치의학석사 학위논문

A Study on the Changes of

Information Processing in

Sevoflurane-Induced Sedation in

Volunteers Using

Electroencephalography

뇌파를 이용한 자원자에서 sevoflurane으로

유도된 진정상태에서 정보자극 처리의 변화에

관한 연구

2018년 2월

서울대학교 치의학대학원

치의학과

김 지 웅

A Study on the Changes of

Information Processing in

Sevoflurane-Induced Sedation in

Volunteers Using

Electroencephalography

지도 교수 신 터 전

이 논문을 치의학석사 학위논문으로 제출함

2018년 2월

서울대학교 치의학대학원

치의학과

김 지 웅

김지웅의 치의학석사 학위논문을 인준함

2018년 2월

위 원 장 현 홍 근 (인)

부위원장 신 터 전 (인)

위 원 김 정 욱 (인)

i

Abstract

1. Purpose

In this study, changes in event-related potential (ERP) in the

auditory passive oddball paradigm were investigated when sedation

was induced by sevoflurane inhalation.

2. Materials and Methods

20 volunteers (11 females, nine males, mean age 26.8 years,

age range 24–32 years) without any systemic diseases or mental

disorders were enrolled in this study. Electroencephalography

(EEG) measurements were obtained for each subject using 32-

channel EEG recording devices. In the arousal state, the subject's

baseline EEG was recorded for 5 minutes. Auditory stimulation

based on the passive oddball paradigm was delivered to the subject

via an earphone. The passive oddball paradigm consisted of a

random sequence of 500 tones; 4/5 were standard stimuli (1000

Hz) and 1/5 were target stimuli (1200 Hz). EEG measurements

were obtained during auditory stimulation. Afterwards, sevoflurane

was administered by inhalation at an initial concentration of 0.8

vol%. Sevoflurane concentration was changed to maintain the

bispectral index (BIS) value around 80. After inducing stable

sedation, EEG was performed while applying auditory stimulation in

the same manner as above. After completion of EEG measurements,

sevoflurane administration was discontinued and 100% oxygen was

administered during the subject’s recovery. After ERP was

extracted from the measured EEG, the topographic distribution of

ERP, the temporal changes of ERP in each channel, and the

statistical difference in ERP was analyzed between the arousal and

sedation states.

ii

3. Results

In the arousal state, P300 was observed at 320–360 ms latency

and was concentrated in the frontal and central areas. P300

amplitude was statistically significantly decreased in the sedation

compared with the arousal state.

4. Conclusion

Sevoflurane-induced sedation caused a decrease in P300

amplitude. This result may reflect the weakening of the cognitive

function regulating the attentional process and stimulus

discrimination during sedation.

Keyword : Event-Related Potential, P300, Oddball paradigm,

Sevoflurane, Sedation, Electroencephalography

Student Number : 2014-23003

iii

Table of Contents

Chapter 1. Introduction........................................................ 1

Chapter 2. Materials and Methods........................................ 32.1. Volunteer recruitment...............................................................3

2.2. Acquisition of EEG.....................................................................3

2.3. Auditory passive oddball paradigm..........................................3

2.4. Sevoflurane administration .......................................................4

2.5. EEG preprocessing and statistical analysis............................4

Chapter 3. Results............................................................... 63.1. Topographic distributions of ERP............................................6

3.2. Temporal changes of ERP in channel views...........................7

Chapter 4. Discussion.......................................................... 9

References ........................................................................13

Abstract in Korean.............................................................16

Figure Index

[Figure 1]........................................................................... 6

[Figure 2]........................................................................... 8

１

Chapter 1. Introduction

Sedation is increasingly being used to relieve anxiety and fear

from dental treatments and facilitate surgical procedures. Sedation

is regarded as a state at the boundary between consciousness and

unconsciousness. Determining the mechanism of sedation could help

in better understanding the process of loss and recovery of

consciousness. However, to date, few studies on the change of

sedative level from the perspective of the whole brain network have

been performed, and most studies have focused on how information

processing in the brain changes in either consciousness or complete

unconsciousness. [1-3]

The response to external stimuli is decreased in the sedated

state, and cognitive function and memory processing are most likely

to deteriorate as consciousness declines. However, little is known

regarding the difference in information processing of external

stimuli under sedation compared with the arousal state.

Oddball paradigm is an experimental method commonly used in

studies utilizing event-related potentials (ERPs). [4] This method

presents the random sequences of two distinct stimuli (either visual

or auditory); one is frequently repeated (standard) and the other is

infrequent and deviant (target). When the cognitive function is

activated to detect the rare target stimulus, a specific type of ERP,

P300, is elicited after a certain time period (approximately 300–400

ms) following the introduction of a stimulus. [5] P300 is activated

when an attention-dependent cognitive task is performed in the

arousal state. [6] Therefore, the ERP should be affected in an

environment in which consciousness is low and attention is prone to

decrease.

Sevoflurane is a widely used inhalant anesthetic agent for

２

general anesthesia. Sevoflurane is preferred for general anesthesia

when various surgical procedures are performed due to its low side

effects and high anesthetic efficacy. [7] Recently, the use of

sevoflurane as a sedative agent is increasing because sedation can

be rapidly induced at low concentrations. [8] However, changes in

cognitive function with decreasing consciousness when sevoflurane

is administered have not yet been studied from the perspective of

changes in ERP.

In the present study, the changes in ERP in an auditory passive

oddball paradigm were investigated when sedation was induced by

sevoflurane inhalation.

３

Chapter 2. Materials and Methods

2.1. Volunteer recruitment

Before the experiments were conducted on volunteers, the

experimental methods were approved by the institutional review

board (IRB No. CME17001). A total of 20 volunteers (11 females,

nine males, mean age 26.8 years, age range 24–32 years) were

enrolled in this study after providing informed consent. The

inclusion criteria were healthy adults without any systemic diseases

or mental disorders.

2.2. Acquisition of EEG

Before electroencephalography (EEG) acquisition, volunteers

were instructed to sit on a chair and listen to auditory tones

delivered through earphones. Volunteers were also instructed to

keep their eyes closed during EEG. Continuous EEG data were

obtained from all patients under comfortable conditions (sampling

rate = 2048 Hz, low passed with 417-Hz cutoff frequency). The

EEG was sampled using custom-made software with 32 electrodes

placed according to the standard 10-20 International placement

(Fp1, AF3, F7, F3, FC1, FC5, T7, C3, CP1, CP5, P7, P3, Pz, PO3,

O1, Oz, O2, PO4, P4, P8, CP6, CP2, C4, T8, FC6, FC2, F4, F8, AF4,

Fp2, Fz, Cz). We also placed one electromyography (EMG) channel

on the right outer canthus to remove muscle artifacts. Data were

saved and analyzed offline. The data were downsampled at 128 Hz

with 60-Hz notch filter. To evaluate sedation depth objectively, a

bispectral index (BIS) sensor was also applied to the forehead and

measured during EEG acquisition.

４

2.3. Auditory passive oddball paradigm

The oddball paradigm used in this study consisted of two

different auditory tone sequences, a 1000 Hz standard tone and a

1200 Hz deviant (target) tone. The ratio of standard tone (p=0.8,

n=400) to deviant tone (p=0.2, n=200) was 4. Each tone was

randomly delivered through earphones. The auditory stimulation

time of each tone was 50 ms, with a rise and fall time of 10 ms. The

time interval between each tone was 800 ms. Each subject was

subjected to an auditory oddball task that consisted of a mixture of

500 tones.

2.4. Sevoflurane administration

After acquisition of EEG simultaneously with auditory stimulus

in passive oddball paradigm through the earphone in the awake state,

sevoflurane was administered to participants. The initial

sevoflurane concentration was set to 0.8 vol%. Sevoflurane

concentration was changed to maintain the BIS value around 80. As

soon as the participants were confirmed to experience strange

feelings (such as numbness in the extremities, drowsiness, or

feeling euphoric), participants received one trial of an auditory

oddball task during sevoflurane administration similar to the awake

state.

2.5. EEG preprocessing and statistical analysis

Each channel’s linear trends in the acquired EEG signals were

removed using the detrend function in Matlab 2017b (MathWorks,

Natick, MA, USA). Detrended signals were filtered using a

bandpass filter between 1 Hz and 30 Hz. The bandpassed EEG

signals were collected with epoch from -100 to 900 ms from sound

onset. Next, the continuous signal with a 1000-ms time-window,

starting 100 ms prior to stimulus onset was epoched. The average

amplitude in each epoch’s 100-ms window prior to stimulus onset

５

was subtracted for baseline correction of each epoch. Each epoched

signal was manually inspected by the researchers to exclude

artifacts such as EMG or electrocardiography (ECG). All epoched

signals were averaged to obtain ERPs for each participant. The

two-dimensional topographic map of a scalp data field was with 40

ms window to average each channel’s voltage in awake and sedation

states and each channel’s ratio which had statistical significance in

all moments of a window using the topoplot function in EEGLAB

(Swartz Center for Computational Neuroscience, UC San Diego, La

Jolla, CA, USA) [9]. To illustrate the signals of each channel, the

signal’s plot with the window that was statistically significant was

plotted with a green window in each channel. The maximum and

minimum EEG voltages between 250 and 500 ms from stimulus

onset were obtained to P300’s peak of each channel. In that peak’s

point, the time between awake and sedation states, the peak voltage

between awake and sedation states, the peak voltage and the

voltage at that time of another condition such as the sedation

voltage at awake peak time were compared using paired t-test. In

all statistical analyses, a P value less than 0.05 was considered

statistically significant.

６

Chapter 3. Results

3.1. Topographic distributions of ERP

Figure 1 shows the average topographic distributions of ERP

amplitude in the 320–360-ms latency range. When the subjects

were in the arousal state, strong positive-going ERPs were

observed in the 320–360-ms latency range in response to both

standard and target stimuli as shown in Figure 1(a). The peak

amplitude of the ERPs was observed in the frontal and central areas.

Conversely, when the subjects were in the sedation state, the ERP

amplitude in the frontal and central areas was markedly reduced as

shown in Figure 1(b). Figure 1(c) shows the p-value distributions

of the statistical differences in ERP amplitude between arousal and

sedation states. These results show ERPs were mainly elicited in

the central area with standard stimuli and in the frontal area with

target stimuli.

Figure 1. The average topographic distributions of ERP amplitude in the

７

320–360 ms latency range. (a) The average distributions of ERP in the

arousal state. The dark blue-colored areas indicate the positive-going

ERPs, which are located in the frontal and central areas. (b) The average

distributions of ERP in the sedation state. The ERP amplitude in the frontal

and central areas was markedly reduced. (c) The p-value distributions of

the statistical differences in ERP amplitude between arousal and sedation

states. ERP was concentrated in the central area with standard stimuli and

in the frontal area with target stimuli.

3.2. Temporal changes of ERP in channel views

Based on the above results, temporal changes in ERP were

examined in the frontal and central electrodes where ERP was

strongly elicited. Figure 2(a) shows the average time-domain

graphs of ERPs measured with the Fz electrode. The characteristic

positive-going ERPs were observed in the latency range of 300–

400 ms, and the ERP amplitude when using target stimuli was

greater than when using standard stimuli. These ERP

characteristics confirmed that P300 was elicited by the target

stimuli in the auditory oddball paradigm. Figure 2(b) shows the

average time-domain graphs of ERPs measured with the Cz

electrode. The P300 detected with the Cz electrode showed the

same tendency as the P300 detected with the Fz electrode; the

P300 amplitude detected with both Fz and Cz electrodes was

statistically significantly decreased by nearly 70% in the sedation

state compared with arousal state (P<0.001).

８

Figure 2. The average time-domain graphs of ERP measured with the Fz

and Cz electrodes. The red solid lines indicate the ERP in the arousal state

and the blue solid lines indicate the ERP in the sedation state. The green

boxes show the statistically significant differences (P<0.05) between

ERPs in the arousal and sedation states. The red-dotted lines highlight the

differences between P300 peak amplitudes in the arousal and sedation

states. (a) The average ERP graphs of the measurements obtained with

the Fz electrode. (b) The average ERP graphs of the measurements

obtained with the Cz electrode. The P300 amplitude detected with both Fz

and Cz electrodes was statistically significantly decreased in the sedation

state compared with the arousal state.

９

Chapter 4. Discussion

In this study, we showed that P300 ERP was induced by

auditory stimulation based on a passive oddball paradigm and its

location was mainly concentrated in frontal and central areas. In

addition, the P300 amplitude decreased statically in the sedation

state compared with the arousal state. To the best of our knowledge,

this is the first study in which the changes of auditory stimulus

processing during the sedation state were investigated.

Reportedly, P300 consists of two subcomponents, P3a and P3b.

[5] Previous studies showed that P3a, which has a shorter latency

(360–380 ms), is different from P3b, which has a longer latency

(380–430 ms). [10] P3a is elicited in the frontal lobe when deviant

novel stimuli are detected which are task-irrelevant. P3b is elicited

in the temporal and parietal lobes when infrequent stimuli are task-

relevant (e.g., pressing a button or counting numbers). [11]

In this study, the experiments were conducted based on an

auditory passive oddball paradigm; the subjects listened to the two

types of auditory stimuli, standard and target, and were instructed

not to respond in a specific manner when target stimuli were

detected. [12] Since P3b is elicited only when the stimulus is task-

relevant, the main subcomponent of the P300 observed in this study,

which did not provide a specific task, was P3a.

Several theories have been introduced for the meaning of P300

in brain information processing. The most widely known theory is

the context-updating theory. [13] According to this theory, the

brain produces a stimulus context which is a hypothesis on

incoming stimuli based on the previously detected stimuli. If a new

stimulus is detected that is different from the previous stimuli, the

brain modifies or updates this stimulus context through internal

１０

information processing. The main idea of this theory is that P300 is

elicited when the stimulus context is updated.

Previous studies have explained the meaning of P300 based on

this context-updating theory. According to a model proposed by

Polich, [14] when infrequent target stimuli appear between

standard stimuli, the frontal lobe is first activated, which

concentrates attentional resources to detect and distinguish these

stimuli. In this process, P3a is elicited in the frontal lobe. The

parietal lobe is then activated to access the memory storage and

update the memory related to the stimulus context. In this process,

P3b is elicited in the parietal lobe. [15]

The above model of P300 and the results of this study can be

summarized to explain the effect of sevoflurane-induced sedation

on brain information processing. Sevoflurane-induced sedation

significantly reduced the P300 amplitude. Since this study utilized a

passive oddball paradigm, the main component of P300 observed in

this study was P3a, which was elicited when the frontal lobe

concentrates attentional resources to discriminate infrequent

deviant stimuli. Thus, the reduction in P3a caused by sevoflurane-

induced sedation may reflect the weakening of the cognitive

function responsible for attentional process and stimuli

discrimination.

The relationship between P300 and sedation induced by several

sedative agents has been described in previous studies. Jessop, et

al. [16] observed changes in P300 when subjects were given

nitrous oxide (N2O) gas inhalation. As a result, the amplitude of the

P300 waveform decreased as the N2O concentration was increased

from the sedative level to the anesthetic level. Engelhardt, et al.

[17] observed changes in P300 when midazolam, a benzodiazepine-

based sedative, was administered, resulting in an increase in the

latency of P300 and an increase in the errors of task performance.

Reinsel, et al. [18] observed changes in P300 in sedation induced

１１

by propofol administration, resulting in a 70% reduction in P300

amplitude and a 50% increase in reaction time. In contrast to our

study, previous studies did not utilize the oddball paradigm. ERP

measured in previous studies only reflected auditory processing,

not auditory attention, since the same auditory stimuli was applied

to patients. Conversely, we utilized the oddball paradigm to

investigate ERP changes under sedation. ERP measured using the

oddball paradigm has gained attention as a neural correlate of

cognitive processing. Consistent with our findings, a recent study

showed that ERP is altered in patients with cognitive impairment

when applying the auditory oddball paradigm. For example, P300

prolongation and loss of P300 potential was observed in patients

with Parkinson disease with mild cognitive impairment. [19]

Alterations of P300 were also observed in obstructive sleep apnea

associated with cognitive impairment. [20] These results indicate

that P300 may provide a diagnostic marker of cognitive impairment

associated with neurological disorders. In this regard, P300 changes

during N2O administration can be considered associated with N2O-

induced cognitive impairment.

The results from this study also indicate that information

processing may be disturbed during sedation considering that it

requires a cognitive task to discriminate rare auditory stimuli under

the auditory oddball paradigm. In fact, patients who are in a sedation

state often experience a slow response to verbal stimuli compared

with the awake state.

The present study had several limitations. First, due to the use

of a passive oddball paradigm, investigation of P3b subcomponent

could not be conducted. Therefore, in future studies, the effect of

sevoflurane-induced sedation on P3b as well as P3a should be

identified using an active oddball paradigm and independent

component analysis (ICA). [21] This study also lacked control over

the factors which may cause changes in P300. By varying the

factors such as difficulty of tasks [22] and target-to-target

１２

interval [23], more accurate tendencies of P300 could be obtained.

In conclusion, the present study results showed that

sevoflurane-induced sedation caused a decrease in P300 amplitude,

which may reflect weakening of the cognitive function governing the

attentional process and stimuli discrimination during sedation.

１３

References

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frontal–parietal communication by ketamine, propofol, and

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[8] Mesnil M, Capdevila X, Bringuier S, Trine PO, Falquet Y, Charbit

J, Roustan JP, Chanques G, Jaber S. Long-term sedation in

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component analysis. J Neurosci Methods. 2004;134(1):9-21.

[10] Courchesne E, Hillyard SA, Galambos R. Stimulus novelty, task

relevance and the visual evoked potential in man.

１４

Electroencephalogr Clin Neurophysiol. 1975;39(2):131–43.

[11] Conroy MA, Polich J. Normative variation of P3a and P3b from

a large sample: Gender, topography, and response time. Journal of

Psychophysiology. 2007;21(1):22–32.

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Clin Neurophysiol. 2007;118(10):2128-48.

[16] Jessop J, Griffiths DE, Furness P, Jones JG, Sapsford DJ,

Breckon DA. Changes in amplitude and latency of the P300

component of the auditory evoked potential with sedative and

anaesthetic concentrations of nitrous oxide. Br J Anaesth.

1991;67(5):524-31.

[17] Engelhardt W, Friess K, Hartung E, Sold M, Dierks T. EEG and

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[18] Reinsel RA, Veselis RA, Wronski M, Marino P. The P300

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Parkinson's disease. Neurol Sci. 2017;38(12):2103-2109.

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P300 response is related with cognitive deficits in Obstructive Sleep

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[21] Debener S, Makeig S, Delorme A, Engel AK. What is novel in

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P3 event-related potential as revealed by independent component

１５

analysis. Brain Res Cogn Brain Res. 2005;22(3):309-21.

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target-to-target interval. Psychophysiology. 2002;39(3):388–96.

１６

초 록

1. 연구 목적

본 연구의 목적은 sevoflurane 흡입으로 유도된 진정상태에서

auditory passive oddball paradigm을 사용함으로써 event-related

potential (ERP)의 변화에 대해 조사하는 것이었다.

2. 연구 방법

전신질환이나 정신장애가 없는 20명의 자원자 (여성 11명, 남성 9명,

평균 연령 26.8세, 연령대 24-32세)가 본 연구에 참여하였다. 각

피험자의 뇌파는 32채널로 구성된 Electroencephalography (EEG)

기록 장비로 측정되었다. 각성상태에서 피험자의 평상시의 뇌파가 5분

동안 측정되었다. 이후 passive oddball paradigm에 따른 청각자극이

이어폰을 통해 환자에게 전달되었다. passive oddball paradigm은

500개의 톤으로 구성되었으며, 이 중 4/5는 표준자극 (1000 Hz),

1/5는 대상자극 (1200 Hz)이었다. 청각자극이 진행되는 동안 뇌파가

측정되었다. 이후 0.8 vol%의 초기농도로 sevoflurane이 흡입

투여되었다. Bispectral index (BIS) 수치가 80 근처에서 유지되도록

sevoflurane 농도가 조절되었다. 안정적인 진정상태가 유도된 후, 위와

동일한 방식으로 청각자극이 가해지면서 뇌파가 측정되었다. 뇌파

측정이 완료된 후 sevoflurane 투여는 종료되었고, 피험자가 회복하는

동안 100% 산소가 투여되었다. 측정된 뇌파에서 ERP가 추출된 후

ERP의 지형적 분포, 각 채널에서 ERP의 시간적 변화, 각성상태와

진정상태에서 ERP의 통계적인 차이가 분석되었다.

3. 결과

각성상태일 때, P300이 320-360 ms latency에서 관찰되었으며,

P300은 frontal 및 central area에 집중되었다. 각성상태에 비해

진정상태에서 P300 amplitude가 통계적으로 유의미하게 감소했다.

１７

4. 결론

sevoflurane을 이용한 진정법은 P300 amplitude의 감소를 야기하며,

이는 진정상태에서 집중과정과 자극구별을 담당하는 인지기능이

약화됨을 반영한다고 할 수 있다.

주요어 : Event-Related Potential, P300, Oddball paradigm,

Sevoflurane, Sedation, Electroencephalography

학 번 : 2014-23003