Age-Related Changes in Processing Auditory Stimuli During Visual Attention: Evidence for Deficits in Inhibitory Controls and Sensory Memory

Transcription

1 Age-Related Changes in Processing Irrelevant Stimuli 1 Age-Related Changes in Processing Auditory Stimuli During Visual Attention: Evidence for Deficits in Inhibitory Controls and Sensory Memory Claude Alain Rotman Research Institute, Baycrest Centre for Geriatric Care and Psychology Department, University of Toronto, Canada David L. Woods Department of Neurology and Center for Neuroscience, University of California at Davis, and Northern California System of Clinics, Martinez, California

2 Age-Related Changes in Processing Irrelevant Stimuli 2 Abstract Age-related declines in performance during selective attention tasks have been associated with a difficulty in inhibiting the processing of task-irrelevant information (i.e., the inhibitory deficits hypothesis). However, evidence supporting the inhibitory deficit hypothesis remains equivocal, in part because of complexities in examining the processing of irrelevant stimuli using purely behavioral techniques. We investigated the processing of task-irrelevant auditory stimuli in young, middle-aged, and older adults using scalp recordings of event-related brain potentials (ERPs). Participants performed a visual discrimination task while standard and deviant auditory stimuli were presented in the background. Visual targets generated P3b responses that were reduced in amplitude and delayed in latency with increasing age. Deviant auditory stimuli generated a mismatch negativity (MMN) wave that decreased with age, in part because of an age-related enhancement in responses evoked by the task irrelevant auditory standard stimuli. The age-related changes in processing task-irrelevant auditory stimuli is consistent with the inhibitory deficit hypothesis. The results also suggest that impaired inhibitory control of sensory input may play a role in the agerelated decrements in MMN amplitude that appear to be a reliable correlate of aging.

3 Age-Related Changes in Processing Irrelevant Stimuli 3 Age-Related Changes in Processing Auditory Stimuli During Visual Attention: Evidence for Deficits in Inhibitory Controls and Sensory Memory Selective attention is an essential component of day-to-day functioning that enables us to preferentially process high priority signals at the expense of less task-relevant information. Recent empirical work has shown that selectively attending to auditory or visual stimuli enhances neural activity and blood flow in the corresponding sensory cortices (e.g., Grady et al., 1997; Heinze et al., 1994; Tzourio et al., 1997; Woldorff et al., 1993; Woodruff et al., 1996). This increase in neural activity is consistent with the hypothesis that selective attention amplifies the processing of sensory information at the central focus or spotlight of attention. Evidence from single-cell recordings (Hocherman, Benson, Goldstein, Heffner, & Hienz, 1976), scalp recordings of cortical evoked brain activity (Alho, Woods, Algazi, & Näätänen, 1992; Woods, Alho, & Algazi, 1992) and functional neuroimaging studies (Haxby et al., 1994; O'Leary et al., 1997; Roland, 1982) suggest that selective attention to one modality (e.g., visual) also modulates neural activity in brain areas that process sensory stimuli of an unattended modality (e.g., auditory). Together, these findings are consistent with a dual-process of selective attention in which processing of relevant input is facilitated while processing of task-irrelevant stimuli is suppressed during focused attention (e.g., Woods, 1990). Several studies have shown that the ability to selectively attend to visual or auditory stimuli is impaired by the aging process (e.g., Alain, Ogawa, & Woods, 1996; Allen, Weber, & Madden, 1994; Barr & Giambra, 1990; Karayanidis, Andrews, Ward, & Michie, 1995; Madden, 1990; McCalley, Bouwhuis, & Juola, 1995; Rabbitt, 1965). For example, older adults have more difficulty than young adults in detecting infrequent auditory targets embedded in a sequence of distractors (Alain et al., 1996; Karayanidis et al., 1995). Impaired inhibitory control has been proposed as a

4 Age-Related Changes in Processing Irrelevant Stimuli 4 mechanism responsible for these age-related declines in performance (Hasher & Zacks, 1988; McDowd & Filion, 1992; Rabbitt, 1965). That is, older adults would have more difficulty than young adults in inhibiting the influence of task-irrelevant information. Consistent with this proposal are results showing increased intrusion errors during free recall (Stine & Winfield, 1987), increased Stroop interference (Comalli, 1962; Hoox, Jolles, & Vreeling, 1993; West & Alain, Submitted), and impaired performance in delayed recognition tasks, particularly when the delay intervals are filled with distractors (Chao & Knight, 1997). Central to the inhibitory deficit hypothesis (Hasher & Zacks, 1988) is the assumption that the processing of task-irrelevant stimuli is sensitive to the aging process. Although behavioral studies have shown that task-irrelevant information can cause more interference in older adults than in young adults, they say little about the effects of age on the processing of task-irrelevant information itself. Psychophysiological measures such as event-related brain potentials (ERPs) provide a more direct method for assessing the effects of aging on the processing of task-irrelevant information. However, psychophysiological investigations have provided mixed results. Using the skin conductance response, McDowd and Filion (1992) found that young adults habituated more quickly to infrequent task-irrelevant tones than older adults, suggesting an age-related decline in inhibitory control. In studies measuring ERPs during attention tasks, older adults often show enhanced amplitude of sensory evoked responses to irrelevant auditory stimuli (e.g., Chao & Knight, 1997; Pekkonen et al., 1995; Woods & Clayworth, 1986). This age-related enhancement in sensory evoked responses may indicate that older participants allocated more processing resources to the taskirrelevant stimuli than the young adults. However, in other ERP studies, young and old adults have exhibited similar sensory evoked response amplitudes (e.g., Ford et al., 1979; Ford et al., 1995;

5 Age-Related Changes in Processing Irrelevant Stimuli 5 Iragui, Kutas, Mitchiner, & Hillyard, 1993; Schroeder, Lipton, Ritter, Giesser, & Vaughan, 1995a; Vesco, Bone, Ryan, & Polich, 1993). The discrepancy between these studies may result from procedural differences in the presentation of auditory stimuli. In studies that showed an age-related increase in sensory evoked responses, the stimuli were presented at a constant intensity above audiometric threshold. Because hearing sensitivity diminishes with increasing age, older adults were thus presented with physically louder tones which may have contributed to the larger observed brain responses. In the current study, we investigated the age-related changes in processing task-irrelevant stimuli using the mismatch negativity (MMN) wave of ERPs. The MMN wave is elicited by deviant stimuli embedded in sequences of standard stimuli. The deviant sounds may differ from the standard sounds in such dimensions as frequency, duration, intensity, spatial location, or spectral pattern (Näätänen, 1992; Näätänen et al., 1997). The MMN can also be generated by deviations from simple auditory patterns, such as occasional repetitions occurring in a sequence of tones that otherwise alternate regularly in frequency (Alain, Woods, & Ogawa, 1994; Nordby, Roth, & Pfefferbaum, 1988). The MMN is isolated as the difference wave between the ERPs to standard and deviant tones, and peaks at a latency of ms post-stimulus over midline frontal areas. In his influential review, Näätänen has suggested that the MMN reflects a neural mismatch between an incoming stimulus and the transient representation of sounds in short-term memory (Näätänen, 1992). MMN generation depends on the ability to maintain a memory of the standard stimulus presented and, thus, provides a direct and noninvasive measure of auditory sensory memory (Näätänen, 1992; Ritter, Deacon, Comes, Javitt, & Vaughan, 1995; Winkler & Näätänen, 1992). For instance, deviant stimuli

6 Age-Related Changes in Processing Irrelevant Stimuli 6 presented alone do not generate an MMN (Näätänen, Paavilainen, Alho, Reinikainen, & Sams, 1989) and backward masking reduces MMN amplitudes in a manner that corresponds to performance decrements (Winkler & Näätänen, 1992; Winkler & Näätänen, 1995). The MMN is particularly well-suited for studying age-related changes in processing taskirrelevant stimuli because it is elicited in paradigms in which overt attention and behavioral responses are not required (e.g., when participants read a book). Because the MMN is isolated in a difference wave between the ERP to standard and deviant stimuli, it is less sensitive to peripheral factors such as hearing sensitivity which would affect ERPs elicited by standard and deviant stimuli in a similar manner. Thus, the MMN provides a unique tool for investigating age-related changes in processing task-irrelevant stimuli and for examining whether sensory memory, as indexed by the MMN, is affected by the aging process. However, electrophysiological studies examining the age-related changes in the MMN have yielded equivocal results. Older adults have been found to have a smaller MMN amplitude than young adults in some studies (Czigler, Csibra, & Csontos, 1992; Karayanidis et al., 1995; Woods, 1992), but in other studies, young and older adults show similar MMN amplitudes (Gunter, Jackson, & Mulder, 1996; Schroeder, Ritter, & Vaughan Jr, 1995b). In another study, reduced MMN amplitude was observed in older adults only when the stimuli were presented at long inter-stimulus intervals, e.g., 3 seconds, whereas no age-related reduction in MMN amplitude was observed when the stimuli were presented at relatively short inter-stimulus intervals (e.g., 1 second, Pekkonen, Jousmaki, Partanen, & Karhu, 1993; see also Pekkonen et al., 1996). The inconsistency between these studies may be related to differences in the control and monitoring of participants attention. That is, age-related differences in MMN amplitude were consistently reported when the participants

7 Age-Related Changes in Processing Irrelevant Stimuli 7 performance at the primary task was behaviorally monitored such as during selective attention tasks. In contrast, no consistent age-related differences in MMN amplitude was found when participants read a book of their choice. It is also difficult to determine whether the age-related changes in MMN amplitude was due to age-related changes in neural refractory period or the mismatch process itself because previous studies only included deviants that differ along some physical dimension from the standards. Evidence from dipole source modeling (Scherg, Vajsar, & Picton, 1989) suggests that the difference wave used to isolate the MMN does not reflect a unitary phenomenon but can be divided into two parts: (1) a component that represents the activation of non-refractory auditory neurons; and (2) a true mismatch process. The goal of the current study was to determine whether the processing of task-irrelevant stimuli is affected by the aging process. To test the age-related decline in inhibitory processing, we compared ERPs elicited by standard and deviant auditory stimuli in young, middle-aged and older adults while they performed a visual discrimination task. An age-related change in ERP amplitude elicited by task-irrelevant stimuli would provide evidence supporting the inhibitory deficit hypothesis. In different blocks of trials, participants were presented with either: (1) a sequence of identical tones that included small and large frequency-deviant stimuli or; (2) a sequence of tones alternating regularly in frequency with deviant repetitions (see Figure 1). Small and large frequency deviant stimuli were used to examine the effect of deviation magnitude on the MMN as a function of age. The alternating tone pattern was included because it is particularly well-suited to evaluate pure mismatch processes. That is, the MMN to pattern-deviant stimuli does not receive any contribution from new afferent inputs because it is elicited by the repetition of a tone. Thus, if the MMN decrement in older adults results from a fundamental impairment in the mismatch process,

8 Age-Related Changes in Processing Irrelevant Stimuli 8 we should observe impaired MMN generation for both pattern and frequency deviance. Both types of sequences were also included to determine whether different patterns of age-related changes would be seen in different varieties of MMNs. Two other design features deserve mention. First, the auditory sequences were presented to either the left or the right ear to evaluate hemisphere asymmetry that has been previously reported (Alain et al., 1994; Paavilainen, Alho, Reinikainen, Sams, & Näätänen, 1991). Second, a group of middle-aged participants was included to more fully characterize age-related changes in auditory processing across the adult life span. SMALL CHANGES IN FREQUENCY FREQUENCY * CHANGES IN PATTERN FREQUENCY * TIME Figure 1 Schemata of the stimuli used. Top: Sequence of identical stimuli mixed with rare frequency-deviant stimuli. Bottom: Sequence of tones alternating regularly in frequency with occasional repetition breaking the alternation. In both sequences, deviant stimuli are shown by an asterisk.

9 Age-Related Changes in Processing Irrelevant Stimuli 9 Method Participants Twelve young (aged between 19 and 30 years, mean = 23.2 ± 3.7 years, 6 men), 12 middleaged (between 36 and 54 years, mean = 43.3 ± 6.6 years, 7 men) and 14 older adults (between 57 and 82 years, mean = 65.7 ± 6.3 years, 6 men) volunteered their time or participated for pay. All participants were screened for neurological or psychiatric disease and drug or alcohol abuse. All participants reported normal or corrected-to-normal vision. Participants were audiometrically screened for excessive hearing loss. Young and middle-aged participants had normal hearing within the frequency range used in the current study (below 15 db HL in all cases), whereas six older participants showed mild hearing loss for high frequencies (between 20 and 35 db hearing loss). The young adults were recruited from local colleges whereas the middle-aged and older adults were recruited from local volunteer groups. Middle-aged and older adults had at least a college degree. All participants gave informed consent according to University of California at Davis and Veterans Administration Medical Center guidelines. Stimuli and Task Participants were presented with two different auditory sequences in a sound attenuated chamber. In one, repeated standard tones (1000 Hz) were mixed with rare deviant tones differing in frequency (1122 or 1414 Hz, probability = 3% each). In the other, a pattern of tones that alternated regularly in frequency (500 and 2000 Hz) was presented with occasional deviant repetitions (probability = 3% for both frequencies). Monaural stimuli (100 ms in duration, 10 ms

10 Age-Related Changes in Processing Irrelevant Stimuli 10 1 rise/fall times, 85 db SPL ) were delivered at a very rapid rate with fixed intervals of 200 ms between consecutive stimuli. Sound intensities were identical for all participant groups. The auditory sequence was presented to one ear with broadband noise (65 db SPL) presented in the opposite ear. Participants were instructed to ignore the auditory stimuli. To control for attention, participants performed a continuous visual discrimination task during the auditory presentation. The visual stimuli consisted of five thick (probability 80%) and five thin vertical bars subtending visual o o o o angles of 2.5 x 0.5 and 2.5 x 0.3, respectively. The bars were presented at central fixation on a o o monitor subtending 14 x 11 at a distance of 160 cm from the participant, with a luminance of cd/m over a gray background (6.2 cd/m ). The bars were presented for 57 ms at central fixation. Inter-stimulus intervals (ISI) between visual stimuli ranged from 450 to 1450 ms (mean 850 ms) according to a rectangular distribution. Participants were asked to attend to the visual stimuli and press a button as fast as possible whenever thin vertical bars appeared (i.e., the targets). The reaction times (RTs) were analyzed for correct trials only, i.e., trials with RTs between 200 and 1000 ms after the thin bars were presented. Responses at other times were classified as false alarms. The accuracy was obtained by subtracting the number of false alarms from the number of correct responses. All participants were presented with four conditions defined by the combination of the two ears and the two sequence types. Trials were blocked by condition and the order of conditions was counterbalanced across participants. Participants were presented with 12 blocks of trials. Each stimulus block contained 220 visual stimuli including 44 targets (probability = 20%) and 734 auditory stimuli including 44 deviant sounds (probability = 6%). In total, 2640 visual and 8800 auditory stimuli were presented to each participant.

11 Age-Related Changes in Processing Irrelevant Stimuli 11 Electrophysiological Recording The electroencephalogram (bandpass Hz, 256 Hz/channel sampling rate) was recorded from 28 electrodes over the scalp (Fp1, Fpz, Fp2, nose, left pre-auricular, right preauricular, T1, F7, F3, Fz, F4, F8, T2, left mastoid, T3, C3, Cz, C4, T4, right mastoid, T5, P3, Pz, P4, T6, O1, Oz and O2). Vertical and horizontal eye movements were recorded from electrodes lateral and below the left eye. All electrodes were referenced to four interconnected electrodes at the base of the neck, balanced through a potentiometer to cancel electrocardiogram artifacts (Woods & Clayworth, 1985). The analysis epoch included 200 ms of pre-stimulus activity and 800 ms post-stimulus activity. Trials contaminated by excessive eye movements, peak-to-peak deflection, or amplifier saturation were automatically rejected before averaging. ERPs were then averaged separately for visual and auditory stimuli and each stimulus type (standards, deviants, and targets). The amplitude of ERP components elicited by visual (the N1, N2, and P3b) and auditory (e.g., N1 and MMN) stimuli were quantified using mean voltage measures relative to a 200-ms pre-stimulus baseline. The MMN was measured in the difference waveform between the standard and deviant auditory stimuli. The effects of age and deviant-type on the MMN amplitude were tested at Fz using analysis of variance for repeated measure with group, deviant-type, and ear of stimulation as factors. In comparing the MMN scalp distribution elicited by different deviant-types in young, middle-aged and older adults, the data were first normalized to control for Group x Electrode or Deviant-Type x Electrode interactions resulting from amplitude differences among the group or deviant type (McCarthy & Wood, 1985). Data from the electrodes lateral and below the left eye as well as the one placed on the tip of the nose were omitted from scalp topography analyses.

12 Age-Related Changes in Processing Irrelevant Stimuli 12 All measurements were subjected to within and between group analysis of variance (ANOVA). Type I errors associated with inhomogeneity of variance was controlled by decreasing the degrees of freedom using the Greenhouse-Geisser Epsilon. Pairwise comparisons were performed using the student t-test with mean square error adjusted for the mixed design. Results Visual Discrimination Task Table 1 shows the different groups mean performance in the visual discrimination task. All participants performed well above chance. Performance was not affected by the type of auditory sequence or the ear of presentation. No significant differences in accuracy and RT were found among young, middle-aged and older adults (F(2,35) = 0.4 and 0.1, respectively). However, middleage and older adults tended to make more false alarms than young adults (the number of false alarm per block of trials averaged 1.9, 4.7, and 5.1 in young, middle-aged and older adults, respectively, F(2,35) = 2.83, p =.07). We also compared the response times to visual targets preceded (up to 1 sec) by standards or deviant auditory stimuli. RTs to visual targets were not affected by the type of auditory stimuli presented in either age group. Table 1. Group mean performance (and standard deviation) at the visual discrimination task. Groups: Accuracy (%) Reaction Times (ms) Young 88.6 (8.7) 429 (34) Middle-aged 88.9 (3.9) 430 (53) Older 90.0 (5.7) 423 (35)

13 Age-Related Changes in Processing Irrelevant Stimuli 13 Visual Evoked Potentials Figure 2 shows the visual ERPs to target stimuli recorded at midline electrodes. Visual targets generated a negative (N2) and a large positive deflection (P3b), both maximum at the midline posterior site (i.e., Pz). In contrast with participants mean response time, the peak latency of the P3b measure at Pz varied with age, F(2,35) = 19.09, p <.01, being earlier for young adults (434 ms), intermediate for middle-aged (475 ms) and latest in older adults (503 ms), all pairwise comparisons significant at p <.05. The P3b latency increased with age at a rate of 1.4 ms per year (see Figure 3, bottom). An analysis of the amplitude data for the P3b Figure 2 ERPs to visual targets recorded at midline electrodes in young (solid line), middle-aged (dashed line) and older (dotted line) adults. In this and subsequent figures, the stimulus onset is shown by the vertical bar and negativity is plotted upward. also revealed a main group effect, F(2,35) = 14.81, p <.001 (mean amplitude for a 100-ms window centered at the P3b peak latency for each group). Pairwise comparisons revealed that the P3b was smaller in middle-aged and older adults compared with the young adults, p <.01 in both cases. Although the P3b amplitude decreases with increasing age (approximately 0.25 uv per year; see Figure 3, top), no significant group difference in P3b amplitude was found between the middle and

14 Age-Related Changes in Processing Irrelevant Stimuli 14 older age groups. There were no age effects on the P3b uv/year scalp topography for the ms interval. Neither the amplitude nor latency of P1, N1, N2, or P3b potentials was affected by the type of auditory sequence presented in the background. 1.4 ms/year Standard Auditory Evoked Potentials Figure 4 shows the ERPs to auditory stimuli recorded at midline frontal and central sites. Because the stimuli were presented at short and fixed ISIs, the pre-stimulus baseline contains ERP activity elicited by previous tones. Standard stimuli generated a biphasic N1-P2 wave peaking, respectively, at 115 and 180 ms Figure 3 Scatterplot showing the progressive age-related changes in P3b amplitude and latency. Each data point reflects the data from one subject. post-stimulus. At Fz, the N1 peaked earlier and was larger in amplitude when the tones alternated regularly in frequency (110 ms; uv) than when the tones were repeated (120 ms; uv), F(1,35) = and , respectively, p <.001 in both cases. Age-related changes in processing task-irrelevant stimuli were first examined on the N1 peak 2 amplitude, the maximum negativity at Fz between 70 and 140 ms post-stimulus, to standard stimuli. The N1 was larger in middle-aged and older adults than in young adults (main group effect at Fz: F(2,35) = 16.21, p <.01, pairwise comparisons were significant at p <.01). There was no significant difference in N1 amplitude between middle-aged and older adults. The Group by Sequence-Type interaction was also significant, F(2,35) = 12.97, p <.01. That is, tones that alternated in frequency generated larger N1s than repeated tones, and the amplitude increase was greater in middle-aged and

15 Age-Related Changes in Processing Irrelevant Stimuli 15 older adults compared with young adults. Lastly, there was a significant negative correlation Figure 4 ERPs to auditory stimuli recorded at three midline scalp sites in young (solid line), middle-aged (dashed line) and older (dotted line) adults. The ERPs to the standard stimuli of both types of sequences are shown on the left column. The center and right columns show the ERP to deviant stimuli.

16 Age-Related Changes in Processing Irrelevant Stimuli 16 Figure 5 Mismatch negativity elicited by the small and large frequency changes and by pattern deviant stimuli at the frontal site (i.e., Fz) and right mastoid (RM) in young (solid line), middle-aged (dashed line) and older adults (dotted line) after the data were re-reference to an electrode placed at the tip of the nose. between the N1 amplitude elicited by task-irrelevant stimuli and the P3b amplitude elicited by visual targets, r = -.252, p <.01, consistent with a dual-process of attention in which responses in the attended modality are enhanced and those in the irrelevant modality inhibited. However, the small magnitude of the correlation suggests that lack of inhibition accounts for only a small portion of P3b latency variability. N1 latency also varied with age, F(2,35) = 5.19, p <.02. Pairwise comparison revealed shorter N1 latency in middle-aged (110 ms) and older adults (114 ms) than in young adults

17 Age-Related Changes in Processing Irrelevant Stimuli 17 (121 ms), p <.05 in both cases. N1 latency was not significantly different between middle-aged and older adults. Mismatch Negativity Both frequency- and pattern-deviant tones elicited a broad negative deflection that began around 100 ms post-stimulus and superimposed the N1 wave. The MMN was isolated by the difference between the ERP to standard and deviant tones (see Figure 5). Because the difference wave may have contained brain activity from both non-refractory auditory neurons and a true mismatch process, the effects of age on the MMN were examined over two consecutive intervals (i.e., and ms post-stimulus). It is assumed that during the first 50-ms window, the difference wave used to isolate the MMN would contain contributions from both non-refractory auditory neurons and the mismatch process. However, the second 50-ms window would include primarily contributions from the true mismatch process since the N1 wave was returned to baseline at 150 ms post-stimulus. In subsequent paragraphs we will refer to MMNa when comparing age effects on MMN during the first interval ( ms) and MMNb when comparing MMN for the second interval ( ms). Table 2 shows the group mean MMNa and MMNb amplitude. For the MMNa, the analysis of variance examining the mean amplitude recorded at the midline frontal electrode (i.e., Fz) with group (young, middle-aged, and older ), deviant-type (frequency and pattern) and ear of presentation (left and right) as factors yielded a main effect of group, F(2,35) = 5.81, p <.01, and a main effect of deviant-type, F(2,70) = 55.57, p <.001. Planned comparisons revealed that the MMNa amplitude was smaller in middle-aged and older adults than in young adults, p <.05 in both cases. There was no significant difference between middle-aged and older adults. The age-related decline in MMNa

18 Age-Related Changes in Processing Irrelevant Stimuli 18 amplitude resulted partly from: (1) an enhanced N1 amplitude to standard stimuli (see Figure 4, left column); and (2) a decreased response to the deviant stimuli (see Figure 4, center and right column). There were also significant interactions between Group and Deviant-Type, F(4,70) = 4.87, p <.01, and between Group and Ear of stimulation, F(2,35) = 3.67, p <.05. The age effects were larger for MMN to large than small frequency changes. Table 2. Group mean amplitude (and standard deviation) for the deviance-related negativity recorded over the midline frontal site (Fz). MMNa ( ms) Group: Ear of Stimulation: small frequency large frequency pattern Young Left -2.7 (1.1) -6.3 (2.9) -3.0 (1.5) Middle -3.4 (2.1) -4.7 (1.7) -2.0 (1.0) Older -1.5 (1.2) -3.5 (2.5) -1.9 (1.2) Young Right -3.5 (3.1) -6.3 (2.8) -3.5 (1.8) Middle -2.5 (1.6) -3.8 (1.5) -2.0 (1.0) Older -2.2 (1.4) -3.0 (1.4) -1.9 (1.0) MMNb ( ms) small frequency large frequency pattern Young Left -3.8 (1.4) -4.5 (2.2) -2.9 (1.1) Middle -3.6 (2.0) -2.5 (1.2) -1.8 (1.0) Older -2.3 (1.5) -2.9 (2.3) -1.8 (1.0) Young Right -4.5 (2.6) -4.3 (3.3) -4.0 (1.8) Middle -2.8 (2.2) -2.7 (2.5) -1.9 (1.0) Older -2.7 (1.7) -3.1 (1.5) -2.1 (1.2)

19 Age-Related Changes in Processing Irrelevant Stimuli 19 A similar pattern of results was observed for the MMNb. The ANOVA revealed a main effect of group, F(2,35) = 5.20, p =.011, and deviant-type, F(2,70) = 6.43, p <.01. Pairwise comparison showed that frequency-deviants (small and large) generated larger MMN than patterndeviant sounds, p <.01 in both cases. Planned comparisons showed a significantly reduced MMNb amplitude in middle-aged and older adults compared with young adults, p <.05 in both cases. There was no difference in MMNb amplitude between middle-age and older participants. No other main effects or interactions were significant. One criterion typically used to identify the MMN wave is a reversal in polarity between frontal and mastoid electrodes. In the current study, the MMN reversed polarity at the mastoid site when the data were re-referenced to an electrode placed at the tip of the nose (see Figure 6). There was no significant effect of age on the MMNa amplitude recorded at the mastoid sites, F(2,35) = The MMNa mean amplitude was larger for frequency-deviant stimuli than for pattern-deviant stimuli at the right mastoid (RM), F(2,70) = 17.81, p <.01, and there was a significant effect of the ear of stimulation, F(1,35) = 10.25, p <.01, the MMNa being larger for the left ear stimulation. However, the effect of age tended toward significance for the MMNb recorded at the mastoid sites, F(2,35) = 2.87, p =.068. As for the MMNa, there was a main effect of condition, F(2,70) = 15.14, p <.01, with the MMNb being larger for frequency- than for pattern-deviant stimuli. In contrast to the P3b deflection, the MMN peak latency remained stable over the adult life span whereas the MMN amplitude decreased progressively by 0.06 uv per year (see Figure 7, top). There was a significant positive correlation between the MMN and the P3b amplitude elicited by visual targets, r =.288, p <.01, i.e., larger MMN amplitudes were associated with larger P3b amplitudes.

20 Age-Related Changes in Processing Irrelevant Stimuli 20 Scalp Distribution Analysis Figure 8 shows the topographic maps of the MMNb as a function of age and deviant-type. There was no significant age-related change in MMNa or MMNb scalp topography. However, there was a significant Electrode x Deviant-type interaction for the MMNa and MMNb, F(52,1820) = 7.47 and 6.82, respectively, p <.01 in both cases. The MMN to small and large frequency-deviant stimuli were more frontally distributed than the MMN to pattern, F(26,910) = 9.23 and 3.40, p <.05 in both cases. A similar difference in topography was also found Latency (ms) Age (Years) Figure 6 Scatterplot showing the progressive age-related changes in MMN amplitude and latency collapsed over the deviant-type. Each data point reflects data from one subject. between the MMNa and MMNb elicited by small and large frequency changes, F(26,910) = 9.40 and 4.29 respectively, p <.05 in both cases. Auditory Discrimination Task

21 Age-Related Changes in Processing Irrelevant Stimuli 21 In a second experiment, a subset of participants (10 young, 12 middle-aged, and 12 older adults) were presented with the same sequences used in the MMN experiment but without ERP recording. They were asked to attend to tones and to press a button to those differing in frequency or, in separate blocks of trials, to changes in the alternating tone pattern. Table 3 shows the group percentage of correct response and the mean RT for frequency- SMALL PITCH LARGE PITCH _ + PATTERN YOUNG MIDDLE ELDERLY Figure 7 Isopotential gray-scale maps of the normalized distribution of the MMN as a function of age and deviant-type. ERPs were averaged over the ear of stimulation with electrodes transposed so that those on the right of the figure are contralateral (c) to the stimulated ear. The original data (27 scalp sites) were interpolated with a spherical spline algorithm (cf. Perrin, Pernier, Bertrand, & Echallier, 1987).

22 Age-Related Changes in Processing Irrelevant Stimuli 22 (small and large) and pattern-deviant sounds. Participants were more accurate and faster in detecting large-frequency than small frequency- or pattern-deviant stimuli, F(2,62) = 5.75 and 51.72, respectively p <.001. The small-frequency deviant and the pattern-deviant stimuli generated similar performance. There was no difference in accuracy and RTs among the three groups, nor was the interaction between Group and target-type significant. Table 3. Group mean (and standard deviation) for accuracy and reaction time during the auditory discrimination task. Groups: Deviant: Accuracy (%) Reaction Time (ms) Young Small Frequency 96 (5) 365 (28) Large Frequency 98 (1) 313 (27) Pattern 92 (5) 390 (49) Middle-Age Small Frequency 94 (8) 357 (78) Large Frequency 96 (4) 317 (58) Pattern 90 (6) 366 (51) Older Small Frequency 94 (5) 385 (70) Large Frequency 98 (2) 324 (49) Pattern 93 (7) 368 (41) Nb. The data were collapsed across ear of presentation Discussion The performance at the visual discrimination tasks was minimally affected by increasing age. Compared to young adults, there was a trend toward increased false alarm rates in older adults, although RTs were not affected by age. This result suggests that older adults may have a different response criterion than young adults and/or difficulties in inhibiting motor responses.

23 Age-Related Changes in Processing Irrelevant Stimuli 23 P3b potentials to visual targets varied systematically in amplitude and latency with age, being largest and earliest in young adults, intermediate in middle-aged adults and smallest and latest in older adults. Our results are consistent with many studies showing progressive P3b amplitude decrement and/or delayed latency with increased age to rare targets presented in auditory (Friedman, Simpson, & Hamberger, 1993; Iragui et al., 1993; Knight, 1987; Picton, Stuss, Champagne, & Nelson, 1984), visual (Ford & Pfefferbaum, 1991; Picton et al., 1984), or somatosensory (Yamaguchi & Knight, 1991) modalities, suggesting that age-related alterations in P3b reflect supramodal changes in stimulus analysis. The fact that response latency was unaffected by aging suggests that the P3b and RT measure different aspects of stimulus processing. For example, P3b may index memory storage for orientation to novelty (Knight, 1996) and/or a context updating (Donchin & Coles, 1988) processing stage that might not be directly reflected in RT measures. The smaller P3b in middle-aged and older adults may partly reflect age-related changes in activation of prefrontal and posterior association cortices, as shown by recent studies using positron emission tomography (Cabeza et al., 1997; Grady et al., 1995). Converging evidence from lesion studies and intracerebral recording of ERPs in humans suggest that these two brain regions play an important role in the modulation of the P3b response (Alain, Richer, Achim, & Saint-Hilaire, 1989; Halgren et al., 1995a; Halgren et al., 1995b; Knight, 1997). There were two age-related differences in the processing of task-irrelevant stimuli. First, an enhanced N1 to standard auditory stimuli was found in middle-aged and older adults. This was a robust and reliable finding, being present for repetitive or alternating standard sounds presented in either the left or right ear. In previous studies, age-related changes in sensory evoked responses may have been explained by peripheral factors such as loudness recruitment. However, this cannot

24 Age-Related Changes in Processing Irrelevant Stimuli 24 account for the results of the current experiment since the stimuli were presented at constant sound pressure levels to all groups. The age-related increase in N1 amplitude to task-irrelevant auditory stimuli contrast with the results of studies showing no age effects on the N1 amplitude to attended auditory stimuli (Anderer, Semlitsch, & Saletu, 1996; Ford et al., 1979; Iragui et al., 1993; Pfefferbaum, Ford, Roth, & Kopell, 1980; Schroeder et al., 1995a). The age-related enhancement in sensory evoked responses to task-irrelevant stimuli would thus appear to reflect deficits in filtering unwanted stimuli, consistent with age-related changes in inhibitory processing (Hasher & Zacks, 1988; McDowd & Filion, 1992; Rabbitt, 1965). Such a deficit in inhibitory processing could result from degenerative changes in the prefrontal cortex and in the temporal cortex that occurs with normal aging (Liu, Erikson, & Brun, 1996; Raz et al., 1997). Evidence from lesion studies in human (Knight, 1994; Knight, 1997; Knight, Scabini, & Woods, 1989) and animal models (Skinner & Yingling, 1976; Yingling & Skinner, 1975) indicate that the prefrontal cortex plays an important role in the inhibition of visual and auditory sensory evoked potentials. Thus, this amplitude enhancement in sensory evoked responses to task-irrelevant auditory stimuli could reflect an age-related decline in prefrontal inhibition during selective attention. The second pattern of activity indicating age-related changes in processing task-irrelevant stimuli was a reduced MMN elicited by both frequency- and pattern-deviant stimuli. There are at least two possible contributing factors. One factor could be an age-related change in frequencyspecific refractoriness, suggested by the enhanced N1 amplitude to standard stimuli as well as by the decreased amplitude in MMN to frequency-deviant stimuli during the ms interval. Another contributing factor is likely to be an age-related change in a "true" mismatch process as suggested

25 Age-Related Changes in Processing Irrelevant Stimuli 25 by an age-related decline in MMN amplitude for the ms interval. Age-related declines in MMN amplitude elicited by pattern-deviant stimuli also strongly support this proposal. Because the perception of changes in sequences of standard stimuli depends on a comparison process between the incoming stimulus and neural representations of the previously presented stimuli (Näätänen, 1992; Winkler & Näätänen, 1995), the age-related decline in MMN amplitude may reflect either impaired sensory memory or impairments in the comparison process itself. For example, representation of the auditory standard stimuli may be less precise in middle-aged and older adults than in young adults, so that deviant stimuli are less likely to generate an MMN because they are not perceived as clearly different from standards. Impaired sensory memory could result from an age-related decline in frequency selectivity (Abel, Krever, & Alberti, 1990; Lutman, Gatehouse, & Worthington, 1991; Patterson, Nimmo-Smith, Weber, & Milroy, 1982). Frequency selectivity refers to the ability of the auditory system to differentiate the spectral components of sounds presented successively or simultaneously. From this perspective, the MMN to frequency-deviant stimuli would be reduced in middle-aged and older adults because they do not distinguish the frequency of standard and deviant stimuli as accurately as young adults. Similarly, the age-related changes in MMN to pattern deviant stimuli could reflect an impaired temporal resolution (McCroskey & Kasten, 1982; Moore, 1995; Schneider, Pichora-Fuller, & Kowalchuk, 1994) and/or difficulties in determining the sequential order of auditory stimuli (Neils, Newman, Hill, & Weiler, 1991; Trainor & Trehub, 1989). In other words, rather than directly influencing the mismatch process per se, aging may degrade the input to the MMN generators. However, it is unlikely that the observed age effects on the MMN reflect solely age-related changes in the resolving power of the peripheral auditory system. The auditory stimuli used in the

26 Age-Related Changes in Processing Irrelevant Stimuli 26 current study were in the optimal range of auditory thresholds for the middle-aged and older adults. Moreover, performance during the auditory discrimination task was similar in young, middle-aged and older adults, suggesting that stimuli were equally discriminable in all three age groups. Lastly, if the MMN amplitude decrement was entirely due to peripheral factors, then the age effects should have been more pronounced for small than large frequency changes. The lack of interaction for the MMNb should, however, be interpreted cautiously because of the relatively small number of participants in each age group. Converging evidence from scalp topography analysis (Giard, Perrin, Pernier, & Peronnet, 1990), neuromagnetic recording (Hari et al., 1984), dipole source modeling (Scherg et al., 1989), animal models (Csepe, Karmos, & Molnar, 1987; Javitt, Schroeder, Steinschneider, Arezzo, & Vaughan, 1992; Javitt, Steinschneider, Schroeder, Vaughan, & Arezzo, 1994), and lesion studies (Alain, Woods, & Knight, In press; Alho, Woods, Algazi, Knight, & Näätänen, 1994) suggest that the scalp recorded MMN reflects enhanced activation in auditory cortical areas under the influence of a distributed cortical circuit that includes both the temporal-parietal region and the prefrontal cortex. The age-related decline in MMN amplitude may reflect impairment in this fronto-temporal network. This proposal is consistent with recent neuroimaging studies measuring cerebral blood flow during memory tasks showing reduced brain activation in prefrontal and temporal cortex during encoding in older adults compared with young adults (Cabeza et al., 1997; Grady et al., 1995). The MMN to frequency-deviant stimuli was symmetrically distributed with the maximum amplitude at midline frontal sites while the MMN to pattern-deviant stimuli was more centrally distributed and larger over the right hemisphere. This finding suggests that different neural systems underlie the generation of the MMN to frequency- and pattern-deviant stimuli and is consistent with

27 Age-Related Changes in Processing Irrelevant Stimuli 27 the hypothesis that frequency and auditory pattern information are represented in different cortical maps (Alain, Achim, & Woods, Submitted). An interesting result was the similarity in pattern processing between middle-aged and older adults, suggesting little change in pattern processing after the fourth decade of life. This finding contrasted with the age-related reduction in MMN amplitude elicited by sounds deviating along simple physical dimensions (e.g., frequency), showing a linear decrement with age (Pekkonen et al., 1993). The pattern of results suggests that automatic detection of changes along a physical dimension is more sensitive to the aging process than is the automatic detection of changes in auditory pattern and is consistent with the proposal that the MMN to frequency- and pattern-deviant stimuli reflect distinct neural networks (Alain et al., Submitted). In summary, the current study provides electrophysiological evidence supporting an agerelated decline in processing task-irrelevant stimuli during selective attention. The pattern of results strongly support the inhibitory deficit hypothesis and suggests that sensory memory is impaired in middle-aged and older adults.

28 Age-Related Changes in Processing Irrelevant Stimuli 28 References Abel, S. M., Krever, E. M., & Alberti, P. W. (1990). Auditory detection, discrimination and speech processing in ageing, noise-sensitive and hearing-impaired listeners. Scandinavian Audiology, 19, Alain, C., Achim, A., & Woods, D. L. (Submitted). Separate memory-related processing for pitch and auditory patterns. Alain, C., Ogawa, K. H., & Woods, D. L. (1996). Aging and the segregation of auditory stimulus sequences. Journal of Gerontology. Series B, Psychological Sciences & Social Sciences, 51, P91-3. Alain, C., Richer, F., Achim, A., & Saint-Hilaire, J.-M. (1989). Human intracerebral potentials associated with target, novel and omitted auditory stimuli. Brain Topography, 1(4), Alain, C., Woods, D. L., & Knight, R. T. (In press). A distributed cortical network for auditory sensory memory in human. Brain Research. Alain, C., Woods, D. L., & Ogawa, K. H. (1994). Brain indices of automatic pattern processing. Neuroreport, 6, Alho, K., Woods, D. L., Algazi, A., Knight, R. T., & Näätänen, R. (1994). Lesions of frontal cortex diminish the auditory mismatch negativity. Electroencephalography and Clinical Neurophysiology, 91(5), Alho, K., Woods, D. L., Algazi, A., & Näätänen, R. (1992). Intermodal selective attention. II. Effects of attentional load on processing of auditory and visual stimuli in central space. Electroencephalography and Clinical Neurophysiology, 82(5), Allen, P. A., Weber, T. A., & Madden, D. J. (1994). Adult age differences in attention: filtering or selection? Journal of Gerontology, 49(5), P Anderer, P., Semlitsch, H. V., & Saletu, B. (1996). Multichannel auditory event-related brain potentials: effects of normal aging on the scalp distribution of N1, P2, N2 and P300 latencies and amplitudes. Electroencephalogy and Clinical Neurophysiology, 99(5), Barr, R. A., & Giambra, L. M. (1990). Age-related decrement in auditory selective attention. Psychology and Aging, 5(4), Cabeza, R., Grady, C. L., Nyberg, L., McIntosh, A. R., Tulving, E., Kapur, S., Jennings, J. M., Houle, S., & Craig, F. I. M. (1997). Age-related difference in neural activity during memory encoding and retrieval: a positron emission tomography study. The Journal of Neurosience, 17(1), Chao, L., & Knight, R. T. (1997). Prefontal deficits in attention and inhibitory control with aging. Cerebral Cortex, 7, Comalli, P. E. (1962). Interference effects of stroop color-word test in childhood, adulthood, and aging. Journal of Genetic Psychology, 100, Csepe, V., Karmos, G., & Molnar, M. (1987). Evoked potential correlates of stimulus deviance during wakefulness and sleep in cat -- animal model of the mismatch negativity. Electroencephalography and Clinical Neurophysiology, 66(6), Czigler, I., Csibra, G., & Csontos, A. (1992). Age and inter-stimulus interval effects on event-related potentials to frequent and infrequent auditory stimuli. Biological Psychology, 33, Donchin, E., & Coles, M. G. H. (1988). Is the P300 component a manifestation of context updating? Behavioral and Brain Sciences, 11, Ford, J. M., Hink, R. F., Hopkins, W. F., Roth, W. T., Pfefferbaum, A., & Kopell, B. S. (1979). Age effects on event-related potentials in a selective attention task. Journal of Gerontology, 34, Ford, J. M., & Pfefferbaum, A. (1991). Event-related potentials and eyeblink responses in automatic and controlled processing: effects of age. Electroencephalography and Clinical Neurophysiology, 78, Ford, J. M., Roth, W. T., Isaacks, B. G., White, P. M., Hood, S. H., & Pfefferbaum, A. (1995). Elderly men and women are less responsive to startling noises: N1, P3 and blink evidence. Biolological Psychology, 39(2-3), Friedman, D., Simpson, G., & Hamberger, M. (1993). Age-related changes in scalp topography to novel and target stimuli. Psychophysiology, 30(4), Giard, M.-H., Perrin, F., Pernier, J., & Peronnet, F. (1990). Brain generators implicated in processing of auditory stimulus deviance: A topographic event-related potential study. Psychophysiology, 27,

29 Age-Related Changes in Processing Irrelevant Stimuli 29 Grady, C. L., McIntosh, A. R., Horwitz, B., Maisog, J. M., Ungerleider, L. G., Mentis, M. J., Pietrini, P., Schapiro, M. B., & Haxby, J. V. (1995). Age-related reductions in human recognition memory due to impaired encoding. Science, 269, Grady, C. L., Van Meter, J. W., Maisog, J. M., Pietrini, P., Krasuski, J., & Rauschecker, J. P. (1997). Attentionrelated modulation of activity in primary and secondary auditory cortex. Neuroreport, 8, Gunter, T. C., Jackson, J. L., & Mulder, G. (1996). Focussing on aging: an electrophysiological exploration of spatial and attentional processing during reading. Biological Psychology, 43(2), Halgren, E., Baudena, P., Clarke, J. M., Heit, G., Liegeois, C., Chauvel, P., & Musolino, A. (1995a). Intracerebral potentials to rare target and distractor auditory and visual stimuli. I. Superior temporal plane and parietal lobe. Electroencephalography and Clinical Neurophysiology, 94(3), Halgren, E., Baudena, P., Clarke, J. M., Heit, G., Marinkovic, K., Devaux, B., Vignal, J. P., & Biraben, A. (1995b). Intracerebral potentials to rare target and distractor auditory and visual stimuli. II. Medial, lateral and posterior temporal lobe. Electroencephalography and Clinical Neurophysiology, 94(4), Hari, R., Hamalainen, M., Ilmoneimi, R., Kaukoranta, E., Reinikainren, K., Salminen, J., Alho, K., Naatanen, R., & Sams, M. (1984). Responses of the primary auditory cortex to pitch changes in a sequence of tone pips: Neuromagnetic recording in man. Neuroscience Letters, 50, Hasher, L., & Zacks, R. T. (1988). Working memory, comprehension, and aging: A review and a new view. In G. H. Bower (Ed.), The psychology of learning and motivation (Vol. 22, pp ). San Diego: Academic Press. Haxby, J. V., Horwitz, B., Ungerleider, L. G., Maisog, J. M., Pietrini, P., & Grady, C. L. (1994). The functional organization of human extrastriate cortex: a PET-rCBF study of selective attention to faces and locations. Journal of Neuroscience, 14(11 Pt 1), Heinze, H. J., Mangun, G. R., Burchert, W., Hinrichs, H., Scholz, M., Munte, T. F., Gos, A., Scherg, M., Johannes, S., Hundeshagen, H., & et al. (1994). Combined spatial and temporal imaging of brain activity during visual selective attention in humans. Nature, 372(6506), Hocherman, S., Benson, D. A., Goldstein, M. H., Jr., Heffner, H. E., & Hienz, R. D. (1976). Evoked unit activity in auditory cortex of monkeys performing a selective attention task. Brain Research, 117(1), Hoox, P. J., Jolles, J., & Vreeling, F. W. (1993). Stroop interference: Aging effects assessed with the Stroop Color-Word Test. Experimental Aging Research, 19, Iragui, V. J., Kutas, M., Mitchiner, M. R., & Hillyard, S. A. (1993). Effects of aging on event-related brain potentials and reaction times in an auditory oddball task. Psychophysiology, 30(1), Javitt, D. C., Schroeder, C. E., Steinschneider, M., Arezzo, J. C., & Vaughan, H. G., Jr. (1992). Demonstration of mismatch negativity in the monkey. Electroencephalography and Clinical Neurophysiology, 83(1), Javitt, D. C., Steinschneider, M., Schroeder, C. E., Vaughan, H. G., Jr., & Arezzo, J. C. (1994). Detection of stimulus deviance within primate primary auditory cortex: intracortical mechanisms of mismatch negativity (MMN) generation. Brain Research, 667(2), Karayanidis, F., Andrews, S., Ward, P. B., & Michie, P. T. (1995). ERP indices of auditory selective attention in aging and Parkinson's disease. Psychophysiology, 32(4), Knight, R. T. (1987). Aging decreased auditory event-related potentials to unexpected stimuli in humans. Neurobiology of Aging, 8, Knight, R. T. (1994). Attention regulation and human prefrontal cortex. In A. Thierry, J. Glowinsky, P. Goldman-Rakic, & Y. Christen (Eds.), Motor and cognitive function of the prefrontal cortex (pp ): Springler- Verlag. Knight, R. T. (1996). Contribution of human hippocampal region to novelty detection. Nature, 383, Knight, R. T. (1997). Distributed cortical network for visual stimulus detection. Journal of Cognitive Neuroscience, 9(1), Knight, R. T., Scabini, D., & Woods, D., L. (1989). Prefrontal cortex gating of auditory transmission in humans. Brain Research, 504, Liu, X., Erikson, C., & Brun, A. (1996). Cortical synaptic changes and gliosis in normal aging, Alzheimer's disease and frontal lobe degeneration. Dementia, 7(3), Lutman, M. E., Gatehouse, S., & Worthington, A. G. (1991). Frequency resolution as a function of hearing threshold level and age. Journal of Acoustical Society of America, 89( ).