991). That is, if the P3s of the present control group were notable, it was for their relatively early latency, not for a particularly late one. The lack of a delay had something to do with the correction for blink artifacts. This is a reliable and valid procedure (Verleger et al. 1982; Berg 1986; Semlitsch et al. 1986; Kenemans et al. 1991)t. Alternatively, one might reject all trials contaminated by blinks (cf., Donchin et al. 1977; Pfefferbaum et al. 1990), but of the 7 patients included in this study, rejection of blink trials would have rendered 4 patients' data useless because less than 5 good target-tone trials would have remained if artifact trials and missing-response trials had also been excluded. (We did not instruct our subjects to refrain from blinking, since even in young university students P3s are diminished under this instruction because the instruction imposes an additional task, see Verleger 1991. For demented subjects this instruction might have even more drastic effects, both on task performance and on event-related potentials.) To get an impression of what would have happened if blinks were neither corrected nor rejected in these 4 patients, their target-tone data were averaged anew, with blink-contaminated trials included. Fig. 5 contrasts the blinks-corrected potentials with the poten-

Note that the blink correction routine was not applied to the EOG records. If this had been done, EOG tracings would have become completely flat, and displaying such tracings would not be informative. Therefore the EOG data in Figs. 2 and 4 display the "raw" EOG, which serves to illustrate the time range and the size of EOG artifacts. The EP data displayed in Figs. 2, 3 and 4 are corrected for these artifacts. Fig. 5 shows what would happen in a relevant part of the data if data contaminated by EOG artifacts were neither rejected nor corrected.

EVENT-RELATED POTENTIALS IN MILD DEMENTIA

blinks corrected blinks included

10

.........

"~/

341

become reduced and, due to this, the probability may increase that some noise peak, e.g.,, "a-ringing" or blinks, would mimick a late P3. The second reason is that counting may in fact delay P3s more than open responding in demented patients. Counting rare targets might be more demanding than simply pressing a button, since the count has to be stored in memory. More data are necessary to resolve this issue. The present data certainly do not disconfirm the notion that P3 is somewhat delayed even in mild dementia. Table II shows that the mean delay of the patients' N2b, which was significant, was not larger than the mean delay of the patients' P3, which was not. The difference between N2b and P3 in the present data is clearly that the interindividual variance of N2b latency is considerably smaller than P3's interindividual variance, both in the patients and in the control group (cf., Table II).

Fz

:"

::

Cz

N2b and mismatch negativity (MMN)

I

f

I

i

I

I

0

200

400

600

800

1000

milliseconds Fig. 5. Grand average of the potentials evoked by oddball targets, recorded in those 4 patients who blinked so often that less than 5 valid trials remained when blink trials were rejected. The bold lines display the potentials when blinks were subtracted from the EEG, as used throughout this paper. The thin lines display the potentials when blink trials were simply included, i.e., when blink trials were neither rejected nor blinks subtracted. Note the moderate-size positive potentials at Cz, Pz, and Oz, caused by blink artifacts.

tials including blinks. Relevant differences exist even at Pz and Oz, which sites are remote from the eyes. In these 4 patients, including blinks caused a median delay of P3 latency by 145 msec at Cz, and by 70 msec at Pz. Further, as was argued by Kraiuhin et al. (1990), the lack of a delay might in part be because open responses were required to the stimuli. In most studies, patients had to count silently the target tones but in 3 studies open responses were required. Of these 3 studies, two (Pfefferbaum et al. 1984; Patterson et al. 1988) obtained a relatively small difference between patients and controls and one (Kraiuhin et al. 1990) even found no difference, as in the present study. Response mode may have this effect for two reasons (cf., Kraiuhin et al. 1990). The first is a possible artifact of counting tasks. Moderately demented patients may not always be able to obey the counting instructions. Nevertheless, lacking an external criterion of which target trials were correctly processed and which ones were not, all target trials have to be averaged. Thus, the proper P3 may

Several previous studies have found that auditory N2 is delayed in demented patients (Neshige et al. 1988; Patterson et al. 1988; Ball et al. 1989; Polich et al. 1990). This delay was here replicated for N2b which was most probably measured by those studies, being the largest component of the N2 complex. In addition, it was here found that the measurable part of MMN was not delayed in the patients. That is, the delay of processing due to dementia occurred between this measurable portion of MMN and N2b. This is remarkable because when comparing the present control group with a group of young adults we found that the delay due to normal aging was already present for this early " M M N " part of the N2 complex (Verleger et al. 1991). Thus, the delay due to dementia does not seem to be an extra delay of the normal delay due to aging but may differ qualitatively. According to N~i~it~inen (e.g., N~i~it~inen 1990), MMN reflects a process that automatically matches the incoming auditory signals against a sensory trace. Provided our early peak of the N2 complex is indeed a measure of MMN, it may be concluded that the patients' MMNs were normal and that the patients were therefore relatively unimpaired in perceiving the tones and in noticing that the target tones differed from the non-targets. N2b's interpretation, on the other hand, is less clear. From the available evidence, it seems safe to conclude that N2b reflects a conscious, controlled stage of processing (N~i~it~inen 1986; Novak et al. 1990). It is also well documented that N2 both precedes the open response and is strongly correlated with response time (Ritter et al. 1979, 1982; Renault et al. 1982). So N2b might reflect the decision on how to respond. Accordingly, after having correctly noticed the mismatch (reflected by MMN), patients were apparently"impaired in deciding on the conse-

342 quences, as reflected by their delayed (and in some patients also reduced) N2b.

Special characteristics of the visual task The occipital P270 obtained in the P u s h / W a i t task cannot be compared with other data as easily as the oddball N2 since there are no studies using visual tasks in Alzheimer patients, except Pfefferbaum et al. (1984) and, recently, De Toledo-Morrell et al. (1991), and in both studies no records were made from occipital sites. It might be hard to find data recorded from normal subjects that will show a similar positive component because when we compared the control subjects of this study with young adults (Verleger et al. 1991), the occipital records did not differ between groups and did not seem to provide much information. However, there are several reports of occipital negative components occurring in young adults in the 240-300 msec time range. Such components were evoked by stimuli that were presented at an attended location (Hillyard and Miinte 1984; Wijers et al. 1989a) or that deviated by a conspicuous feature (Czigler and Csibra 1990) or that were presented in a color to be attended (Hillyard and MiJnte 1984; Wijers et al. 1989a,b). Of interest, the N240-300 was sometimes accompanied by a positive Fz component, peaking at about 200 msec. Similarly, in the present data (Fig. 4) the patients not only had less occipital negativity but also differences ~it Fz and Cz in the same time range, that may be interpreted as less frontal positivity. The N240-300 probably reflects conscious allocation of attention, so the present P270 may be seen as reflecting a failure to consciously allocate attention to a visually perceived stimulus. The most simple explanation, then, might consist of drawing a parallel between the auditory N2 and this visual P270 by assuming that the patients' occipital P270 was large in the visual task for the same reason that N2 was delayed in the auditory task, i.e., because the patients were impaired in transmitting the results of perceptual analysis to further processing. Speculatively, P270 may reflect premature deactivation of the visual areas, in analogy with parietal P3 that has been suggested to reflect deactivation of higher perceptual control (Verleger 1988). Of interest, the amplitude of P270 correlated with the number of errors in our control subjects (r (19) = 0.61, P < 0.01), thus suggesting a functional significance of the lack of positivity for successful performance. In the group of patients, this correlation was not present (r ( 6 ) = -0.03), presumably because all patients performed on a level, both in terms of P270 and errors, that only the worst-performing individuals were approaching within the control group. A further finding in the P u s h / W a i t task was that the P3 component did not change its focus from " P u s h "

R. VERLEGER ET AL. to "Wait" as it did in the control subjects and in the (normal) subjects of Pfefferbaum et al. (1985) and of Pfefferbaum and Ford (1988). Many patients' behavior in the practice trials suggested as a possible reason that the bright-dim distinction i n t e r f e r e d with the P u s h / W a i t distinction: patients tended to respond to all bright stimuli and to withhold their response with all dim stimuli. In addition, all dim stimuli seemed to be more difficult to process. Therefore bright "Push" was the easiest stimulus, combining the relevant and the irrelevant dimension in a congruent way. As Table III shows (confirmed by the brightness x meaning x recording interaction on P3 amplitude) both groups displayed a distinct parietal focus to these bright "Push" stimuli. In contrast, patients had a rather flat topography with the 3 other stimuli, perhaps reflecting their uncertainty on the nature of the stimulus and on the appropriate response. On the whole, we consider this result of minor importance, reflecting a special problem with the special configuration of stimuli presented. In conclusion, the patients' delayed N2b and enhanced P270 possibly reflected the interruption of cognitive processing after the perceptual stage. This suggests that the patients had problems in deciding what to do with the perceived stimuli. One might think of at least two reasons for this problem: it might be a problem of memory, i.e., it might have been difficult for the patients to keep in mind what response was appropriate to which stimulus. Or it might be a problem of cognitive control, i.e., it might have been difficult for the patients to coordinate their processing such that perceptual analysis could be smoothly followed by response processing. Appropriately designed experiments might help to decide between these alternatives, thus promoting our understanding of the dementing process.

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