Life-span alterations in visually evoked potentials and inhibitory function

Neurobiology of Aging, Vol. 2, pp. 187-192,1981. Printed in the U.S.A.

Life-Span Alterations in Visually Evoked Potentials and Inhibitory Function R . E. D U S T M A N , 1 E. W. S N Y D E R A N D C, J. S C H L E H U B E R

Veterans Administration Medical Center and University of Utah College o f Medicine, Salt Lake City, UT 84148 R e c e i v e d 20 M a y 1981 DUSTMAN, R. E., E. W. SNYDER AND C. I. SCHLEHUBER. Life-span alterations in visually evokedpotentials and inhibitoo'function. NEUROBIOL. AGING 2(3)187-192, 1981.--Visually evoked potentials (VEPs) elicited by patterned and unpatterned flashes were recorded from 211 healthy males aged 4--90 years. A measure of similarity between the two kinds of VEPs was obtained by correlating the digital values comprising the two waveforms. Across the life-span, correlations followed a U-shaped curve; patterned and unpatterned flash VEPs were most alike for the youngest and oldest subjects. This age effect, localized to scalp areas overlying visual cortex, is compatible with a concept of reduced inhibitory functioning within the visual systems of the young and the old. At central scalp, patterned and unpatterned flash VEP waveforms were more effectively differentiated by the right hemisphere. This observation agrees with reports that the right hemisphere specializes in analyses of spatial material. Visually evoked potentials (VEPs) Hemisphere asymmetry

Pattern

Life-span

T H E visual system is organized to maximize the detection of lines, edges and contours [30,31]. It is not surprising, therefore, that the waveform of visually evoked potentials (VEPs) elicited by patterned flashes differs from the waveform of VEPs to unpatterned, diffused, flash stimuli [5,51]. Inhibitory processes within the visual system apparently contribute to the configuration of VEP waves evoked by patterned flashes by enhancing the contrast between an edge and its surround [27, 28, 39, 53]. The effectiveness of inhibitory processes, at least for some brain systems, changes across the life span since, in comparison to young adults, inhibitory deficits have been reported for the young [9, 12, 13, 20] and the old [22,32]. The deficits are likely related to neurotransmitters and brain structures which are believed to be involved in inhibitory control but are not fully developed in children [1, 48, 49, 61] and are beginning to deteriorate with approaching old age [4, 8, 40, 54, 67]. Thus, one might expect that subtle changes in the perception of patterns would occur across the life span, paralleling the reported fluctuations in inhibitory functioning, and that these changes would be reflected in evoked potential waveform alterations as the EP has previously been reported to be sensitive to inhibitory deficits [3, 6, 16, 24, 36, 55, 591. The present study was done to determine if the suggested age-related changes in inhibitory function are paralleled by changing relationships between VEP waveforms elicited by patterned and by diffused flashes. We expected that VEP waveforms to the two kinds of stimuli would be most alike during childhood and old age when inhibitory function is believed to be relatively low. Conversely, we expected that

Inhibitory Functioning

Visual system

during late adolescence and early adulthood patterned flash VEPs would be relatively more differentiated from VEPs to diffused flashes due to enhanced inhibitory surround effects.

METHOD Two-hundred and twenty right handed males ranging in age from 4 to 90 years were initially studied. They comprised 11 age groups of 20 subjects. Each was screened for health problems with a detailed health questionnaire and those older than 60 years were given a physical and a neurological examination. Only those with no detected health problems participated in the study. VEPs were recorded from each subject via disc electrodes attached to the scalp at F3, C3, C~, Oj, and 02 (International "10--20" System) with collodion and referred to linked ears. Resistances were below 5 kfL Eye movement was monitored by electrodes attached above and below the outer canthus of the right eye. EEG was recorded on a Grass Model 78B EEG/polygraph with lower and upper band pass settings of 1 and 100 Hz and stored on a Hewlett Packard Model 3968A 8-channel instrumentation recorder. Flashes of 10 tzsec duration were generated by a Grass PS-22 photostimulator set at an intensity of PS8 and delivered by a lamp enclosed in a sound attenuating container. A viewing box, into which 12x 12 cm stimulus slides and Wratten neutral density filters could be inserted, was attached to the container and positioned 40 cm distant from, and level with, subjects' eyes. Subjects were asked to direct their gaze at a luminous dot in the center of a 10×10 cm opening in the front of the viewing box while stimuli and filters were

1Send reprint requests to Robert E. Dustman, Neuropsychology Laboratory 151A, Veterans Administration Medical Center, Salt Lake City, UT 84148.

187

188

DUSTMAN, SNYDER AND S C H L E H U B E R TABLE I

Z

r

AGE A N D V I S U A L T H R E S H O L D S (Log~o Lux) FOR 211 M A L E SUBJECTS

,.0

,,'*

Age (Years) Group

r

o-3oo,,,,~.

,,.o ~

Threshold

N

Range

Mean

S.D.

Mean

S.D.

I 2

II 20

4.-6 7-9

5.5 8.2

0.69 0.81

- 3.092 -3.242

0.346 0.454

3 4 5 6 7 8 9 10 11

20 20 20 20 20 20 20 20 20

10-12 13-15 16--20 21-30 31--40 41-50 51--60 61-70 71-90

11.0 14.2 17.5 26.9 33.6 45.3 55.4 65.8 75.8

1.00 0.70 1.15 2.00 2.81 2.83 3.14 3.05 5.69

-3.267 -3.192 -2.937 -3.022 -3.092 -2.982 -2.607 -2.207 -2.202

0.502 0.400 0.359 0.353 0.442 0.363 0.464 0.522 0.349

backlighted by the photic stimulator. The opening subtended a visual angle o f about 14 degrees. Prior to VEP recordings a visual threshold was measured for each subject. Visual threshold was defined as the lowest flash intensity at which subjects could correctly report the orientation (45 degrees left or right from vertical) of a narrow black line (0.5×65 ram) placed in the viewing box. Neutral density filters were used to change intensity. The visual threshold obtained for each subject was used to determine stimulus intensities employed for his VEP recordings. Four recordings were made. For three, a checkerboard pattern inserted in the viewing box was used to elicit VEPs. Checks were 2.55 ram square with each edge subtending a visual angle of 22 rain. VEPs were obtained for flash intensities which were 1.0, 2.0 and 3.0 logao steps above threshold. For the other recording, diffused (unpatterned) flashes were presented. These had a light transmission value equal to that of the patterned flashes at 2.0 logs above threshold. The order of the recording conditions was randomized across subjects. Approximately 60 flashes were presented during each recording so that VEPs could be averaged from 50 artifact free trials. The EEG was digitized at a 500/see rate for a period of 650 msec following each flash by a Terak (LSI-11 based) computer which summed and averaged evoked potentials. To promote their attention subjects were asked to count flashes and to press a response key upon the occurrence of every tenth stimulus. Nine of the children in the 4--6 year old group were unable to perform this task. Their data are not included. Similarity between VEP waveforms was obtained by correlating (Pearson product-moment) the digital values spanning a time segment of one VEP with corresponding digital values of the second VEP. For example, in some instances wavefonns of VEPs elicited by diffused flashes were correlated with waveforms elicited by patterned flashes. The remaining comparisons were among the "patterned" VEPs evoked by each of the three flash intensities. Correlations were computed for four time intervals: 0-300, 0-100, 100200, and 200-300 msec. Coefficients of correlation were transformed to Fisher z-coefficients prior to statistical analyses [25]. An overall amplitude measure for each time segment was obtained by computing the standard deviation of the digital

,1~ 4o AGE

FIG. 1. Life-span changes in similarity of VEP waveforms elicited by patterned and diffused flashes for four time bands. Intensity was two logs above threshold. Each data point represents the mean correlation (r) and equivalent Fisher z-coefficient (z) obtained by correlating digital values within each time segment. Recordings were from occipital scalp. values within that segment [11 ]. Across our initial population o f 220 subjects this measure correlated 0,98 and 0.99 with two other estimates of overall amplitude: Overuse ~ t u d e [11 ] and largest peak to trough difference [36], The standard deviation measure is reported in the text and figures. One and two factor analyses of variance (ANOVAs) and Student's t-test were used. The Duncan multiple range test [65] was used as a post-hoc mean difference test for those ANOVAs which indicated a significant difference among three or more means. RESULTS

Visual Threshold Table 1 provides information regarding visual thresholds for the 11 age groups. Thresholds varied significantly with age, 10/200 df; F=16.51, p<0.001. Mean thresholds for the three oldest groups (55, 66 and 76years) were reliably higher than those for the younger groups, i.e., flash intensifies had to be significantly greater for the older subjects to see the stimulus line. Thresholds for the two oldest groups (66 and 76 years) were significantly higher than those of the 55 year old subjects. An F-max test [65] indicated that between subject variability of thresholds did not differ reliably across age groups.

VEP Waveform Correlations Figure 1 (upper left quadrant) illustrates age means obtained for correlations of the 0..300 msec epoch ofoccipitaUy derived VEP waveforms elicited by patterned and diffused flashes. The data follow a U.shaped curve with significant differences across age, 10/200 df; F=2.83, p=O.003. In an attempt to identify a time band which contributed most to these changes, waveforms occurringduring each of the three time segments, 0-100, 100-200, and200-300 msec, were correlated. A pattern of age changes similar to that observed for the total VEP segment was found for each 100 msec segment, although the effect was strongest for the 0-100 and 100-200 msec intervals (see Fig, 1). F-ratios for the three intervals were 3.91 (p<0.001), 5,56 (p<0.001), and 1.90 (p <0.05), respectively. ANOVAs were also computed on similar correlational data from central and frontal locations. These analyses were for comparisons of waveforms occurring during the 0-300

LIFE-SPAN COMPARISONS OF VEP W A V E F O R M S •

189 01,02 CHECKS X 100

r 4O 20

1.oOjiot

0-100 Msec.

.70

.60

OL8O

VS. CHECKS x 1000

.~

6O

I 0-300 MSEC.I

.40

o

"6

¢-i

40

.20 T ' 2 0

i

I W

I 0

I 10

I 20

I

I

t

30 40 SO AGE IN YEARS

I 60

, I 70

I

-

20 ~-

80

FIG. 2. Life-span changes in similarity of VEP waveforms to two intensities of patterned flashes. Intensities were 2 and 3 logs above threshold (x 100 and 1000, respectively). Each data point represents the mean correlation (r) and equivalent Fisher z-coefficient obtained by correlating 0-300 msec epochs of the two VEPs. Data from left and right occipital scalp (O~, 02) were combined. msec time period. Results were quite different from those obtained for the occipital areas. For central scalp mean correlations did not change significantly across age but did differ between hemispheres. Correlations were significantly higher for C3 than for C4 recordings, 1/200 df; F=8.35, p<0.005. However, a significant age relationship was observed for the frontal area, F=3.64; p<0.001. Correlations decreased systematically to adolescence and remained stable thereafter. Thus, age-related changes in VEP waveform similarity showed clear topographic differences. The 0-300 msec interval of occipital VEPs to the three intensities of patterned flashes were also intercorrelated. Significant age relationships were observed only for the correlation of VEPs evoked by the two brightest intensities, 2 and 3 logs above threshold, 10/200 df; F = 2.34, p <0.02. VEP waveforms were most similar for the three adult groups aged 27, 34 and 45 years (see Fig. 2).

VEP A mplitude Striking changes in VEP amplitudes occurred across the life-span, particularly for potentials recorded from occipital scalp, Figure 3 portrays mean amplitudes of occipital VEPs to patterned flashes at an intensity of 2 logs above threshold. A N O V A s indicated significant differences among age means for the 0-100, 100-200 and 200-300 msec intervals: F's = 19.44, 16.24, I0.18, respectively (I 0/200 df; p's
¢.

0 2 0 0 - 3 0 0 Msec.

20

'°f 0

I O

I 10

1 20

I 1 I 30 40 50 AGE IN YEARS

I 60

I 70

P 80

FIG. 3. Life span changes in occipital VEP amplitude for three time periods. Amplitude was determined by computing the standard deviation of the digital values comprising each 100 msec epoch. VEPs were elicited by patterned flashes which were two logs above threshold. sal related to recording site. From occipital areas, VEPs elicited by checks were larger than those to diffused flashes, while the opposite was the case for VEPs from central and frontal scalp, F's=78.97, 28.70, and 15.33; 1/200 df; p's <0.001 (Figs. 4 and 5). Eye movements were not differentially affected by stimulus type. An analysis of VEP amplitudes (0-300 msec) across recording sites revealed that potentials from the eye were reliably smaller than VEPs from all other areas and that VEPs from frontal and central areas were reliably smaller than those from occipital scalp (see Fig. 5). DISCU SSION

Inhibitory function is diminished in the young [9, 12, 13, 33]. However, during maturation an excitatory/inhibitory balance is attained which is reflected in complex and highly coordinated behaviors not possible at an earlier stage of development [13, 20, 42, 44, 60, 64]. Approaching senescence appears to be accompanied by a disturbance of this excitatory/inhibitory balance, such that, in some brain areas, there is once again a relative inhibitory deficit [4, 22, 32, 40, 47]. The age curves describing the relationship between VEP waveforms elicited by patterned and diffused flashes in the present study are compatible with a concept of reduced inhibitory functioning during the age extremes (Fig. 1). Inhibition within the visual system is apparently essential for optimal detection of edges and contours [27, 28, 53] and may vary with monoamine level. Schafer and McKean [53] reported that following stimulation of the monoaminergic system of patients with phenylketonuria, a disease which is associated with low levels of the catecholamines and their amino acid precursors [41,53], patterned flash VEPs were clearly differentiated from VEPs to diffused flashes. Such a

l~o

DUSTMAN, SNYDER AND SCHLEHUBER ~JCHECKS x 100

i

35

q~O-

"~

!.

3o

!I-

$I= o

W

EYE ~..J eL

15

:E

< MEAN AGE IN YEARS

FiG. 4. A comparison of patterned (checks) and diffused flash VEP amplitudes across age. VEPs were record~ from occipital (O1, 02) and central (C3, C4) scalp. Note that, in general, patterned flashes produce larger VEPs at occipital scalp while diffused flashes produce larger VEPs at central scalp. Stimulus intensity was two logs above threshold. differentiation was not evident before monoammergic stimulation. They speculated that the greater responsiveness to patterns could be explained by "...an increase in the activity of feature-sensitive inhibitory neurons in striate and extrastriate cortex due to increased synaptic availability of critical mononmines present in all cortical structures" [53]. Monoamine concentrations are apparently highest during late adolescence and early adulthood and decrease towards the age extremes. There are many reports of reduced catecholaminc concentrations, particularly dopamine, in the aged (for reviews see [4, 40, 47]). The converse appears to be true during developmental years: catecholamin~gic activity increases with maturation [1, 42, 50]. An enzyme involved in catecholamine degradation, monoamine oxidase (MAC)) follows an age course which suggests decreased availability of the catecholamines during young and old age [35, 43, 52, 61 ]. We speculate that age changes in monoamine levels are related to our principal findings. Reduced inhibitory function, associated with lowered monoamine utilization, should result in a less differentiated VEP to patterns, such that pattented and diffused flash VEP waveforms would be relatively similar. In general, VEPs to the two types of stimuli were most alike during ages when it is believed that catecholamin¢ levels are relatively low, the young [1,42, 50] and the old [4, 40, 47], and were most dissimilar during late adolescence and early adulthood when catecholamine levels and inhibitory effects should be highest. This a l e effect was localized to scalp areas overlying visual cortex where cortical tissue is organized to maximize the detection of lines and edges [30,31]. Furthermore, the effects were much stronger for the earlier VEP intervals which encompass waves known to be associated with checkerboard stimulation [29,34]. Comparisons of VEP waveforms elicited by patterned flashes of different interisities were also consistent with a concept of reduced inhibitory capability during young and old age. VEP waveforms were most similar for ages when inhibitory potential is presumed to be relatively high (Fig. 2). Thus. due to increased inhibitory surround activity in visual cortex during this period of life, patterned stimulation would

lO

,,f CHECKS

, ,0

, ,~L,, DIFFUSE

FIG. 5. Amplitude of p a t t e ~ (checks) ~ difftmmdflash VEPs recorded from 5 scalp i o c ~ and from e ~ ~ve below the riSht eye. F.aeh ~ ~ :~, the m ~ s

from 21I Ss. At o c c ~ ~ ~

t o t e m

~

than those to diffused ~ S . ~ ~site ~ for VE:Ps from more anterior locations. ~ l u s intens~y was two logs above threshold. be expected to elicit welt differentiated YEPs with relatively similar waveforms across recordings. However, reduced inhibitory surround capacity should result in more variable patterned VEP wavefor~s atMlower correlations such as we report for the children and oldsters. For recordings from central scalp there were no agerelated variations in correlations of ~ vs diffused flash VEP waveforrns. However, a hifllsly sil~ficant hemispheric difference was observed: waveforms to the two kinds of stimuli were more ~ in r e c o r d h ~ from the left hemisphere. This asymmetry may relate w the presumed difference in functional specialization o f the t w o hemispheres. The processing of verbal and m ~ h e i ~ f i a a l information is largely restricted to the left-hemisph~ while the right hemisphere predominates in spatieJ ~ s e s [I0, 23, 45]. Thus, our data indicate that "v'EP wa~dorms to patterned and diffused flashes were more clearly differentiated by the right hemisphere (lower correlations). This differentiation appears to be a relatively high order function since it occurred in a nonvisual area. The comparison of VEP waveforms via correlational methods appears to be quite ~ s i t i v e to CNS t~iag. As illustrated in Figs. 1 and 2, distinct c h a i ~ s inthcse measures occurred by the fifth decade,-considerably earlier than has been reported for e l e c t r o e n c . e p ~ c measures. It should be emphasized that those ~ e ~ t S were observed in normals who had been screened for h ~ ~ s . The relatively early onset of noticeable changes inVEPn~easures agrees with our previous reports of s ~ a n t ~erations in early waves of occipitalEPs prior to age-50 [i$A9]-. It is unlikely that the age-~htted f l u c t ~ o n s reported above were the result of a mMuring and deteriorating l~eripheral visual system. The primary visual pathways are well developed soon after birth [2, 49, 67], visual acuhies of 6-month old infants measured by patterned VEPs are not different from those of adults [26, 57, 58] and visual thresholds of the 4-6 year old children in the present study were no different from those of older children (see Table 1). It is known that retinal illumination is often reduced in older

LIFE-SPAN COMPARISONS OF VEP WAVEFORMS subjects because of smaller pupil diameter and opacification and yellowing of the crystalline lens [7]. H o w e v e r , in the present study a visual threshold was obtained for each subject and flash intensities for VEP recordings were adjusted accordingly. The 40 subjects over 60 years of age required a mean flash intensity about 6.5 times that needed by the 20-30 year old subjects if they were to report correctly the orientation of a line during threshold determinations. This age differential in flash intensity agrees rather closely w/tb figures supplied by Weale [63], who reported that for a standard source o f white light only about one-third as much light reaches the retina of a 60 year old as reaches the retina of a young adult. The difference can be as large as 8 or 9 if the light is blue (the stimulus lamp used in the present study produces a bluewhite flash). The overall pattern of age changes in visual thresholds (see Table 1), relatively stable until the 50s when thresholds were slightly, but significantly, elevated followed by a large increase in threshold after age 60, parallel visual acuity measures across the life-span [56] and changes in absolute visual thresholds during adult aging [38]. The alterations in check-diffuse V E P waveform similarity do not appear to be related to large life-span fluctuations in VEP amplitude. Inspection of the two kinds of data show that while the correlational measures (Fig. 1) followed a U function across age, VEP amplitudes did not (Figs. 3 and 4). Amplitude was maximal at about age eight years, then rapidly decreased, reaching an adult level by late adolescence, a pattern we have previously reported for occipital VEPs [14, 15, 1%19]. N o r do the changes in correlational measures appear to he related to differential relationships between patterned and diffused flash VEP amplitudes across age, since amplitudes o f the two kinds of VEPs followed parallel trends (Fig. 4).

19l The dramatic changes in occipital VEP amplitude which occur during early childhood fit interestingly with other observations. Woodruff [66] suggested that critical periods during physiological and behavioral development may be associated with measureable changes in the brain's electrical activity. The brain continues to expand in size until about six years [62], different structures developing at different rates [20,49]. Between 6--8 years of age " a remodeling of the cortex o c c u r s " in terms of cortical thickness and number and configuration of brain cells [49]. During this period of development significant behavioral changes occur. White [64] reports that the character of learning changes significantly between the ages of 5-7 years and that theories of Freud, Luria and Piaget [21,37, 46] suggest behavioral restructuring prior to the age of eight years. In summary, a comparison of VEP waveforms elicited by patterned and diffused flashes revealed a U-shaped pattern of changes across age which may reflect diminished inhibitory capacity within the visual system of the young and the old. Stabilization of waveform similarity measures did not occur until late adolescence; distinct aging effects were noted by the fifth decade. At central scalp, patterned and diffused flash VEP waveforms were more effectively differentiated by the right than by the left hemisphere. This finding is in accord with reports that the right hemisphere specializes in analyses of spatially oriented information. ACKNOWLEDGEMENTS We thank Mrs. Treva Barnson who typed this manuscript and Drs. Linda Gummow and Diana S. Woodruff for their helpful comments. The study was supported by the Medical Research Service of the Veterans Administration and by the National Institutes of Health Grant AG00568.

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