Am J Otolaryngol 12:267-271.

1991

Contingent Negative Variation Enhancement in Tinnitus Patients T. SHIRAISHI, MD, K. SUGIMOTO, MD, T. KUBO, MD, T. MATSUNAGA, MD, Y. NAGEISHI, PHD, AND M. SIMOKOCHI, MD

Contingent negative variations recorded in 20 tinnitus patients with an average hearing level within 40 dB were compared with those from age-matched healthy controls. In addition, negative and positive potentials (NlOO and P300), which are presumed to reflect stimulus information processing, were examined. Contingent negative variation amplitude was significantly greater in patients than in controls (P < .05, ANOVA), but no significant differences were observed in the NlOO and P300 latencies and amplitudes for the two groups. We interpret these results as evidence of abnormalities in the central information processing mechanism of tinnitus patients. AM J OTOLARYNGOL 12:267-271. Copyright 0 1991 by W.B. Saunders Company an imperative

stimulus (S2) following a warning signal (Sl). Very few reports have sought objective evidence showing tinnitus to be a psychopathic phenomenon.’ Tonndorfl’ suggested an analogy between tinnitus and intractable pain based on the gate control theory.” Timsit et al” reported an amplitude increase in CNV in migraine patients. The CNV in patients with tinnitus of unknown etiology was analyzed in this study. In addition, NlOO (a negative peak at a latency of approximately 100 milliseconds after Sl) and P300 (a positive peak at a latency of approximately 300 milliseconds after Sl), which are presumed to reflect stimulus information processing, were examined.13*14

Tinnitus is an aberrant perception of sound unrelated to any external source of stimulation. Approximately 20% to 40% of the general population have experienced tinnitus at some time,l but it is doubtful whether all tinnitus sufferers actually possess an ear abnormality. During the last decade, many studies have tried to quantify tinnitus These reports confirmed that psychophysically.z-4 tinnitus patients have some deficit in cochlear function. Although peripheral processes in these patients should be investigated, it is also important to study their information processing in the brain. Considerable knowledge has been accumulated about abnormalities of event-related potentials in various psychiatric diseases.5-7 One example of event-related potentials in the brain is contingent negative variation (CNV).* Sometimes referred to as the expectancy wave, CNV is a slow negative cortical potential shift appearing in the frontocentral regions of the human scalp. It can be recorded during an Sl-S2-key press task, in which subjects are told to press a key as quickly as possible upon

MATERIALS

AND METHODS

Twenty tinnitus patients were chosen from among our outpatients: 15 men and five women. Their ages ranged from 21 to 60 years (mean age, 41.4 years; SD, 11.40 years). None of these patients reported any subjective hearing loss. Table 1 shows the results of pure tone audiometry for these patients. Patients were also subjected to psychological tests such as the Cornell Medical Index test. A control group comprised 17 men and three women ranging in age from 24 to 60 years (mean age, 37.0 years; SD, 11.94 years). The patient and control groups were age matched. Control subjects had neither tinnitus nor hearing loss, nor any history of head trauma. Event-related potentials (NlOO, P300, and CNV) were recorded during an Sl-S2-key press task. Sl was a l&Hz tone burst of 300 milliseconds’ duration with a rise and fall time of 10 milliseconds. The stimulus intensity was approximately 85 dB hearing level. S2 was a light flash of 300 milliseconds’ duration showing a red cross composed of a IO-cm horizontal bar and a

Received April 16, 1991, from the Department of Otolaryngology, Osaka University Medical School, Osaka, Japan: and Department of Behavioral Phvsioloav__ Facultv of Human Science, Osaka University, Suita;Japan. Accepted for publication August 12, 1991. Supported by a Grant-in-Aid for Scientific Research (no. 62480356) from the Ministry of Education, Science and Culture of Japan. Address correspondence and reprint requests to T. Shiraishi, MD, Department of Otolary&ology, Osaka University Medical School, Fukushima l-1-50. Fukushima-ku. Osaka, Japan 553. Copyright 0 1991 by W.B. Saunders Company 0196-0709/91/1205-0008$5.00/O

267

268

CONTINGENTNEGATIVEVARIATIONS IN TINNITUS

TABLE 1. Auditory

Thresholds

(dB HLJ for the Tinnitus

Group (n = 20). Measured

by Pure Tone Audiometry

FREQUENCY (Hz)

dB hearing level (ISO)

250

500

1,000

2,000

4,000

8,000

23.0 (9.51)

15.5 (7.76)

5.5 (9.16)

9.8 (10.4418

20.5 (17.61)

22.8 (21.36)

NOTE. Numbersin parentheses represent 1 standard deviation. lo-cm vertical bar. The interstimulus (Sl-SZ) interval was set at 2.0 seconds. Individuals were tested in an electrically shielded light- and sound-attenuated room. The intertrial interval was varied randomly between 10 and 30 seconds. The subjects practiced short runs several times before starting the electroencephalogram record. Scalp electroencephalograms were recorded with AgAgCl disc electrodes placed at the midline of the frontal, central, and parietal regions. The ground electrodes were attached to the earlobes of both sides. Vertical eye movement was also recorded through electrodes placed above and below the right eye. The signals were amplified after passing through a bandpass filter of 0.053to 30 Hz. The data was digitalized at a rate of 10 milliseconds per point with a laboratory computer (NEC-SANE1 i’T17, NEC-SANE1 Co, Tokyo, Japan). The CNV became visible against the electroencephalogram background activity at an average of 18 to 23 performances of the Sl-SZ trial sequence. Recordings with an electrooculogram potential exceeding '100 ~.LV were excluded from the averaging process. Amplitudes of CNV were measured against the pre-Sl baseline of 400 milliseconds’ duration. The CNV was divided into four latency ranges: early 1 (400 to 600 milliseconds), early 2 (600 to 1,000 milliseconds), middle (1,000 to 1,500 milbseconds), and late (1,500 to 2,000 milliseconds). This division was determined after studying the averaged waveforms for the two groups (see Fig 1 and Results). Peak amplitude and latency were also measured for the NlOO and P300 waves in each subject. P300 was defined as the maximum positive peak in the latency range of 240 to 380 milliseconds after the Sl onset. NlOO was defined as the maximum negative peak in the

m I -400

0

500

1000

1500

2000

2400 ms

Figure 1. Mean CNV waveforms for the two groups. The solid line indicates the CNV waveforms for tinnitus patients and the broken line shows those for the control subjects. The recordings from the Fz, Cz, and Pz electrode positions are shown. Negativity at the electrodes is represented by an upward deflection.

latency range of 50 to 150 milliseconds after the Sl onset. A two-way, mixed-type ANOVA test was used for statistical analysis of the difference between the peak and mean amplitudes.

RESULTS Difference in Contingent Negative Variation. Figure 1 shows the group mean waveforms for the tinnitus subjects [solid line) and controls (broken line). The tinnitus group had a greater CNV amplitude than the control group at a latency of 600 to 1,500 milliseconds after the start of the warning signal (Sl). This difference was especially prominent in the frontal and central recordings. Table 2 shows the mean amplitudes for each of the four CNV components: the early 1, early 2, middle, and late ranges. The amplitudes of the early 1 and late ranges for each recording site were roughly equal in the tinnitus and control subjects. The mean amplitudes of the early 2 and middle ranges, however, were greater for the tinnitus patients. Analysis of the early 2 range showed significant differences among electrode sites (F(2,76) = 20.03; P < .OOl) as well as between groups (F(1,38) = 4.12; P < .05). In the middle range, significant differences were also noted in comparing electrode sites (F(2,76) = 11.94; P < .OOl) and for the groups (F(1,38) = 5.00; P < .05). The mean amplitudes of the early 1 and early 2 ranges were greater at the frontal and central than at the parietal site (F(2,76) = 30.92; P < .OOOl), while those of the middle and late components were largest at the central site (F(2,76) = 11.24; P < ,001). Average amplitudes of the integrated wave of the early 2 and middle ranges with a latency between 600 and 1,500 milliseconds are shown in Fig 2 for both tinnitus and control subjects. The recording was obtained from the frontal electrode regions. In terms of distribution of the amplitude of the integrated CNV, patients and control subjects showed a clear difference.

Comparison of N700 and P300. Mean and standard deviations for NlOO-evoked potential amplitudes and latencies for the tinnitus and control subjects are shown in Table 3. Although the amplitude of NlOO for the patients was slightly greater than that for the controls at the central

SHIRAISHI

269

ET AL TABLE 2.

Mean Amplitudes of Contingent Negative Variations for Four Latency Ranges (pV) (400-600

MIDDLE (l,OOO-1,500 ms)

EARLY 2

EARLY~

RECORDING

(600-1,000

LATE (1,500-2,000

ms)

SITE

Tinnitus (n = 20)

FZ CZ PZ

- 6.0 (3.85) - 6.5 (3.61) - 2.4 (3.01)

- 7.2 (4.21) - 8.5 (4.14) - 5.8 (2.99)

- 5.7 (4.29) - 7.5 (3.88) - 6.0 (3.05)

-4.2 -6.1 -4.7

Control (n = 201

Fz cz Pz

- 5.0 (3.37) -6.2 (3.28) - 2.1 (3.01)

-4.1 (3.23) - 6.6 (3.701 -4.2 (3.30)

- 2.6 (2.91) - 5.4 (4.05) -4.0 (3.96)

- 2.4 (3.67) - 5.6 (3.05) - 4.7 (4.15)

NOTE. Numbers in parentheses represent Abbreviations: Fz, Cz, and Pz: midfrontal,

ms)

ms)

GROUP

1 standard deviation. midcentral, and midparietal

recording site, the difference was not significant (F < 1.0); neither was the difference in NlOO latency. Mean and standard deviations for P300 amplitudes and latencies for tinnitus and control subjects are shown in Table 4. The P300 latency was similar for tinnitus and control subjects (F < l.O), whereas the amplitude of P300 was greater in patients than in controls, particularly at the parietal site. Analysis of this data did not, however, reveal

/11 0

0

-1c

0

0

l

0

-5

0 0

0

V

$0

1 :

l

recording

electrode

DISCUSSION

The CNV amplitude was greater for the tinnitus patients than for the controls during that part of the SI-S2 interval that we have termed the early 2 range. The early component of CNV that occurs after the Sl presentation and develops most clearly at the frontocentral regions of the scalp is considered to be associated with the information processing of, and orienting reflex elicited by, a warning signal (Sl).15,16 Our results suggest that tinnitus patients do have an abnormality in their information processing that is related to the auditory warning signal. The amplitude of the late range (1,500-to 2,000-millisecond latency), which had a central dominant scalp distribution,*’ did not differ for the two groups. However, the mean amplitude of the l,OOO- to 1,500-millisecond latency component, which we have termed the middle range, was greater in the patients than in the controls. Middle range scalp distribution was more similar to that of the late range than of the early ranges (Table 2). This difference in the middle range suggests that the late CNV component TABLE 3.

e

0

l

l l

+2

Tinnitus (n=20)

Control (n=20)

Figure 2. Average amplitudes of the integrated wave of the early 2 and the middle ranges for the two groups. The latency range was between 600 and 1,500 ms after the warning signal. The recording was obtained from the midfrontal electrode. The y-axis indicates amplitude of CNV (pV).

sites on the scalp, respectively.

a significant difference in the effect on the two groups (F < l.O), but there was a significant difference in terms of the electrode sites (F(2,76) = 9.35; P < .OOl).

Mean Amplitudes and Latencies of the Nloo Wave

leo

0

(4.63) (4.13) (3.49)

Tinnitus Fz cz Pz

AMPLITUDE (CLV

LATENCY (MS)

- 12.7 (4.20) - 12.6 (3.82) - 8.4 (2.76)

115 (18.9) 115 (20.6) 116 (23.9)

- 12.6 (4.29) - 14.3 (4.49) - 8.9 (4.16)

125 (23.7) 124 (20.6) 124 (21.7)

(n = 20)

Control (n = 20) Fz cz Pz

NOTE. NlOO is the negative component of an event-related potential with a peak latency of approximately 100 milliseconds. Numbers in parentheses represent 1 standard deviation. Abbreviations: Fz, Cz, and Pz: midfrontal, midcentral, and midparietal recording electrode sites on the scalp, respectively.

270 TABLE

CONTINGENT NEGATIVE VARIATIONS 4.

Mean

Amplitudes and Latencies P300 Wave AMPLITUDE (CLV)

of the

LATENCY (MS)

Tinuitus (n = 20) FZ cz Pz

5.9 (4.73) 4.2 (5.11) 8.3 (4.15)

295 (49.2) 297 (49.9) 308 (38.8)

Control (n = 20) FZ Cz Pz

8.0 (5.20) 5.7 (8.39) 8.1 (8.10)

304 (30.1) 300 (29.8) 310 (22.0)

NOTE. P300 is the positive component of an event-related potential with a peak latency of approximately 300 milliseconds. Numbers in parenthese represent 1 standard deviation. Abbreviations: Fz, Cz, and Pz: midfrontal, midcentral, and midparietal recording electrode sites on the scalp, respectively.

developed somewhat earlier in the tinnitus patients than in the controls. An increase in CNV amplitude can be found in some neurotic patients.” However, since neurotic patients, as evaluated by the Cornell Medical Index test, accounted for only 17.6% of our patient group, the present finding cannot be solely the result of such a correlation. Other reports have demonstrated greater CNV amplitudes in psychosomatic patients, such as those with asthma bronchialelg and hyperthyroidism.” If tinnitus combined with normal hearing or mild hearing loss is considered a psychosomatic disorder, our results could be seen to support these findings. In contrast, low CNV amplitudes have been associated with such psychiatric disorders as dementia, schizophrenia, and depression.21-23 It has also been reported that tinnitus patients in a depressive state show a low-amplitude CNV.‘* However, tinnitus patients judged to be in a depressive state by a psychiatrist were excluded from this experiment. On the basis of these considerations, it is expected that CNV recordings will contribute useful information to the task of selecting appropriate treatment for tinnitus patients. Those with a large CNV amplitude may have psychosomatic disorders requiring psychotherapy or drugs. Patients with low CNV amplitudes may be treated effectively with antidepressants. On the other hand, patients with normal CNV amplitudes are considered candidates for conventional medication, such as vasodilators and vitamins. Hoke et al9 reported that the magnetic wave MlOO, which corresponds to the electric wave NlOO, increased significantly in tinnitus patients. On the other hand, MZOO, which corresponds to the electric wave PZOO, was either poorly developed, with a longer latency, or was missing. How-

IN TINNITUS

ever, we found no significant increase in NlOO amplitudes in our patient group. This discrepancy may be attributed to a difference in stimulus conditions. The warning signal in our experiment was task relevant and required strong mental concentration, whereas the stimuli applied in the experiment of Hoke et al9 required no special task, so that their subjects may have been less attentive. Further study is needed to test this hypothesis. P300 is thought to reflect human brain functions during cognitive processing. There is broad agreement on changes in the P3OO wave found in patients; patients with schizophrenia showed amplitude reduction,7 while prolongation of peak latency was found in dementia.” In our experiment, neither the amplitude nor the latency of P~OO changed significantly in the tinnitus patients. However, amplitudes recorded in the tinnitus subjects tended to be smaller than those for the controls. Contingent negative variation recording is a noninvasive method to assess the brain function in relation to tinnitus. Our experiment suggests that CNV measurements can be used to classify tinnitus patients with normal hearing into several subgroups, facilitating the choice of appropriate treatment and subsequent follow-up. References 1. Hinchcliffe R: Prevalence of the commoner ear, nose and throat conditions in the adult rural population of Great Britain. Br J Prevent Social Med 1981; 15:128-140 2. Tyler RS, Conrad-Armes D: The determination of tinnitus loudness considering the effects of recruitment. J Speech Hear Res 1983; 28:59-72 3. Penner MJ: Variability in matches to subjective tinnitus. J Speech Hear Res 1983; 28:283-287 4. Burns EM: A comparison of variability among measurements of subjective tinnitus and objective stimuli. Audiology 1984; 23:428-483 5. Roth WT. Donchin E, Pfefferbaum A, et al: Applications of cognitive ERPs in psychiatric patients. Electroencephalogr Clin Neurophysiol Suppl 1988; 38:419-438 8. Rohrbaugh JW, Gaillard AWK: Sensory and motor aspects of the contingent negative variation, in Gaillard AWK, Ritter W (eds]: Tutorials in Event Related Potential Research: Endogenous Components. Amsterdam, The Netherlands, NorthHolland, 1983, pp 289-310 7. Ogura C, Nageishi Y, Shimokochi M, et al: Evaluation of event-related potentials in schizophrenia using principal component analysis. Electroencephalogr Clin Neurophysiol Suppl 1987; 40:733-737 8. Walter WG, Cooper R, Aldridge VJ, et al: Contingent negative variation: An electric sign of sensori-motor association and expectancy in the human brain. Nature 1984; 203:380-384 9. Hoke M, Feldmann H, Pantev C, et al: Objective evidence of tinnitus in auditorv evoked magnetic fields. Hear Res 1989; 37:281-288 10. Tonndorf J: The analogy between tinnitus and pain: A suggestion for a nhvsiological basis of chronic tinnitus. Hear Rei-1987; 283271-275 11. Melzack R, Wall PD: Pain mechanism: A new theory. Science 1985; 150:971-979 12. Timsit M, Timsit-Berthier M, Schoenen J, et al: Contingent negative variation and EEG power spectrum in headache,

SHIRAISHI ET AL in Barber C, Blum T (eds]: Evoked Potential III. Boston, MA, Butterworth, 1986, pp 370-374 13. Ntiatanen R. Picton T: The Nl wave of the human electric and magnetic response to sound. A review and an analysis of the component structure. Psychophysiology 1987; 24:375425 14. Sutton S, Braren M, Zubin J, et al: Evoked potential correlates of stimulus uncertainty. Science 1965; 150:1187-1188 15. Loveless NE, Sanford AJ: The impact of warning signal intensity on reaction time and components of the contingent negative variation. Biol Psycho1 1981; 13:271-279 16. Rohrbaugh JW, Syndulko K, Lindsley DB: Brain wave components of the contingent negative variation in humans. Science 1976; 191:1055-1057 17. Nageishi Y, Shimokochi M: Contingent negative variation related to attention given an informative stimulus and to the preparation for a motor-response. Jpn J Physiol Psychophysiol 1983; l:l-10 18. Dongier M: Clinical applications of the CNV, in McCallum WC, Knott JR (eds): Event-Related Slow Potentials of the Brain: Their Relations to Behavior. Amsterdam, The Netherlands, Elsevier, 1973, pp 309-315

271 19. Dongier M, Koninckx N: Present-day neurophysiological models of mind-body interaction. Psychother Psychosom 1970; 18:123-129 20. Lolas F, De la Parra G, Gramegna G: Event-related slow potentials (ERSP) correlates of thyroid gland function level. Psychosom Med 1978; 40:236-244 21. O’Connor K: Slow potentials correlates of attention dysfunction in senile dementia. I and II. Biol Psycho1 1980; 11:193-216 22. McCallum WC, Abraham P: The contingent negative variation in psychosis. Electroencephalogr Clin Neurophysiol Suppl 1973; 33:329-336 23. Timsit-Berthier M, Delaunoy J, Gerono A: Morphological analysis of the CNV in psychiatry: Comparison of resolution mode and cumulative curve methods, in Otto D (ed): Multidisciplinary Perspectives in Event-Related Brain Potential Research. Washington, DC, US Government Printing Office, 1978, pp 389-391 24. Shiraishi T, Sugimoto K, Matsunaga T, et al: Contingent negative variation in tinnitus patients. Audio1 Jpn 1988; 31:527-528

Contingent negative variation enhancement in tinnitus patients.

Contingent negative variations recorded in 20 tinnitus patients with an average hearing level within 40 dB were compared with those from age-matched h...
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