Mismatch negativityを用いて短時間に聴覚中枢を評価するためのパラダイム 日耳鼻 2005

1. 146
Mismatch negativity を用いて短時間
に聴覚中枢を評価するためのパラダ
イム
東京大学耳鼻咽喉科
狩野章太郎 加我君孝

2. 要旨
注意を傾けない条件下においても、均一な聴覚刺激列の中に異
種の刺激が出現すればおよそ１００－２００ｍｓの潜時で誘発
電位の変化が現れる。このｍｉｓｍａｔｃｈ ｎｅｇａｔｉｖ
ｉｔｙは、聴覚皮質障害例の診断に応用できる。しかし従来の
ｏｄｄｂａｌｌ paradigm を用いて、純音や音声など複数の音
響刺激に対する反応を測定するには、長い測定時間を要し、臨
床例への検査としては限界があった。今回我々は、１）左右の
耳に異なるモダリティの音響刺激を並行して交互に提示するこ
と、２）音響刺激間の間隔を最小限に切り詰めること、により
３０分以内に終了するパラダイムの作成を試みた。脳磁図を用
いて新手法と従来の手法によるｍｉｓｍａｔｃｈ ｎｅｇａｔ
ｉｖｉｔｙを比較し、十分な精度で聴覚皮質の反応を検出でき
ることを確認した。

3. はじめに
均一な音刺激列の中に少ない頻度の異質な音刺激が提示されると
、約 100-200ms の潜時の事象関連電位が陰性の方向に偏倚するこ
とが知られている (Mismatch negativity (MMN)) 。
均一な刺激が連続すると Auditory echoic memory が形成され、次
に提示される刺激との比較対照が行われて、音刺激の高さ・音圧
などの属性の違いを検出するものと考えられている。
脳波・脳磁図による解析では Mismatch negativity は主に聴覚皮質
を発生源とすることが確かめられている。
音刺激列の時間間隔 (Inter-stimulus interval (ISI)) を長くしていく
と、 Auditory echoic memory が減衰するために MMN の振幅が小
さくなることが知られている。

4. 純音や語音といった複数の種類の音刺激を用い、また ISI を変化さ
せて MMN の減衰の仕方を調べようとすると、検査時間が長くなり
、特に臨床検査としては実際的ではなくなる。
本研究では、
•純音 / 語音といった２種類の音刺激列を左右別々に交互に提示する
ことによって、２種類の MMN を同時に測定すること
•一律な提示間隔をやめて、できる限り間隔を狭めること
で短時間で多くの加算回数を可能とするパラダイムを考案し、正常
被験者を対象としてその有効性を確認した。

5. 方法
聴覚に異常のない６人の日本人（男性３人 / 女性３人）、平均３
７歳、全員右利きを対象とした。
イヤホンから以下の設定で Tone burst 、および合成された音声
を提示した。いずれも持続時間は 100ms で音圧は約 85 dB SPL
とした。
Tone burst は左耳に提示し右半球の反応を検討した
頻回の刺激 (Standard) 1000 Hz
少数の刺激 (Deviant) 1100 Hz
Phoneme は右耳に提示し左半球の反応を検討した
頻回の刺激 (Standard) /ka/
少数の刺激 (Deviant) /ga/

6. 従来の Oddball paradigm
p = 5/6
p = 5/6
p = 1/6
p = 1/6
Short: 1.0s
Long: 3.0s

7. p = 5/6
p = 1/6
p = 5/6 p = 1/6
Short: 1.0s
Long: 3.0s

8. 脳磁図
Elekta 社製全頭型２０４チャネル脳磁計を用いた。
サンプリング周波数は 600 Hz 、加算波形には 1.0-200Hz の帯域
フィルターを使用した。

9. （ Deviant 刺激による加算波形）－ （ Standard 刺激による加算
波形）
を各チャネルにおいて算出し、 90-200ms の区間での差分波形の
振幅を MMN とした。
側頭部の 40 チャネルの中での MMN 振幅が最大となるチャネル
を抽出した。
Peak amplitude
Peak latency

10. 側頭部の４０チャ
ネルの差分波形を
用いて 90-200ms
の区間で Goodness
of fit が最高と潜時
で双極子を求め、
MRI 上に重ねた。
←Phoneme
Tone→
ＲＬ

11. Peak amplitude と Peak
latency について、
方法（ New vs.
Conventional)
刺激間隔 (Short vs. Long)
の効果を 2 way repeated
measures ANOVA で検定し
た
方法の主効果は見られなかった
が、刺激間隔に関しては
Short(1.0s) の方が Long(3.0s)
よりも有意に振幅が減衰してい
た ( 右半球で p=0.014 、左半球
で p=0.012 ）
潜時についてはいずれの効果も
見られなかった。

12. 測定時間
New paradigm では１００回加算の Short １回と Long １回であわせ
て２０分
Conventional oddball paradigm では２５回加算の Short （ Tone １
回と Phoneme １回）と Long （ Tone １回と Phoneme １回）で計
４回で約３０分
加算回数４倍になり、測定時間は短縮された。

13. 考察
Auditory echoic memory の形成には刺激間隔が必ずしも均等でな
くてもよいことを利用して、検査時間の短縮を試みた。
従来の Oddball paradigm と同様な結果が得られ、刺激間隔を延
長することにより MMN の振幅は減衰した。

14. P-2-26
A modified parallel paradigm for clinical
evaluation of auditory echoic memory using
magnetoencephalography
Shotaro Karino a,*
, Masato Yumoto b
, Kenji Itoh c
Keiko Yamakawa c
, Tomomi Mizuochi c
and Kimitaka Kaga a
a Department of Otolaryngology, Faculty of Medicine, University of
Tokyo
b Department of Laboratory Medicine, Faculty of Medicine, University
of Tokyo
c Department of Cognitive Neuroscience, Faculty of Medicine,
University of Tokyo

15. Abstract
Mismatch negativity (MMN) represents an automatic stimulus change-detector
system, which compares each new auditory input with a neural trace of the previous
standard stimuli developed and maintained in the auditory echoic memory. To
evaluate echoic memory duration, it is necessary to explore the relationship
between inter-stimulus interval (ISI) and MMN amplitude. To shorten the duration of
measuring MMN with multiple combinations of stimuli and ISIs using
magnetoencephalography (MEG), we modified a parallel paradigm for phonetic and
acoustic changes [Takegata et al., 2003] and applied it to normal listeners to verify
its usefulness. Repetitive trains which consisted of three consonant-vowel syllables
in one ear and those of three sinusoidal tones in the other ear were delivered
alternatively [Grau et al., 1998]. The trains started randomly with a standard
stimulus or a deviant which causes changes of consonant in the phonetic trains and
those of frequency in the acoustic trains, respectively. MMN was obtained by
subtracting responses to the standard from those of the deviant. By employing
relatively short intra-train ISI, measurements of MMN between standard and deviant
was enabled for both phonetic and acoustic changes in limited period for clinical
evaluation.

16. Introduction
Mismatch negativity (MMN) is an auditory event-related brain
potential (ERP) elicited by infrequent deviant sounds occurring in
a sequence of repeated tones. The MMN appears as a negative
displacement on the ERP to the ERP to deviant sounds relative
to that to standard sounds, with a peak latency between 100 and
200 ms from stimulus onset.
MMN is generated in the supratemporal auditory cortex [Alho,
1995; Naatanen and Alho, 1995], apparently as the output of an
automatic stimulus change-detector system, which compares
each new auditory input with a neural trace of the previous
standard stimuli developed and maintained in the auditory
sensory echoic memory [Naatanen, Paavilainen, Alho et al.,
1989; Naatanen, Paavilainen, andReinikainen, 1989; Ritter et al.,
1995].

17. The use of MMN for sensory memory evaluation purposes is based
on studies which, in healthy adult subjects, have shown that MMN is
no longer elicited when the interval between the stimuli delivered to
the subject exceeds a certain limit [Bottcher-Gandor and Ullsperger,
1992; Cowan et al., 1993; Mantysalo and Naatanen, 1987], for
instance about 10 s, reflecting the decay of the sensory memory
trace.
If various long inter-stimulus intervals (ISIs) need to be tested, as is
the case when obtaining an ISI-MMN amplitude function, sessions
can last up to several hours.

18. The major disadvantages arising from the excessive duration of
this test are considerable outlay in time required for apparatus and
personnel, boredom and fatigue of the subjects under study, which
can affect the quality of the signal recorded, and potential
difficulties in recording with children and patients who do not easily
tolerate long sessions without moving.
To shorten the duration of measuring MMN with multiple
combinations of stimuli and ISIs using magnetoencephalography
(MEG), we modified a parallel paradigm for phonetic and acoustic
changes [Takegata et al., 2003]and applied it to normal listeners to
verify its usefulness.

19. Methods
Subjects
Subjects were five native Japanese speakers (24 - 44 years old,
mean 33.4 years, 2 males and 3 females) who had normal hearing
and were right handed. They gave their written informed consent
after the nature and possible consequence of the study had been
explained to them.

20. MEG recording
The brain’s neuromagnetic signals were recorded using VectorViewk (Neuromag,
Helsinki, Finland), which has 102 magnetometers and 204 planar first-order
gradiometers at 102 measurement sites on a helmet-shaped surface that covers the
entire scalp. In this study, all magnetometers were inactivated. The passband of the
MEG recordings was 1.0–172.2 Hz and the data were digitized at 600.6 Hz. The
position of the head under the helmet was determined by attaching four coils to the
head surface and measuring the coil positions with respect to landmarks on the
skull with a three-dimensional (3-D) digitizer; the coil locations in the magnetometer
coordinate system were determined by leading current through the coils and
measuring the corresponding magnetic fields. MEG epochs were averaged
separately for standard and deviant stimuli online. The duration of the averaging
period was 300ms, including a 50 ms prestimulus analysis time for baseline.
Epochs coinciding with MEG exceeding 3000 fT/cm were excluded from averaging.
Averaged responses were digitally filtered with a bandpass of 1-20 Hz.

21. Stimuli and Procedures
Auditory stimuli were generated with a STIM2 unit (NeuroScan, El
Paso, USA) and were presented binaurally through ER-3A (Etymotic
Research, Illinois, USA) foam insert earphones at 85 dB SPL. Tone
stimuli were sinusoidal sounds generated at a sampling rate of 44
kHz. The tone standard stimulus was 1000 Hz in frequency and 100
ms in duration (including 7 ms rise and fall times), whereas the tone
deviant stimulus was 1100 Hz in frequency and 100 ms in duration.
Phoneme stimuli consisted of two consonant-vowel syllables (/ka/
and /ga/) produced by a speech synthesizer (SMARTTALK 3.0 OKI,
Japan). The stimulus durations were all adjusted to 100 ms by partly
removing the steady-state vowel portions. The phoneme standard
stimulus was the syllable /ka/, and the phoneme deviant stimulus
was /ga/.

22. The new faster paradigm was based on sequences of three-tone
trains, each starting on a random basis, either with a standard (p
= 0.50, n = 100) or deviant (p = 0.50, n = 100) tone, and followed
by two standard tones. Similarly, we employed sequences of
three-phoneme trains, each starting on a random basis, either
with a standard (p = 0.50, n = 100) or deviant (p = 0.50, n = 100)
phoneme, and followed by two standard phonemes. The intra-
train ISI (onset-to-onset) was 250 ms. These sequences,
consisted of three components of tones or phonemes, were
combined so that tone and phoneme sequences appeared
alternately at inter-train interval (onset of sequence to onset of
sequence) was 750 or 1750 ms. Consequently, the memory probe
interval (MPI) was 1.0 or 3.0 s in separate blocks. Measurements
by the new method were divided into two blocks according to the
combinations of MPI (“short”: 1.0 s vs. “long”: 3.0 s). In each
block, two kinds of averaged data, namely for tone and phoneme,
were simultaneously gained.

23. Fig. 1. A schematic illustration of new parallel and conventional
oddball paradigm. TS: tone standard stimulus (1000 Hz); TD: tone
deviant stimulus (1100 Hz); PS: phoneme standard stimulus (/ka/);
PD: phoneme deviant stimulus (/ga/); MPI: memory probe interval.
In both methods, tone stimuli were presented to the left ear
(denoted ‘L’), whereas phoneme stimuli were delivered to the right
ear (‘R’). Measurements by the new method were divided into two
blocks according to the combinations of MPI (“short”: 1.0 s vs.
“long”: 3.0 s). In each block, two kinds of averaged data, namely for
tone and phoneme, were simultaneously gained. Each separate
block by the conventional method had two variables for MPI
(“short”: 1.0 s vs. “long”: 3.0 s) and stimuli (tone vs. phoneme), and
four kinds of blocks in total were executed for one subject.

24. In the conventional oddball paradigm to elicit the MMN, standard (p
= 0.80, n = 100) and deviant (p = 0.20, n = 25) stimuli were randomly
presented at a constant MPI of 1.0 and 3.0 s, respectively, in separate
blocks. Each separate block had two variables for MPI (“short”: 1.0 s
vs. “long”: 3.0 s) and stimuli (tone vs. phoneme), and these four kinds
of blocks were executed in a randomized order across subjects.
In total, averaged responses in eight conditions were gained for one
subject (table 1). In both methods, tone stimuli were presented to the
left ear, whereas phoneme stimuli were delivered to the right ear.
Subjects were instructed to watch a video movie on a screen in front
of them to ignore the auditory stimuli during measurement.

25. MMNm measurement
For each subject under each condition, equivalent current dipoles
(ECDs) for MMNm were calculated primarily. The MMNm was
determined from the difference curves obtained by subtracting the
response to standard stimuli from that to deviant stimuli. Then, ECDs
were determined using a least-squares fit at 0.1 ms intervals from 100
to 250 ms. The calculation was performed separately for each
hemisphere, utilizing a spherical head model which was constructed
based on the individual magnetic resonance images (MRIs) and a
subset of 40 channels over the temporal brain areas. In this
procedure, we reduced the number of channels to 37–39 when the
dipole was not calculated or a certain channel had a considerable
amount of artifacts. The mean GOFs of the total of 40 hemispheres (5
subjects *8 conditions) ranged from 55.0 to 97.5% (mean ± SD: 80.7 ±
9.7).

26. The individual locations and orientations of single dipoles found by
this procedure were fixed and the dipole strengths were adjusted
according to each data set of 40 channels over the temporal brain
areas and over the analysis period mentioned above. In short MPI
measurement, the sources were analyzed by using single own
dipole estimated in each condition. In long MPI measurement, the
dipole estimated in corresponding short condition was employed
instead of own dipole because MMNm in long condition was not
expected to be large enough to estimate dipole accurately. Peak
amplitudes within the time range between 50 and 250 ms, and its
latencies were determined from the source strength waveforms of
the single dipole model.

27. Statistical analyses
Two way Repeated-measures ANOVAs were performed for the
comparison of SS peak amplitude/latency, adopting MPI (fast vs.
slow) and method (new vs. conventional) as within-subjects factors.
We considered P < 0.05 to be statistically significant for the ANOVAs.

28. Results
In both new parallel and conventional paradigm, MMNm were
displayed in the characteristic MMN latency range of
approximately 100-200 ms from stimulus onset. Figure 2 shows
representative evoked fields by the new parallel method in a
constant set of two channels of a subject. In each channel,
deviant-minus-standard differences demonstrate MMNm.

29. In both new parallel and conventional paradigm, a single dipole
was successfully determined in the neighborhood of auditory
cortex and time behavior of the dipole strength was adjusted
according to each data set of 40 channels over the temporal brain
areas (Figure 3). The source waveforms in the new method had a
similar amplitude, latency and morphology to those of the
corresponding waveforms in the conventional method. Table 1
and Figure 4 show peak amplitudes of source strength (SS) within
the time range between 50 and 250 ms, and its latencies.
The total duration of the measurement for one subject by the new
method was approximately forty minutes, while the conventional
method, consisted of four separate blocks, cost more than an
hour.

30. Fig. 2. Representative
evoked fields of a
subject. In each channel,
differences between
waves by standard
stimulus and deviant
stimulus demonstrate
MMNm.

31. Fig. 4. Means ± SEMs of peak amplitude and its latency of SS were
plotted.
(a) SS on left hemisphere under the presentation of phoneme stimuli
on the right ear.
(b) SS on right hemisphere under the presentation of tone stimuli on
the left ear.
a b

32. Discussion
Both the new and conventional method enabled to elicit MMNm for
tone and phoneme stimuli. We adopted a single source wave for one
hemisphere as an index of MMNm. As to peak latency of source
wave, small variances were revealed across both factors of methods
and MPIs. Concerning peak amplitude, no significant effect of
methods was found. These results demonstrated that our new
combined paradigm has reliability and efficacy equivalent to the
conventional oddball paradigm. The advantage of this new method is
that MMNs for two modalities of stimuli, namely tone and phoneme,
can be evaluated simultaneously with a shorter examination period.
This merit is considered to be valuable especially in case of clinical
tests for patients with a limitation of time..

33. Although no significant difference was shown, the tendency that SS
amplitudes with MPI of 3.0 s were smaller than those with shorter MPI
of 1.0 s was revealed. This decrement in amplitude might demonstrate
the attenuation of auditory echoic memory because of prolonged MPI.
Further study with conditions of more kinds of MPIs is required to
confirm whether our method could detect life time of auditory echoic
memory accurately

34. Conclusions
We modified a parallel paradigm using stimulus-trains with short intra-
train intervals and applied it to normal listeners to verify its usefulness
in MMN evaluation.
Concerning peak amplitude and its latencies of source wave of
MMNm, no significant difference was found between the new parallel
paradigm and the conventional paradigm.
The advantage of this new method was that MMNs for tone and
phoneme can be evaluated simultaneously with a shorter examination
period.

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36. Table 1. Mean ± SEM of peak amplitude and its latency of SS in
the eight conditions.