Estimation of Chronic Stress by Measuring Sympathetic Sedation Time

Masahiro Inazawa, Yuki Ban

, Naoki Tateyama

and Shin’ichi Warisawa

Graduate School of Frontier Science, The University of Tokyo, Kashiwa, Chiba, Japan

Keywords:

Chronic Stress, Sympathetic Activity, Corticotropin-releasing Hormone, Cortisol.

Abstract:

Intermittent exposure to stressors disrupts the negative feedback mechanism of cortisol toward corticotropin-

releasing hormones. In this study, this condition is referred to as chronic stress. Chronic stress causes a variety

of recurring, long-term, incurable illnesses, such as major depression. Therefore, it is important to understand

chronic stress on a daily basis. We propose a chronic stress estimation method using sympathetic sedation

time measurements as a non-invasive, short-time, and highly accurate method. This method determines the

degree of chronic stress according to the length of time until the sympathetic activity subsides after stressor

loading. To verify the feasibility of the proposed method, we conducted an experiment comparing the sympa-

thetic sedation times among a healthy group, middle group, and chronic stress group classiﬁed by the Quick

Inventory of Depressive Symptomatology. We calculated sympathetic sedation time from the trend of change

in RRV at calm after stressor loading due to a two-back task. As a result of the experiment, which consisted

of nine participants, the sympathetic sedation time in the chronic stress group was longer than in the healthy

and middle groups, supporting the feasibility of this method.

1 INTRODUCTION

Normally, when a person is exposed to a stressor,

corticotropin-releasing hormone (CRH) is secreted

from the hypothalamus. As a result, adrenocorti-

cotropic hormone (ACTH) is secreted from the ante-

rior pituitary gland, which promotes the secretion of

cortisol from the adrenal cortex. Even though cortisol

causes various stress responses, including hippocam-

pal atrophy, it has a negative feedback mechanism for

CRH and ACTH, and this feedback will eventually

cause the stress response to disappear. However, in-

termittent exposure to stressors deteriorates the neg-

ative feedback function of cortisol (Fink, 2010; Con-

toreggi, 2015) (Fig.1). In this study, we deﬁne a con-

dition in which the negative feedback function of cor-

tisol deteriorates as chronic stress.

Chronic stress can cause a variety of illnesses.

Chronically high levels of cortisol can cause hip-

pocampal atrophy and impaired memory (Vachon-

Presseau et al., 2013). In addition, it causes chronic

high blood pressure and blood sugar levels, which

can lead to diabetes. Chronically high levels of

CRH due to the deterioration of the negative feedback

https://orcid.org/0000-0001-7349-6383

https://orcid.org/0000-0001-6747-5295

https://orcid.org/0000-0001-9815-6801

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mechanism of cortisol may promote fear conditioning

by the amygdala and predispose individuals to post-

traumatic stress disorder (Hashimoto et al., 2017).

High CRH levels can also lead to high dopamine lev-

els and impair cognitive function (Fink, 2010). If

these diseases persist for a long period of time, they

can lead to major depression. These diseases, in-

cluding major depression, are prone to recurrence and

have a long treatment period (Clinic, 2020). More-

over, high levels of cortisol exposure damages the

hippocampal and prefrontal cortex nerves, and may

292

Inazawa, M., Ban, Y., Tateyama, N. and Warisawa, S.

Estimation of Chronic Stress by Measuring Sympathetic Sedation Time.

DOI: 10.5220/0010326502920298

In Proceedings of the 14th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2021) - Volume 4: BIOSIGNALS, pages 292-298

ISBN: 978-989-758-490-9

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not cause neurogenesis, depending on age and sever-

ity of the depression (Contoreggi, 2015; Van Wingen

et al., 2012). Chronic stress conditions can cause var-

ious diseases that are prone to recurrence, have a long

treatment period, and may not be completely cured.

Therefore, we believe it is important to understand the

chronic stress state on a daily basis to prevent these

diseases.

The prior methods of chronic stress estimation can

be broadly classiﬁed into two types. One method

measures changes in behavior and cognition caused

by chronic stress, and the other measures biological

information related to the negative feedback mecha-

nism of cortisol.

As a method for measuring changes in behavior

and cognition, questionnaires, such as PSS-14, and

the estimation of a chronic stress state from a change

tendency of the pressure distribution on the seat sur-

face of a chair are used (Katsunori, 2006; Cohen et al.,

1983; Kuroha et al., 2019). In addition, chronic stress

can be estimated by lifestyle change such as sleep-

ing time collected from smartphones (Opoku Asare

et al., 2019; Dogan et al., 2017; Rohani et al., 2018;

Wang et al., 2018). PSS-14 is a questionnaire that

consisting of 14 question items on a ﬁve-level Likert

scale. It is assumed that the response is made by re-

membering the events within one month or one week,

and the chronic stress state can be estimated in a short

time. Since the answers in the questionnaire are sub-

jective evaluations, there are difﬁculties of inaccurate

answers if the participant does not answer seriously

or if they are not aware of their own stress. In the

method using the change in seat pressure, the chronic

stress state can be easily estimated non-invasively by

sitting on a chair for a long duration using a cush-

ion equipped with a pressure sensor. In the method

using smartphones, chronic stress can be easily esti-

mated from information such as screen startup time

and sleep time collected from them. However, the es-

timation accuracy is low in these methods because the

biological reaction under chronic stress is not directly

measured.

Two of the methods for estimating biological

information with regards to the negative feedback

mechanism of cortisol are the DEX/CRH test and

salivary cortisol concentration measurement (Heuser

et al., 1994; Hellhammer et al., 2009). In the

DEX/CRH test, dexamethasone (DEX) is adminis-

tered before bedtime, and the blood cortisol concen-

tration when CRH is administered in the next morn-

ing is measured. Dexamethasone is a long-acting ar-

tiﬁcial cortisol. Healthy individuals have low cortisol

levels even after CRH administration due to the neg-

ative feedback mechanism. On the contrary, under

chronic stress, high cortisol is measured after CRH

administration, thus, the chronic stress state can be

measured. The challenge with this method is that it

is invasive, requiring at least three injections of DEX

and CRH administration, and cortisol collection. An-

other difﬁculty is that the load test time is up to several

hours. Estimating by salivary cortisol concentration,

another measurement method, can measure chronic

hypercortisol status non-invasively. The challenges

of this method is that the salivary hypercortisol sta-

tus is caused not only by a decrease in the negative

feedback mechanism of cortisol, but also by the di-

urnal variation of cortisol and acute stressors, thus,

strict control is required for measurements. Another

difﬁculty is that it takes several hours to analyze the

salivary cortisol concentration.

Overall, the behavioral and cognitive changes due

to chronic stress can be assessed non-invasively and

quickly, but the accuracy is low. On the contrary, the

method for measuring biological information with re-

gards to the negative feedback mechanism of cortisol

is highly accurate because it directly measures the bi-

ological reaction in a chronic stress state, but the mea-

surement is long-term or invasive. Therefore, the pur-

pose of this study is to design a non-invasive, fast, and

highly accurate chronic stress measurement method

and to evaluate its accuracy.

2 CHRONIC STRESS

ESTIMATION METHOD BY

MEASURING SYNPATHETIC

SEDATION TIME

In this study, we propose chronic stress estimation

by sympathetic sedation time measurements as a non-

invasive, fast, and highly accurate chronic stress mea-

surement method. A stressor is applied to an user,

the time during which the sympathetic nerve activity

subsides is measured, and the chronic stress state is

estimated from this time duration. We believe that the

sympathetic nerve activity sedation time is longer un-

der chronic stress, as detailed below (Fig.2).

The negative feedback function of cortisol is dete-

Estimation of Chronic Stress by Measuring Sympathetic Sedation Time

293

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riorated under chronic stress. As a result, those with

chronic stress are considered to have high CRH for

a long time after stressor loading. CRH may pro-

mote sympathetic nerve activity. Habib et al. found

that male rhesus monkeys orally administered with

the CRH antagonist antaramine have reduced sympa-

thetic nerve activity when confronted with other male

individuals compared to placebo individuals (Habib

et al., 2000). Therefore, we believe that under a

chronic stress state, the sympathetic nerve activity ac-

tivated by the stressor is difﬁcult to sedate because

CRH does not decrease after stressor loading(Fig.1).

Therefore, we believe that the chronic stress state

can be estimated by loading the stressor on the user

and measuring the time for the subsequent sympa-

thetic nerve activity to subside. This method is ex-

pected to be highly accurate as it measures biological

reactions related to the negative feedback mechanism.

In addition, since it is a sympathetic nerve measure-

ment, it can be measured non-invasively by a sensor,

such as an electrocardiogram. The measurement time

is approximately 30 min. This time is shorter than

that of the DEX/CRH test and saliva cortisol concen-

tration measurements, which is an advantage.

We describe the details of the proposed method.

First, the user remains calm for 5 min to soothe sym-

pathetic activity. During this time, respiratory con-

trol is performed to enhance the effect of calming.

The respiratory cycle is set to 12 times/min as a suf-

ﬁciently slow cycle to sedate the sympathetic nerves.

Next, user is loaded the stressor for 5 min. Then, the

user remains calm for 10 min. During this period,

the sympathetic nerve activity is measured, and sym-

pathetic sedation time is calculated. As sympathetic

nerve activity changes depending on the respiratory

cycle, it may be necessary to suppress the variation in

sympathetic sedation time due to the respiratory cy-

cle by controlling breathing during calming after the

stressor. Therefore, the effect of sympathetic sedation

time due to respiratory control during calming after

the stressor was examined. The ﬂow of the proposed

method is described in Fig.3.

In this study, the required function of the stres-

sor used in the proposed method was deﬁned as caus-

ing a stress response that causes cortisol secretion. In

addition, as a constraint condition, the load can be

loaded within a short time of several minutes. We

selected the two-back task as the stressor that satisﬁes

these functions. Even though there are many varia-

tions of this task, we selected one in which recordings

of numbers from one to ﬁve are played through head-

phones every second and a participant has to press the

space key only when the number matches that read

two prior.

In this study, we assumed that the sympathetic

nerve was sedated when the R-R interval variabil-

ity (RRV) at calm after the two-back task exceeded

60% of the maximum value of RRV at calm. The

time taken until the sympathetic nerve was sedated

for the ﬁrst time after the two-back was deﬁned as

the sympathetic nerve sedation time (Fig.4). RRV is

the variance of the interval between R waves during

1 min for electrocardiography and is a parasympa-

thetic index. Since the sympathetic and parasympa-

thetic nerves have an antagonistic effect, the sympa-

thetic nerve appears to be sedated by the increase of

RRV.

3 EXPERIMENT

3.1 Overview

To verify the possibility of estimating chronic stress

by measuring the sympathetic sedation time, we re-

cruited experimental participants and conducted an

experiment. Assuming that the higher the degree of

depression, the higher the degree of chronic stress,

the participants were divided into three groups using

the Quick Inventory of Depressive Symptomatology

(QIDS), which is a diagnostic criterion for depres-

sion (Rush et al., 2003). The QIDS scores ranged

from zero to ﬁve points in the healthy group, six to

10 in the middle group, and at least 11 points in the

chronic stress group. The sympathetic nerve sedation

time of each group was compared. In addition, as de-

scribed in the previous chapter, the sympathetic nerve

sedation time may change depending on the respira-

tory control, thus, the effect of the respiratory control

at calm after the two-back task shown in Fig.3 was

examined. This experiment is approved by the Ethics

Review Board.

BIOSIGNALS 2021 - 14th International Conference on Bio-inspired Systems and Signal Processing

294

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3.2 Experiment Flow

First, the participants ﬁlled in the QIDS within one

week prior to the sympathetic sedation time measure-

ment experiment. Then, the participants were sub-

jected to a sympathetic sedation time measurement

experiment three times on different days. The three

sympathetic sedation time measurement experiments

differed only in the respiratory control conditions at

calm after the two-back task. The ﬁrst and last ex-

periments for each participant were scheduled within

seven days so that the chronic stress status of the par-

ticipants did not change signiﬁcantly between exper-

iments. Since the sympathetic nerve sedation time

changes depending on the diurnal variation of corti-

sol, the sympathetic nerve sedation time measurement

experiment was performed from 15:00 to 17:00 when

the diurnal variation of cortisol was small. In addi-

tion, to suppress ﬂuctuations in the diurnal variation

of cortisol, alcohol and caffeine intake, strenuous ex-

ercise, and staying up late the day before the experi-

ment were prohibited. The ﬂow of the experiment is

shown in Fig.5.

In the sympathetic sedation time measurement ex-

periment, the process described in the previous chap-

ter was performed using a GUI.

1. Calm1: Participants were instructed to look at

a cross gaze point for 5 min and rest to calm

the sympathetic nerves (Fig.6). At that time,

respiratory control was performed at a cycle of

12 times/min to enhance the effect of sympa-

thetic nerve sedation. Respiratory control was

performed according to the expansion and con-

traction cycle of the blue bar shown in Fig.6.

2. 2-Back Task (Stressor Loaded): Participants

were instructed to perform the two-back task for 5

min while looking at the same gazing point as in

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Calm1. This task involves the playing of a read-

ing of any number from one to ﬁve through head-

phones every second, and participants press the

space key when the number matches two numbers

prior (Fig.7). Unlike Calm1, respiration was not

controlled. This is because we believe that res-

piratory control reduces the ability to concentrate

on the two-back task and reduces stress load.

3. Calm2: To measure the sympathetic sedation

time, participants were instructed to look at the

gaze point for 10 min and calm. Three condi-

tions were prepared for respiratory control as fol-

lows: no respiratory control, fast respiratory con-

trol (20 times/min), and slow respiratory control

(12 times/min). Under the no respiratory con-

trol condition, the blue breathing control bar did

not appear, participants were instructed to breathe

naturally. Under fast or slow respiratory control

conditions, participants were instructed to breathe

according to the expansion and contraction cycle

of the blue bar. Before the experiment, partici-

pants were told under which respiratory control

conditions the experiment would be conducted.

The order of these conditions was counterbal-

anced among the participants.

This process was performed by looking at the PC

screens installed in the compartments separated by

partitions. During this process, the electrocardiogram

was measured and the R-R Interval (RRI) was calcu-

lated. Electrocardiogram was measured at 1000 Hz

using biosignalsPlux. R waves were detected by ﬁrst

passing the electrocardiogram through a Butterworth

ﬁlter from 0.05 to 26 Hz and then using the biosppy li-

brary(Carreiras et al., 15). Furthermore, the RRI vari-

ability (RRV) was calculated for each minute window

and used as a parasympathetic nerve activity index.

The time when RRV after the two-back task exceeded

the threshold for the ﬁrst time was deﬁned as sympa-

thetic sedation time. The threshold was set to 60%

of the maximum value of RRV after the two-back

task (Fig.4).

Estimation of Chronic Stress by Measuring Sympathetic Sedation Time

295

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4 RESULTS

We recruited nine participants to this study. The

QIDS classiﬁcation revealed three healthy individuals

(one male and two females in their 20s), three middle

groups (three males in their 20s), and three chronic

stress groups (three males in their 20s). The mean

and standard errors of the QIDS scores were 3.33 ±

0.98 in the healthy group, 6.00 ± 0.00 in the middle

group, and 13.66 ± 1.78 in the chronic stress group.

Fig.8 shows the RRV data of a participant in a

healthy group under no respiratory control and that

of another participant in the chronic stress group un-

der no respiratory control. In the healthy participant

(left), RRV increased immediately after the two-back

task, that is, the sympathetic nerves were sedated im-

mediately. On the contrary, in the chronic stress par-

ticipant (right), RRV increased approximately 5 min

after two-back (experimental time 15 min), that is, it

took some time to sedate the sympathetic nerves.

Next, we calculated the mean and standard error

of the sympathetic sedation time described in Chapter

3 for each respiratory control condition and partici-

pant group. The results are shown in Fig.9. In ad-

dition, the threshold values of sympathetic nerve se-

dation used when calculating the sympathetic nerve

sedation time were 70% and 80% of the RRV maxi-

mum value, shown in Fig.10.

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5 DISCUSSION

5.1 Respiratory Control

As shown in Fig.9,under no and slow respiratory con-

trol,the hypotheses of shorter sympathetic sedation

time in the healthy group and longer sympathetic se-

dation time in the chronic stress group were not met.

However, under fast respiratory control conditions,

the hypothetical tendency was conﬁrmed. A similar

tendency was conﬁrmed when the threshold for sym-

pathetic sedation was set to 70% or 80% of the max-

imum RRV value (Fig.10).The hypothesis being met

only under fast respiratory control was considered to

be because this respiratory control at calm is also a

stressor, and the sympathetic nerve sedation time is

longer than that of no respiratory control in both the

healthy and chronic stress groups. However, in the

chronic stress group, the negative feedback function

of cortisol was reduced, and the effect of prolonging

the sympathetic sedation time by fast respiratory con-

trol was greater than that of other groups. The chronic

stress state may be estimated from the sympathetic se-

dation time by performing fast respiratory control at

calm after two-back. To make the feasibility veriﬁ-

cation of the proposed method more reliable, the fol-

lowing factors could be improved.

BIOSIGNALS 2021 - 14th International Conference on Bio-inspired Systems and Signal Processing

296

5.2 Sympathetic Sedation Time

In this veriﬁcation, the sympathetic sedation time was

calculated using only the RRV of the electrocardio-

gram as an index, but RRV is affected by the respira-

tory cycle as well as the sympathetic nerves. The re-

sults must be veriﬁed from various angles using other

sympathetic nerve indexes, such as pupil diameter,

electro dermal activity, etc. In addition, the sym-

pathetic nerves were sedated when RRV after two-

back exceeded 60% of the maximum value for the

ﬁrst time, but the threshold value of 60% is necessary

for comparison with various threshold values of other

sympathetic nerve indexes.

5.3 Stressor

In this study, the two-back task was selected as a stres-

sor that secretes cortisol, but this task leads to a low

amount of cortisol secretion (Henckens et al., 2011).

Since the proposed method is intended to measure the

decrease in the negative feedback mechanism of cor-

tisol, the stressor needs to cause the secretion of corti-

sol. For example, the Trier Social Stress Test (TSST)

results in the secretion of cortisol, but the process is

very long and the second presentation shows acclima-

tization and signiﬁcantly reduced cortisol secretion

(Yao et al., 2016; Dhabhar et al., 1997; W

ust et al.,

2005; Schommer et al., 2003). We need to design a

cortisol-secreting stressor that can be presented in a

short period of time and with little familiarity.

6 CONCLUSION

In this study, we propose chronic stress estimation

through sympathetic sedation time measurements as

a non-invasive, fast, and highly accurate method. In

this method, a stressor is applied to an user, the time

until the sympathetic nerve activity subsides is mea-

sured, and the chronic stress state is estimated from

the length of time.

We recruited nine participants to this study. As

a result, we conﬁrmed that the sympathetic sedation

time tended to be longer in the chronic stress group

than in the healthy group by performing fast respira-

tory control after stressor loading. Moreover, we be-

lieve that the following improvements could make the

demonstration of feasibility more reliable.

1. Multifaceted veriﬁcation of whether the sympa-

thetic nerve has sedated.

2. Optimal stressor design for sympathetic sedation

time measurement.

After demonstrating the feasibility of chronic

stress estimation by measuring sympathetic sedation

time through the above improvements, we aim to de-

sign a wearable device that integrates a sensor for

measuring sympathetic sedation time as well as a

stressor presentation device. We believe that with the

development of such devices, anyone will be able to

identify their chronic stress state on a daily basis and

prevent mental illnesses, such as major depression.

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