Neurobiology of Aging, Vol. 8, pp. 109-113. ©PergamonJournals Ltd., 1987. Printedin the U.S.A.
019%4580/87$3.00 + .00
Aging Decreases Auditory
Event-Related Potentials to
Unexpected Stimuli in Humans
1
R O B E R T T. K N I G H T
Department o f Neurology, University o f California, Davis
VA Medical Center, 150 Muir Road, Martinez, CA 94553
R e c e i v e d 14 A u g u s t 1984
KNIGHT, R. T. Aging decreases auditory event-related potentials to unexpected stimuli in humans. NEUROBIOL
AGING 8(2) 109--I13, 1987.--A P300 event-related potential (P3a) was recorded to unexpected, deviant auditory stimuli
requiring no behavioral response. This brain potential underwent systematic latency prolongation and amplitude decrease
with advancing age. The age-related changes paralleled those of the P300 (P3b) recorded in target detection tasks. These
results provide physiological evidence of a decremented CNS response to unexpected stimuli with aging.
Orienting response
P300
Aging
TWO subtypes of P300 event-related brain potentials
(ERP's) have been described. Tasks which require subjects
to detect the occurrence of infrequently occurring stimuli
(targets) generate a parietally distributed P300 (P3b) in all
sensory modalities. This is often preceded by an N200 potential which has a modality specific scalp distribution
[21,22]. Numerous laboratories have reported that the P3b
undergoes either latency prolongation or a combined latency
prolongation and amplitude diminution with advancing age
[3, 7, 8, 13, 17, 18].
Whereas P3b generation requires active subject participation in the behavioral task, delivery of deviant, unexpected stimuli (novels) requiring no overt behavioral response also generates a P300 wave (P3a). In contrast to the
P3b, the P3a is equipotential in amplitude at midline scalp
sites, occurs approximately 50 msec earlier than the P3b in
both the visual and auditory modalities and undergoes rapid
habituation over repeated trials. Based on these characteristics the P3a to deviant, unexpected stimuli has been
proposed to represent a CNS component of the orienting
response [5, 11, 20, 23, 26].
The novelty P3a has not received as much clinical attention as the target P3b, although its independence from behavioral response makes it a potentially valuable tool for
analysis of orientation ability in clinical syndromes, particularly those in which behavioral output or cooperation might
be impaired. Although the orienting response is reportedly
reduced with advancing age, only a few studies in the visual
modality have investigated the effects of age on the P3a.
Both latency prolongation and latency prolongation coupled
with amplitude decrements of the P3a have been reported
[2,24]. In order to examine whether a decrease in the P3a is a
generalizable effect across stimulus modalities, we investigated the effects of age on the P3a generated to deviant,
unexpected auditory stimuli.
METHOD
Subjects
An initial group of 27 subjects ranging in age from 21 to 71
was recruited after exclusion of subjects with history of
audiological or neurological disease. All subjects had normal
neurological exams and were naive to the experimental procedures.
Procedure
The experiments were conducted with the subjects comfortably seated in a reclining chair in a sound attenuated
room. In each ear, audiometric thresholds at 500 and 1500
Hz were determined by the method of ascending and descending limits. Briefly, stimuli were decremented in 2dB
steps until the subject behaviorally reported disappearance
of the tones. The tones were then incremented in 2dB steps
until the tones reappeared. The entire procedure was repeated three times and the mean obtained was defined as the
subject's threshold (SL). Five subjects with greater than 15
dB interaural threshold difference were excluded from
further analysis leaving a group of 22 subjects. This group
was divided into 10 subjects below 45 and 12 above. At 500
1This research was supported by the Medical Research Service of the Veterans Administration and by grants from the NIH (NS 21135) (R.
T. Knight).
109
110
KNIGHT
TABLE 1
AMPLITUDE IN MICROVOLTS (-+SEM) AND LATENCIES IN MILLISECONDS (+-SEM) FOR THE N200, SLOW NEGATIVITY AND P300
RECORDED TO EITHER TARGET OR NOVEL AUDITORY STIMULI
Targets Alone
N200
Slow
Negativity
P300
Novels
Fz
Cz
Pz
Latency
Fz
Cz
Pz
Latency
4.8_+1.0
7.4_+1.5
5.7_+1.5
6.8_+1.8
0.9-+0.9
0.5_+0.9
231.3-+ 8.0
586 +_18
5.7+1.7
4.1-+1.1
9.6-+1.5
3.6+1.2
4.6+1.5
0.2-+1.1
222-+ 8
526_+14
6.5-+1.5
7.1_+2.5
11.7_+2.5
406 _+ 9.0
11.3_+2.3
12.1+1.7
11).9+1.5
361+ 8.0
YOUNG
AGED
23
71
69
62
I
I
300
,
,
I
+
I
,
t
SO0
NOVELTY
L
3o0
,
,
t
,oo
P300
FIG. 1. Event-related potentials to a deviant, unexpected auditory stimulus (novel)
in three young and three aged subjects. Note the decreased novelty P300 (P3a) in
the aged group (hatched area) accompanied by a decrease in the tbllowing
negativity. Each tracing is the average of 20 trials from the Pz electrode.
H z the m e a n d b difference b e t w e e n t h e s e two g r o u p s
s h o w e d a n e l e v a t i o n of 6.2_+3.1 dB at 500 H z a n d 9.4-+4.3 dB
at 1500 H z in the elderly group. In o r d e r to a c c o u n t for the
t h r e s h o l d i n c r e a s e w i t h age, all stimuli w e r e p r e s e n t e d
binaurally at 45 dB a b o v e e a c h individual t h r e s h o l d at 1500
H z (45 d B S L ) . T o n e s w e r e d e l i v e r e d t h r o u g h s t e r e o headp h o n e s w h i c h p r o d u c e d a s u b j e c t i v e midline s o u n d localization.
T w o different t o n e s e q u e n c e s w e r e used. T h e first seq u e n c e w a s d e s i g n e d to elicit only a t a r g e t P3b. It c o n s i s t e d
o f 3 b l o c k s o f t o n e s e a c h lasting 3 m i n u t e s w i t h e a c h b l o c k
c o n t a i n i n g 150 t o n e s o c c u r r i n g e v e r y s e c o n d . In this seq u e n c e 91.4% o f the t o n e s w e r e at 500 H z a n d 200 m s e c
d u r a t i o n ( d e s i g n a t e d s t a n d a r d s ) a n d 8.6% o c c u r r e d r a n d o m l y
at 375 H z a n d 200 m s e c d u r a t i o n ( d e s i g n a t e d targets). T h e
subjects w e r e i n s t r u c t e d to p r e s s a b u t t o n w h e n they det e c t e d a t a r g e t tone. A c c u r a c y a n d n o t s p e e d was stressed.
T h e s e c o n d s e q u e n c e was d e s i g n e d to elicit b o t h a target
P3b a n d a n o v e l t y P3a. It c o n s i s t e d of 500 H z s t a n d a r d s
(82.8%), 375 H z r a n d o m l y o c c u r r i n g t a r g e t t o n e s (8.6%) and,
in addition, a r a n d o m l y o c c u r r i n g s i m u l a t e d d o g b a r k (160
msec d u r a t i o n , 8.6%) d e s i g n a t e d as the " ' n o v e l " stimulus.
T h e dog b a r k was m a t c h e d in l o u d n e s s to the target 375 Hz
tone by n o r m a l listeners a n d had a p e a k to peak voltage
slightly less t h a n e i t h e r o f the pure tones. T h e r e were no
large t r a n s i e n t s in the novel stimulus a n d its spectral e n e r g y
c e n t e r e d at 1600 Hz. S u b j e c t s w e r e not w a r n e d o f the occurr e n c e o f the dog b a r k and were i n s t r u c t e d to c o n t i n u e pressing a b u t t o n only w h e n they d e t e c t e d the target 375 H z stimuli. T h e s i m u l a t e d dog b a r k was c h o s e n as the n o v e l stimulus
since in prior studies it h a d b e e n s h o w n to elicit large e v o k e d
r e s p o n s e s w h i c h did not h a b i t u a t e in a m p l i t u d e after the first
two or t h r e e stimuli [1 I]. T h i s p e r m i t t e d us to o b t a i n c l e a r
a v e r a g e s with a small n u m b e r of stimuli a n d also allowed us
to e x a m i n e single trial r e s p o n s e s in s o m e subjects.
B r a i n electrical activity was r e c o r d e d with Ag/AgCI electrodes placed at Fz, Cz, Pz and u n d e r the right eye, all refere n c e d to linked m a s t o i d s . T h e E E G was amplified ( b a n d p a s s
0.1-70 c/sec) and stored o n F M tape for off-line a n a l y s i s by a
c o m p u t e r . T h e a v e r a g i n g e p o c h was 1024 m s e c , including
100 m s e c o f p r e - s t i m u l u s baseline. I n d i v i d u a l trials with exc e s s i v e m u s c l e activity or eye blinks w e r e e x c l u d e d .
E V E N T - R E L A T E D POTENTIALS IN AGING
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AGE
AGE
FIG. 2. Amplitude of novelty P3a in microvolts as a function of age
in years. Data from the Pz electrode.
FIG. 3. Latency of novelty P3a in microvolts as a function of age in
years. Data from the Pz electrode.
The P300 components to both the target and novel stimuli
were defined as the most positive peak occurring in a poststimulus window of 250-450 msec. Latency was measured at
the peak positivity in this window and amplitude at this latency point was measured relative to the pre-stimulus
baseline. In 5 subjects (3 under 40, 2 above 60) a clear
bipeaked P300 was observed and latency was taken at the
intersection of the descending and ascending slopes of the
positivity in the 250-450 msec window. Amplitude was
measured in microvolts at the most positive point in the
250-450 msec epoch in all cases. The N200 was defined as
the most negative peak occurring in a post-stimulus window
of 150-250 msec and the negative slow wave was defined as
the most negative peak occurring 400-700 msec post
stimulus. Latency and amplitude measures were obtained at
these points and the data were subjected to linear regression
with calculation of Pearson coefficients (r).
(I.29 msec/year, r--.62, p<0.005) and amplitude diminished
(at Pz=0.21/~V/year, r = - . 7 1 , p<0.001) in the targets alone
condition. Similarly for the P3b during the targets plus novel
condition, latency increased (1.35 msec/year, r=.57,
p<0.025) and amplitude diminished (at Pz=0.23 /~V/year,
r = - .66, p <0.025).
A centrally distributed N200 (231 msec) was generated to
target stimuli. No systematic changes in N200 amplitude or
latency with age were observed in either condition (target
alone, at Cz r=.35, p = n . s , for amplitude vs. age). A frontocentral negative slow wave (586 msec for targets alone, 601
msec for targets plus novels) similarly did not show clear
evidence of age-related changes in amplitude or latency
(targets alone, Cz, r=.34, p = n . s , for amplitude vs. age).
Novelty ERPs. In contrast to the parietal maximal P3b,
the novel stimulus elicited an equipotential amplitude P3a at
Fz, Cz and Pz (see Table l) with a mean latency of 361 msec.
Similar to the target P3b systematic decreases in the novelty
P3a were observed with increasing age (see Fig. 1). P3a amplitude underwent a progressive diminution at all electrode
sites with a decrease of 0.38 /xV/year at the Pz electrode
( r = - . 8 4 , p<0.001, see Fig. 2). Latency also systematically
lengthened at a rate of 1.13 msec/year (4=.60, p<0.01, see
Fig. 3).
An enhanced centrally distributed N200 (222 msec) was
generated by the novel stimulus. As for the target stimulus,
systematic age-related changes were not observed in amplitude or latency. The novel stimulus generated a frontocentral slow wave (526 msec). The novelty slow wave did
undergo an age-related decrease in amplitude at all electrode
sites (at Cz=0.19/~V/year, r = - . 6 4 , p<0.005), although no
systematic changes in latency were observed.
RESULTS
Behavior
During both conditions (target alone, target plus unexpected novels) all subjects performed at near ceiling levels
with rare misses of targets. Overall target detection was
99.2°~ for the targets alone condition and 98.4% for the
targets plus novel condition. False alarms were rare to the
novel stimulus. Three subjects were eliminated from electrophysiological analysis due to excessive eye blink artifactual contamination of the EEG.
Event-Related Potentials
Target ERPs. In the remaining 19 subjects a well delineated parietal maximal P3b was observed (see Table 1)
with a mean latency of 406 msec in the targets alone condition and 411 msec in the targets plus novel condition. This
difference was not significant. Both the latency and the amplitude of the P3b underwent comparable systematic changes
with increasing age in both the targets alone and the targets
plus novels conditions. Latency progressively increased
DISCUSSION
These results provide evidence of parallel age-related
changes in the P3b generated in active target detection tasks
and in the P3a generated to an unexpected stimulus requiring
no overt behavioral response. Both these potentials undergo
112
KNIGHT
a comparable progressive amplitude diminution and latency
prolongation with increasing age. The P3b results of latency
prolongation coupled with amplitude diminution are similar
to those reported in the visual and auditory modalities by
others [3, 7, 8, 13, 18, 27]. The auditory novelty P3a findings
of age-related amplitude diminution and latency prolongation
are c o m p a r a b l e to the changes reported in the visual novelty
P3a [2,24]. It is unlikely that the d e c r e a s e in the P3a is due to
peripheral age-related hearing loss since the stimuli were delivered at a fixed dB above each subject's threshold which
was near the peak threshold of the deviant auditory stimulus.
F u r t h e r m o r e only the P300 and not the N200 to the deviant
stimulus was d e c r e m e n t e d with age. The parallel findings in
the visual and auditory modalities of an age related decrease
in the novelty P3a provide e v i d e n c e o f a generalized decrease in response to u n e x p e c t e d stimuli with advancing age.
A more general question arises in separating late positive
potentials into a P3a and P3b classification. For instance, in
the current paradigm our P3a to the deviant stimulus might be
considered simply a N o - G O P3b response. Several lines of
evidence, h o w e v e r , indicate that the P3a to deviant stimuli is
a separate brain potential from the P3b. The P3a to deviant
auditory and visual stimuli has a more frontal distribution
and occurs approximately 50 msec earlier than the P3b generated in N O - G O tasks [5, 10, 11, 30]. In addition recent
intracerebral recordings in pre-surgical epileptics report an
earlier, frontal P300 response which may be a depth analogue
of the surface P3a [29].
Both the target and novelty P300 may represent neural
elements of a c o m m o n cerebral mismatch d e t e c t o r underlying the orienting response [25] with the target P3b generated
by active and the novelty P3a generated by passive engage-
ment of the circuitry activated during orientation. The prolonged latency of the target P3b relative to the novelty P3a
may be related to the interposed decision processes required
in identifying the stimulus as a target and subsequently
orienting to it, whereas highly deviant unexpected stimuli
would generate a novelty P3a without the need of an intervening decision process.
We did not find e v i d e n c e of an age-related decrease in the
N200 generated to either target or novel stimulus. This may
in part be due to the large P300 responses recorded in the
young subjects which partially obscured the N200 response.
The slow negative w a v e to the novel stimulus occurring after
the P300 did undergo a systematic decrease in amplitude
with age. This is not surprising since this potential is
routinely found to a c c o m p a n y the novelty P3a in orienting
experiments [ 12].
The neural substrate underlying the age related changes in
P3a and P3b is uncertain, although the fact that amplitude
and latency for both the P3a and P3b undergo parallel
changes with aging suggests that these brain potentials may
share elements of a c o m m o n neural system. Various
generator sites of the P300 potential have been proposed
including sources in neocortical, limbic, thalamic and corpus
callosum regions [6, 9, 16, 19, 31]. The recent attempts to
develop an animal model of P300 may help to resolve these
critical anatomical questions [1, 4, 14, 15,281.
ACKNOWLEDGEMENTS
1 would like to thank Neal Cohen for use of stimulus tapes developed by him and David Woods for helpful discussions of the data.
REFERENCES
1. Arthur, D. L and A. Starr. Task-relevant late positive component of the auditory event-related potential in monkeys resembles P300 in humans. Science 223: 186-188, 1984.
2. Beck, E. C., C. Swanson and R. E. Dustman. Long latency
components of the visually evoked potential in man: effects of
aging. Exp Aging Res 6: 523-545, 1980.
3. Brown, W. S., J. T. Marsh and A. LaRue. Exponential electrophysiological aging: P3 latency. Electroencephalogr Clin
Neurophysiol 55: 277-285, 1983.
4. Buchwald, J. S. and N. S. Squires. Endogenous auditory potentials in the cat: A P300 model. In: Conditioning, edited by C.
D. Woody. New York: Plenum Publishing Co., 1982, pp. 503515.
5. Courchesne, E., S. A. Hillyard and R. Galambos. Stimulus
novelty, task relevance and the visual evoked potential in man.
Electroeneephalogr Clin Neurophysiol 39:131-143, 1975.
6. Desmedt, J. E. Scalp-recorded cerebral event-related potentials
in man as point of entry into the analysis of cognitive processing. In: The Organization of the Cerebral Cortex, edited by F.
O. Schmitt, F. G. Worden, G. Adelman and S. D. Dennis. Cambridge, MA: M.I.T. Press, 1981, pp. 441-473.
7. Ford, J. M., C. C. Duncan-Johnson, A. Pfefferbaum and B. S.
Kopell. Expectancy for events in old age: stimulus sequence
effects on P300 and reaction time. J Gerontol 37: 696-704, 1982.
8. Goodin, D. S., K. C. Squires, B. H. Henderson and A. Starr.
Age-related variation in evoked potentials to auditory stimuli in
normal healthy subjects. Eleetroencephalogr Clin Neurophysiol
44: 447-458, 1978.
9. Halgren, E., N. K. Squire, C. L. Wilson, J. W. Rohrbaugh, T.
L. Babb and P. H. Crandall. Endogenous potentials generated
in the human hippocampal formation and amygdala by infrequent events. Science 210: 803-805, 1980.
10. Karlin, L., M. J. Martz, S. E. Brauth and A. M. Mordfkoff.
Auditory evoked potentials, motor potentials and reaction time.
Electroen('ephalogr Clin Neurophysiol 31: 129-136, 1971.
1I. Knight, R. T. Decreased response to novel stimuli after prefi-ontal lesions in man. Ele('troen('eplmlo~,,r Clin Neurophy.~iol 59:
9-20, 1984.
12. Loveless, N. The orienting response and evoked potentials in
man. In: Orienting and Habituation: Per.weetives in Human
Research. edited by D. Siddle. New York: John Wiley and Sons
Ltd.. 1983, pp. 71-108.
13. Michaelweski, H. J.. M. A. Patterson, T. E. Bowan, D. K.
Litzleman and L. W. Thompson. A comparison of the emitted
late positive potential in older and young adults. J Gerontol 37:
52-58, 1982.
14. Neville, H. J. and S. L. Foote. Auditory event-related potentials in the squirrel monkey: parallels to human late wave responses. Brain Re.s 298: 107-116, 1984.
15. O'Brien, J. H. P300 wave elicited by a stimulus-change
paradigm in acutely prepared rats. Phy~siol Behav 28:711-713.
1982.
16. Okada, Y. C., L. Kaufman and S. J. Williamson. The hippocampal formation as source of the slow endogenous potentials. Ele~'troencephahL~,r Clin Neurophy.~iol 55:417-426, 1983.
17. Pfefferbaum, A., J. M. Ford, W. T. Roth and B. S. Kopell.
Age-related changes in auditory event-related potentials. Ele¢'troeneephalogr Clin Neurophysiol 49: 266-276, 1980.
18. Pfefferbaum, A., J. M. Ford, B. G. Wenegrat, W. T. Roth and
B. S. Kopell. Clinical applications of the P3 component of
event-related potentials I. Normal Aging. Eleetroencephalogr
Clin Neurophysiol 59: 85-103, 1984.
EVENT-RELATED
POTENTIALS
IN AGING
19. Radilova, J., J. Kropotov, J. Gogolicin, N. Bechtereva and T.
Radii. The late positive component of EEG evoked responses in
patients with implanted electrodes. Act Nerv Super (Praha) 25:
174-175, 1983.
20. Ritter, W., H. G. Vaughan, Jr. and L. D. Costa. Orienting and
habituation to auditory stimuli: a study of short term changes in
averaged evoked responses. Electroencephalogr Clin Neurophysiol 25: 550-556, 1968.
21. Ritter, W., R. Simson, H. G. Vaughan, Jr. and M. Macht. Manipulation of event-related potential manifestations of information processing stages. Science 218: 90%911, 1982.
22. Simson, R., H. G. Vaughan, Jr. and W. Ritter. The scalp topography of potentials associated with missing visual or auditory
stimuli. Electroencephalogr Clin Neurophysiol 40: 33-42, 1976.
23. Snyder, E. and S. A. Hillyard. Long-latency evoked potentials
to irrelevant, deviant stimuli. Behav Biol 16: 31%331, 1976.
24. Snyder, E. and S. A. Hillyard. Changes in visual event-related
potentials in older persons. In: Bayer-Symposium VII, Brain
Function in Old Age, edited by F. Hoffmeister and C. Muller.
Berlin: Springer-Verlag, 1979, pp. 112-125.
25. Sokolov, E. N. Higher nervous functions: the orienting reflex.
Annu Rev Physiol 25: 545-580, 1963.
113
26. Squires, N. K., K. C. Squires and S. A. Hillyard. Two varieties
of long-latency positive waves evoked by unpredictable auditory stimuli in man. Electroencephalogr Clin Neurophysiol 38:
387-401, 1975.
27. Syndulko, K., E. C. Hansch, S. N. Cohen W. Pearce, Z.
Goldberg, B. Montan, W. W. Tourtellotte and A. R. Potvin.
Long-latency event-related potentials in normal aging and dementia. In: Clinical Application of Evoked Potentials in Neurology, edited by J. Courjon, F. Mauguiere and M. Revol. New
York: 1982, pp. 27%285.
28. Wilder, M. B., G. R. Farley and A. Starr. Endogenous late
positive component of the evoked potential in cats corresponding to P300 in humans. Science 211: 605-607, 1981.
29. Wood, C. C. and G. McCarthy. A possible frontal lobe contribution to scalp P300. Soc Neurosci Abstr l h 879, 1985.
30. Woods, D. L. and E. Courchesne. The recovery functions of
auditory event-related potentials during split-second discrimination. Electroencephalogr Clin Neurophysiol 65: 304-315,
1986.
31. Yingling, C. D. and Y. Hosobuchi. A subcortical correlate of
P300 in man. Electroencephalogr Clin Neurophysiol 59: 72-76,
1984.