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Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life


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Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases, evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inflammation cause deteriorations in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent inflammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13 females, 13 males; mean age, 34.4 ± 9.9 years) were randomized to either a group administered oral HRW (600 mL/d) or placebo water (PLW, 600 mL/d) for 4 weeks. Change ratios (post-treatment/pre-treatment) for K6 score and sympathetic nerve activity during the resting state were significantly lower after HRW administration than after PLW administration. These results suggest that HRW may reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function.
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© 2017 Medical Gas Research | Published by Wolters Kluwer - Medknow 247
Hydrogen-rich water for improvements of mood, anxiety, and
autonomic nerve function in daily life
Kei Mizuno1-5, Akihiro T. Sasaki1-3, 6, Kyoko Ebisu1, 3, Kanako Tajima2, 3, Osami Kajimoto1, 5, Junzo Nojima7,
Hirohiko Kuratsune8, Hiroshi Hori1-3, Yasuyoshi Watanabe1-4, 6, *
1 Osaka City University Center for Health Science Innovation, Osaka, Japan
2 Pathophysiological and Health Science Team, RIKEN Center for Life Science Technologies, Kobe, Japan
3 Health Evaluation Team, RIKEN Compass to Healthy Life Research Complex Program, Kobe, Japan
4 Health Metrics Development Team, RIKEN Compass to Healthy Life Research Complex Program, Kobe, Japan
5 Department of Medical Science on Fatigue, Osaka City University Graduate School of Medicine, Osaka, Japan
6 Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan
Department of Laboratory Science, Faculty of Health Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
8 Department of Health Science, Faculty of Health Science for Welfare, Kansai University of Welfare Sciences, Kashihara, Japan
*Correspondence to: Yasuyoshi Watanabe, M.D., Ph.D.,
Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases,
evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inammation cause deteriora-
tions in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several
hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and
daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent
inammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich
water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve
function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13
females, 13 males; mean age, 34.4 ± 9.9 years) were randomized to either a group administered oral HRW (600 mL/d)
or placebo water
(PLW, 600 mL/d) for 4 weeks. Change ratios (post-treatment/pre-treatment) for K6 score and sympathetic nerve activity during the
resting state were signicantly lower after HRW administration than after PLW administration. These results suggest that HRW may
reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function.
Key words: anxiety; autonomic nerve function; hydrogen-rich water; mood; quality of life
doi: 10.4103/2045-9912.222448
How to cite this article: Mizuno K, Sasaki AT, Ebisu K, Tajima K, Kajimoto O, Nojima J, Kuratsune H, Hori H, Watanabe Y.
Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life. Med Gas Res. 2017;7(4):247-255.
Health and a vibrant life are much craved by everyone. To
improve quality of life (QOL), maintain a healthy state,
and prevent the onset of various diseases, evaluation of
interventional effects for improving QOL is important. The
high metabolic rate of the brain results in the generation of
disproportionate amounts of reactive oxygen and nitrogen
species, leading to increased oxidative stress.1 Increased
oxidative stress and lipid peroxidation initiate a cascade of
proinammatory signals, leading to inammation. Altered
homeostasis of oxidation, inammation, and protein ag-
gregation has been suggested to contribute to the death of
neurons, which is directly related to impairments in various
cognitive domains. As such, chronic oxidative stress and
inammation may cause deteriorations in the function of
the central nervous system, leading to reductions in QOL.
Hydrogen has antioxidant activity and can prevent inam-
mation.2-4 The distribution of hydrogen throughout the
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Mizuno et al. / Med Gas Res
and body indicates actions both in the central and
peripheral nervous systems. Previous clinical studies
have shown that hydrogen-rich water (HRW) reduces
concentrations of markers of oxidative stress in patients
with metabolic syndrome,
improves lipid and glucose
metabolism in patients with type 2 diabetes,
mitochondrial dysfunction in patients with mitochon-
drial myopathies, and reduces inammatory processes
in patients with polymyositis/dermatomyositis.
In an-
other study, exercise-induced declines in muscle function
among elite athletes were also improved by administering
Although such ndings suggest that HRW may
help alleviate symptoms of several diseases and increase
the physical performance of athletes, the effects of pro-
longed HRW ingestion on the QOL of individuals in the
general population remain unknown.
Some reports have demonstrated that oxidative stress
is associated with QOL in patients with chronic obstruc-
tive pulmonary disease and cervical cancer.
oncological treatment among patients with cervical
cancer, antioxidant supplementation was found to be
effective in improving QOL.
In addition, Kang et al.
reported that treatment with HRW for patients receiving
radiotherapy for liver tumors decreased oxidative stress
and improved QOL. Although the association between
oxidative stress and QOL in healthy individuals is still
unclear, aging, job stress, and cognitive load over the
course of several hours in healthy individuals have also
been found to induce increases in oxidative stress,
suggesting that preventing the accumulation of oxida-
tive stress caused by daily stress and daily work may
contribute to the maintenance of QOL and amelioration
of the effects of aging. Continuous HRW intake might
therefore be expected to reduce accumulation of oxida-
tive stress, thus helping to prevent decreases in QOL.
The aim of the present study was to investigate the effects
of drinking 600 mL of HRW per day for 4 weeks on the
QOL of adult volunteers using questionnaires for sleep,
fatigue, mood, anxiety, and depression, an autonomic
function test, and a higher cognitive function test.
subjects and Methods
Thirty-one adult volunteers between 20 and 49 years old
participated in this double-blinded, randomized, placebo-
controlled study with a two-way crossover design. Exclu-
sion criteria comprised: history of chronic illness; chronic
medication or use of supplemental vitamins; employment
in shift work; pregnancy; body mass index ≤ 17 or 29
kg/m2; food allergy; history of smoking; or history of
drinking excessive amounts of alcohol (≥ 60 g/day). Shift
workers were excluded because the water was administered
at breakfast and dinner, the timings of which are irregular
among shift workers. In addition, the mental and physical
conditions of shift workers can be greatly affected by the
shift schedule for the preceding 2 days, which may impact
the results obtained from the questionnaires used in this
study. Before each experiment, participants were asked
to refrain from drinking alcohol, since drinking excessive
amounts of alcohol carries signicant risks of uctuations
in physical condition. All experiments were conducted in
compliance with national legislation and the Code of Ethical
Principles for Medical Research Involving Human Subjects
of the World Medical Association (the Declaration of Hel-
sinki) and registered to the UMIN Clinical Trials Registry
(No. UMIN000022382). The study protocol was approved
by the Ethics Committee of Osaka City University Center
for Health Science Innovation (OCU-CHSI-IRB No. 4),
and all participants provided written informed consent for
participation in the study.
Study design
We used a double-blinded, placebo-controlled study with
a two-way crossover design, as summarized in Figure 1.
After admission to the study, participants were randomized
in a double-blinded manner to receive HRW in an aluminum
pouch (0.8–1.2 ppm of hydrogen, 300 mL/pouch; Melodian
Corporation, Yao, Japan) or placebo water (PLW), repre-
senting mineral water from the same source (i.e., same
components without hydrogen) in an aluminum pouch
(0 ppm of hydrogen, 300 mL/pouch; Melodian Corpora-
Figure 1: Time course of the experiments.
Note: Participants were randomly divided into two study groups.
The experiment consisted of 4 weeks of hydrogen-rich water
(HRW) administration or placebo water (PLW) administration,
a 4-week washout period, and then another 4 weeks of PLW
administration or HRW administration. Before (pre) and after
(post) each period of HRW or PLW administration, subjective
and objective measurements for quality of life were obtained,
such as results for sleep, mood, anxiety, feelings of depression,
autonomic nerve function, and cognitive function.
Medical Gas Research ¦ December ¦ Volume 7 ¦ Issue 4 249
Mizuno et al. / Med Gas Res
Studies Depression Scale.21 General sleepiness and daytime
sleepiness scores were calculated using the Pittsburgh Sleep
Quality Index (PSQI)22 and the Epworth Sleepiness Scale,23
respectively. The reliability and validity of the Japanese
versions of these questionnaires have been conrmed.19,24-28
Autonomic function test
Participants underwent simultaneous electrocardiography
and photoplethysmography using a Vital Monitor 302
system (Fatigue Science Laboratory, Osaka, Japan) while
sitting quietly with their eyes closed for 3 minutes. These
data were analyzed using MemCalc software (GMS, Tokyo,
Japan). Frequency analyses for R-R interval variation from
electrocardiography and a-a interval variation as the second
derivative of photoplethysmography (accelerated plethys-
mography) were performed using the maximum entropy
method, which is capable of estimating the power spectrum
density from short time series data, and is adequate for
examining changes in heart rate variability under different
conditions of short duration.29,30 The power spectrum resolu-
tion was 600 Hz. For frequency analyses, the low-frequency
component power (LF) was calculated as the power within
a frequency range of 0.04–0.15 Hz, and the high-frequency
component power (HF) was calculated as that within a fre-
quency range of 0.15–0.4 Hz. HF is vagally mediated,31-33
whereas LF originates from a variety of sympathetic and
vagal mechanisms.30,34 Some review articles35-37 mentioned
that LF reects sympathetic nerve activity and is used as
a marker of sympathetic nerve activity in original articles.
Before autonomic nerve function testing was conducted
for 3 minutes, a practice test was conducted for a period
of 1 minute, in accordance with previous studies.38-40 The
reliability of these tests has been conrmed.41,42
Cognitive function test
Since previous studies have revealed that a switching at-
tention task is useful for evaluating reduced performance
under fatigue conditions,43-45 we used task E of the modi-
ed advanced trail making test (mATMT) as a switching
attention task for evaluating executive function.46,47 Circles
with numbers (from 1 to 13) or kana (Japanese phonograms,
12 different letters) were shown in random locations on a
screen, and participants were required to use a computer
mouse to alternately touch the numbers and kana; this
task thus required switching attention. When participants
touched a target circle, it remained in the same position,
but its color changed from black to yellow. Participants
were instructed to perform the task as quickly and correctly
as possible, and continuously performed this task for 5
minutes. We evaluated three indices of task performance:
the total count of correct responses (number of correctly
tion) twice a day for 4 weeks. Fifteen participants were
administered PLW rst, and then HRW. The remaining 16
participants were administered HRW rst, and then PLW.
Participants consumed water within 5 minutes twice a day,
at breakfast and dinner in their home, and conrmed the
water intake at breakfast and dinner in a daily journal for
4 weeks. We assessed the intake rate of water by checking
the daily journal every 4 weeks, on the 2nd and 4th experi-
mental days. No participants reported any difference in taste
between HRW and PLW. Previous studies have reported
interventional effects of administering HRW to humans at
hydrogen concentrations under 1.3 ppm.5,12 We therefore
used a similar concentration of 0.8–1.2 ppm in the present
study. Absolute volumes (600 mL) of HRW and PLW were
provided to participants rather than a volume proportional
to body mass, based on previously reported results.5-7,12
The duration of supplementation was set based on previous
ndings with HRW administration for 2–8 weeks.5,12,17 A
4-week washout period was provided between HRW and
PLW administrations based on a previous study.8 The day
before starting each experiment, participants were told to
nish dinner by 21:00, and were required to fast overnight
to avoid any inuence of diet on concentrations of mea-
sured parameters (markers of inammation and oxidative
stress) in blood samples. At 09:00 the next day, participants
completed the questionnaires after conrming that they had
refrained from drinking alcohol, had nished dinner by
21:00, and had fasted overnight. Autonomic nerve func-
tion was measured at 09:30. Cognitive function testing was
conducted at 09:45. Blood samples were collected at 10:00.
These measurements were performed a total of four times
for each participant, before (pre) and after (post) each of
the two 4-week administration periods. From 24 hours (the
day before the visit day) before each visit for measurements,
participants were told to refrain from drinking alcohol or
performing strenuous physical activity and to follow their
normal diets, drinking habits, and sleeping hours. During the
4-week PLW or HRW administration periods, daily daytime
activity (amount of physical exertion) of participants was
measured using a pedometer and participants kept a daily
journal to record drinking volume and times of PLW or
HRW intake, physical condition (e.g., pain, lassitude, and
indenite complaints), sleeping times, etc.
Severity of fatigue was measured using the Chalder Fatigue
Scale (CFS)18 and a modied version of the Osaka City
University Hospital Fatigue Scale.19 Mood and anxiety
were evaluated using the K6 scale.20 Symptoms of depres-
sion were measured using the Center for Epidemiologic
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Mizuno et al. / Med Gas Res
distributions) of each measured parameter using the Kol-
mogorov-Smirnov test. Values are presented as the mean
± standard deviation or median and interquartile range
based on the results of Kolmogorov-Smirnov test. The
Wilcoxon signed-rank test for non-parametric parameters
and paired t-test for differences between HRW and PLW
administrations after two-way repeated-measurement
analysis of variance for parametric parameters were con-
ducted. If signicant changes were observed by compari-
sons within each condition (pre- vs. post-HRW; pre- vs.
post-PLW) or between post-treatment values (post-HRW
vs. post-PLW), then we compared change ratios between
post-HRW/pre-HRW and post-PLW/pre-PLW using the
Wilcoxon signed-rank test or paired t-test. All P values
were two-tailed, and those less than 0.05 were considered
statistically signicant. Statistical analyses were performed
using IBM SPSS Statistical Package version 20.0 (IBM,
Armonk, NY, USA).
General results
During the study, we excluded ve participants from data
analyses due to symptoms of hay fever, prolonged medica-
tion use because of a cold, insufcient intake of HRW or
PLW intake (≥ 85%), or a frequency of special events ≤ 15%
as recorded in the daily diary. We thus analyzed data from
a total of 26 participants (13 females, 13 males; mean age,
34.4 ± 9.9 years; mean body mass index, 21.5 ± 2.6 kg/m
No side, order, and carry-over effects were observed from
the oral administrations of HRW and PLW in any participant.
Questionnaire results
Results from the questionnaires are summarized in Table 1.
questionnaire scores at baseline (pre) showed any signicant
differences between HRW and PLW administration groups.
With HRW administration, scores for K6, CFS, and PSQI
were signicantly decreased after the 4-week administration
period. In addition, the change ratio (post/pre) for K6 score
was signicantly lower in the HRW administration group
than in the PLW administration group (Figure 2). No sig-
nicant changes were seen in any other questionnaire scores
(modied version of the Osaka City University Hospital
Fatigue Scale, Center for Epidemiologic Studies Depression
Scale or Epworth Sleepiness Scale) after HRW administration
and no signicant changes in any of the scores were seen after
PLW administration. Likewise, these scores did not differ
signicantly between HRW and PLW after administration.
Autonomic function results
Results for the autonomic nerve function are summarized
in Table 1. LF, HF, and LF/HF ratio at baseline (pre) did
touched numbers and letters); the total count of errors
(number of incorrectly touched numbers and letters); and
the motivational response (reaction time from a nished
trial to the next trial). Based on our previous study,47 be-
fore participants performed task E of the mATMT on each
experimental day, they practiced for a period of 1 minute.
The reliability of this test has been conrmed.43,44
Blood sample analyses
Blood samples were collected from the brachial vein. The
amount of blood sampled was 13 mL per experimental day.
We thus collected blood samples on four occasions (once
per experimental day) in the study. Blood samples for serum
analyses were centrifuged at 1,470 × g for 5 minutes at 4°C.
The concentration of high-sensitivity C-reactive protein
(hs-CRP) in each serum sample was assessed by particle-
enhanced immunonephelometry using a BNII analyzer (BN
II ProSpec; Siemens, Munich, Germany). Oxidative activity
in each serum sample was assessed with the reactive oxygen
metabolites-derived compounds (d-ROMs) test (Diacron
International, Grosseto, Italy), while anti-oxidative activ-
ity was measured with the biological anti-oxidant potential
(BAP) test (Diacron International) using a JCABM1650
automated analyzer (JEOL, Tokyo, Japan).48 The concentra-
tions of ROMs are expressed in Carratelli units (1 CARR U
= 0.08 mg of hydrogen peroxide/dL).49 The oxidative stress
index (OSI) was calculated using the following formula:
OSI = C × (d-ROMs/BAP), where C denotes a coefcient
for standardization to set the mean OSI in healthy individu-
als at 1.0 (C = 8.85).45 All supernatants were stored at -80°C
until analyzed. Assays for hs-CRP were performed at LSI
Medience Corporation (Tokyo, Japan) and those for serum
d-ROMs and BAP were performed at Yamaguchi University
Graduate School of Medicine.
Daily daytime activity and daily journal
Daily daytime activity, representing the expenditure of
calories and amount of physical activity (METs × time) was
recorded using an Active style Pro HJA-350IT pedometer
(OMRON, Kyoto, Japan). A daily journal was kept for 4
weeks, and included information on fatigue (based on a
visual analogue scale from 0, representing “no fatigue”,
to 100, representing “total exhaustion”) just after waking
up and before bedtime, sleeping times, physical condition
(1, good; 2, normal; or 3, bad), and special events (if the
day was different from a usual day: 1, no; or 2, yes). We
carefully checked the daily journal every four weeks, on
the 2nd, 3rd, and 4th experimental days.
Statistical analyses
First, we tested the normality (parametric or non-parametric
Medical Gas Research ¦ December ¦ Volume 7 ¦ Issue 4 251
Mizuno et al. / Med Gas Res
not differ significantly between HRW and PLW admin-
istrations, indicating similar autonomic nerve function
in the two groups before water intake. Although the
HF and LF/HF ratio were not significantly affected by
4-week administrations of HRW or PLW, LF after HRW
administration was significantly lower than that after
PLW administration. The change ratio (post/pre) for LF
was also significantly lower in the HRW administration
group than in the PLW administration group (Figure 2).
Cognitive function results
Results for the cognitive function test are shown in
Table 1. Motivational response and total counts of cor-
rect responses and errors at baseline (pre) did not differ
signicantly between HRW and PLW administrations,
indicating similar cognitive function between groups
Table 1: Changes in parameters related to quality of life due to hydrogen-rich water (HRW) or placebo water (PLW)
Pre Post Pre Post
CFS 2.0 (04.8) 0 (03.8)* 2.5 (05.8) 0.5 (04.0)
mOCUH-FS 70.6±21.5 68.2±18.3 68.2±21.4 67.9±22.5
K6 8.5 (6.012.8) 7.0 (6.010.0)* 7.0 (6.012.3) 8.5 (6.011.0)
CES-D 6.0 (4.313.8) 9.0 (4.016.0) 8.5 (4.016.8) 9.0 (4.016.0)
PSQI 4.0 (3.36.8) 3.0 (3.04.8)* 3.5 (3.05.8) 4.0 (3.05.0)
ESS 9.3±4.9 9.6±5.6 9.7±4.9 9.0±5.1
Autonomic function
LF (ms2)519 (2681,152) 426 (290594)† 377 (270639) 504 (2421,004)
HF (ms2)239 (185559) 219 (124403) 249 (97519) 243 (170345)
LF/HF 1.9 (1.14.5) 2.0 (1.03.6) 1.8 (0.93.6) 1.9 (1.33.0)
Task E of mATMT
TCCR (number) 167.5±42.2 175.2±38.8 166.3±35.6 175.5± 8.5
TCE (number) 1.0 (0.52.2) 0.9 (0.51.6) 1.4 (0.72.3) 1.6 (0.62.2)
MR (second) 0.83 (0.670.93) 0.73 (0.620.86)* 0.75 (0.690.92) 0.78 (0.650.91)
Biochemical marker
hs-CRP (mg/L) 0.02 (0.010.04) 0.02 (0.010.04) 0.02 (0.010.04) 0.01 (0.010.03)
d-ROMs (CARR U) 301.1±47.3 297.3±48.8 300.3±53.1 303.9±51.2
BAP (µM) 2,645±231 2,598±252 2,683±232 2,660±274
OSI 1.02±0.19 1.02±0.20 1.00±0.20 1.02±0.21
Note: CFS: Chalder Fatigue Scale; mOCUH-FS: modified version of the Osaka City University Hospital Fatigue Scale; CES-D: The Center for
Epidemiologic Studies Depression Scale; PSQI: the Pittsburgh Sleep Quality Index; ESS: Epworth Sleepiness Scale; HF: high-frequency component
power; LF/HF: the ratio of low-frequency component power and HF; mATMT: modified advanced trail making test; TCCR: total counts of correct
responses; TCE: total counts of errors; MR: Motivational response; hs-CRP: high-sensitivity C-reactive protein; d-ROMs: reactive oxygen metabolites-
derived compounds; CARR U: Carratelli units ; BAP: biological anti-oxidant potential; OSI: oxidative stress index; Pre: before the 4-week administration
period; Post: after the 4-week administration period. Values are shown as the mean ± standard deviation or medians (inter-quartile ranges). *P < 0.05,
vs. Pre conditions; †P < 0.05, vs. PLW.
Figure 2: Comparison of
change ratios (post-treatment/
pre-treatment) for parameters
related to quality of life with
administration of hydrogen-rich
water (HRW) or placebo water
(PLW) for 4 weeks.
Note: Change ratios for K6 score
for mood (A) and anxiety and the
low-frequency component power
(LF) for autonomic nerve function
(B). *P < 0.05.
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Mizuno et al. / Med Gas Res
before water intake. Motivational response after HRW
administration was signicantly faster than that before
HRW administration. The change ratio (post/pre) for
motivational response was not signicantly different in
the HRW administration group than in the PLW adminis-
tration group. No signicant differences in motivational
response, total counts of correct responses, or errors
after water administration were seen between HRW- and
PLW-administered conditions.
Blood sample results
No signicant differences were seen in any blood param-
eters (hs-CRP, d-ROMs, BAP, and OSI) before HRW or
PLW administration (Table 1), indicating the comparability
of the two groups before water intake. After HRW and PLW
administrations, we again found no signicant differences
in these blood parameters.
Daily daytime activity and daily journal results
The daily expenditure of calories and amount of physical
activity during the 4-week administration periods did not
differ signicantly between HRW and PLW administration
conditions (Table 2). Similarly, visual analogue scale scores
for fatigue just after waking and before bedtime, sleeping
times, physical condition, and counts of special events
were comparable between HRW and PLW administration
conditions (Table 2), indicating that living habits were
successfully controlled during the experimental period in
the two groups.
Table 2: Daily daytime activity and data recorded in the
daily journal during the hydrogen-rich water (HRW) or
placebo water (PLW) administration period (4 weeks)
Daily daytime activity
Expenditure of calories (kcal)
2,071±306 2,082±299
Physical activity
METs ×
4.07±1.66 4.27±1.59
Daily journal
VAS-F of wake-up 38.7±20.4 35.9±17.8
VAS-F of bedtime 35.7±21.7 33.4±17.5
Physical condition
2.00 (2.002.04) 2.00 (2.002.04)
Special event
1.04 (1.001.11) 1.00 (1.001.10)
Note: METs: Metabolic equivalents; VAS-F: visual analogue scale for
fatigue. Values are shown as the mean ± standard deviation or medians
(inter-quartile ranges).
The present ndings suggest that HRW administration for 4
weeks may have improved the QOL of adult volunteers in
terms of improved mood and anxiety and reduced activity
of the sympathetic nervous system at rest.
In terms of associations between hydrogen and the central
nervous system, a report by Ohsawa et al.
was the rst to
demonstrate that molecular hydrogen acts, at least in part, as
an anti-oxidant as it binds to hydroxyl ions produced in central
nervous system injuries. Previous studies have proposed that
HRW administration has neuroprotective effects
and anti-
aging effects on periodontal oxidative damage in healthy aged
In a rat model of Alzheimer’s disease, hydrogen-rich
saline prevented neuroinammation and oxidative stress,
and improved memory function.
In terms of the association
between HRW and QOL, only one study reported that HRW
administration for 6 weeks improved QOL scores in patients
treated with radiotherapy for liver tumors.
Although reports
on the effects of HRW administration in healthy populations
have not been accumulated, job stress
and acute fatigue
caused by mental and physical loading for several hours
have been shown to enhance oxidative stress. As for physical
fatigue, in order to alleviate acute physical fatigue in healthy
volunteers not including athletes, we have previously demon-
strated that treatment with antioxidant supplements is effec-
The present study provided new ndings that HRW
affects not only physical condition but also mental conditions
such as mood, anxiety, and autonomic nerve function. One of
the advantages of HRW is the ability to cross the blood-brain
barrier, offering high potential to reduce oxidative stress in the
brain. A previous study in rats found that levels of malondi-
aldehyde, a marker of oxidative stress, were around 4.8-fold
higher in the brain than in the blood (plasma).
These results
suggest that HRW may be effective for reducing accumulated
oxidative stress in the brain in daily life, potentially contribut-
ing to the maintenance of central nervous system activity and
preventing decreases in QOL.
In the present study, mood and anxiety levels improved
after HRW administration. These negative emotions are
also known to be involved in conditions related to oxidative
stress; social phobia,58,59 depression,60 anxiety,61,62 and other
neuropsychiatric disorders63 have been shown to be associ-
ated with increased oxidative stress. Neuroinammation
is also related to fatigue, mood, anxiety, and sleep.64-67 In
older mice, HRW administration succeeded in suppressing
depression-like behaviors.68 These ndings suggest that ad-
ministration of HRW for 4 weeks may be effective for con-
trolling such negative emotions by reducing oxidative stress
and inammation of the central nervous system. Increasing
evidence suggests that oxidative stress and inammation
in neurons are involved in the pathological manifestations
of many neurological and neuropsychiatric disorders, and
HRW administration may thus help alleviate the symptoms
of these disorders. Previous study revealed that oxidative
stress of the brain causes cognitive and motivational decits
in a mouse model of neuropsychiatric disorder (schizo-
Medical Gas Research ¦ December ¦ Volume 7 ¦ Issue 4 253
Mizuno et al. / Med Gas Res
phrenia).69 In the present study, motivational response of
cognitive function test was improved by prolonged HRW
intake, suggesting that a reduction of oxidative stress in
the brain by the intake of HRW may increase motivational
performance of cognitive task.
Stressors can enhance sympathetic hyperactivity, promote
oxidative stress, and boost pro-inammatory cytokine pro-
Autonomic nerve function is thus closely associ-
ated with oxidative stress and inammation. Attenuation of
sympathetic nervous system activity during the resting state
in adult volunteers may therefore be the result of decreases
in inammation and oxidative stress as an effect of pro-
longed HRW administration. However, the lack of changes
in oxidative stress markers noted in the present study after
HRW intake for 4 weeks could be due to the low severity of
oxidative stress in the participants. Actually, serum d-ROMs
(307.1 ± 49.4 CARR U) and BAP (2,549 ± 194 µM) concen-
trations at the rst measurement point in the present study
were within normal ranges based on the results of serum d-
ROMs (286.9 ± 100.2 CARR U) and BAP (2,541 ± 122 µM)
concentrations measured in 312 healthy participants in our
previous study.
However, levels of oxidative stress uctuate
depending on daily work load and stress. In addition, the rat
study by García-Niño et al.
that found malondialdehyde
levels around 4.8-fold higher in the brain than in plasma
indicate that oxidative stress in the brain is more severe.
Daily administration of HRW for 4 weeks may thus con-
tribute to attenuation of and prevention from the cumulative
oxidative stress in the brain. Mood, anxiety, and autonomic
nerve function could thus potentially be improved. Although
the range of sympathetic nerve activity in the present study
considers to be normal based on our previous studies,
sympathetic nerve activity also uctuates depending on
daily work load and stress.
Therefore, lower sympathetic
nerve activity of resting state may contribute to suppress an
excessive increase in sympathetic nerve activity after the
daily work load and stress.
We conducted this study with a limited number of par-
ticipants. Before our results can be generalized, studies
involving larger numbers of participants are essential.
Although we mainly examined the effects of HRW on
the central nervous system, we did not directly evaluate
the dynamics of inammation and oxidation in the brain.
Neuroimaging studies using positron emission tomography
and magnetic resonance imaging are thus underway in
our laboratory to identify the mechanisms underlying the
effects of HRW intake on the central nervous system that
can improve QOL.
In conclusion, HRW administration for 4 weeks in adult
volunteers improved mood, anxiety, and autonomic nerve
function, suggesting that HRW administration may offer
an effective method to reinforce QOL and maintain good
health. In a further study, we will try to identify the effects
of HRW administration in participants with ongoing stress
or chronic fatigue.
We would like to thank Ms. Mika Furusawa for her excellent tech-
nical assistances and Forte Science Communications for editorial
help with this manuscript.
Author contributions
KM, OK, HK, and YW conceived and designed the experiments;
KM, ATS, KE, and HH performed the experiments; KM, ATS, KE,
KT, and JN analyzed the data; and KM, ATS, and YW wrote the
paper. All the authors approved the nal version of manuscript.
Conflicts of interest
This work was presented at Japanese Society of Fatigue Science,
Yamaguchi City, Japan on May 16, 2016. Yasuyoshi Watanabe
received funding for the present study from Melodian Corporation.
The other authors have no conicts of interest to declare.
Research ethics
All experiments were conducted in compliance with national leg-
islation and the Code of Ethical Principles for Medical Research
Involving Human Subjects of the World Medical Association (the
Declaration of Helsinki) and registered to the UMIN Clinical Trials
Registry (UMIN000022382). The study protocol was approved by
the Ethics Committee of Osaka City University Center for Health
Science Innovation (OCU-CHSI-IRB No. 4).
Declaration of participant consent
The authors certify that they have obtained all appropriate partici-
pant consent forms. In the form the participants have given their
consent for their images and other clinical information to be re-
ported in the journal. The participants understand that their names
and initials will not be published and due efforts will be made to
conceal their identity, but anonymity cannot be guaranteed.
Data sharing statement
Datasets analyzed during the current study are available from the
corresponding author on reasonable request.
Plagiarism check
Checked twice by iThenticate.
Peer review
Externally peer reviewed.
Open access statement
This is an open access article distributed under the terms of the
Creative Commons Attribution-NonCommercial-ShareAlike 3.0
License, which allows others to remix, tweak, and build upon the
work non-commercially, as long as the author is credited and the
new creations are licensed under identical terms.
Open peer reviewers
Lei Huang, Loma Linda University, USA; Qin Hu, Shanghai Jiao
Tong University, China.
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... Recently, hydrogen molecules (H 2 ) has gained much attention because of its biological effects (Kawamura et al., 2020) that can benefit brain function (Mizuno et al., 2017). The brain is susceptible to damage from reactive oxygen species (ROS) (Cobley et al., 2018) which often increase dramatically along with the increase of the demand for energy and metabolism, especially during high-intensity exercise (Fisher-Wellman and Bloomer, 2009;Kawamura and Muraoka, 2018). ...
... The H 2 acts as a powerful antioxidant that can cross the blood-brain barrier (Hayashida et al., 2012) and then protect neuronal cells by selectively eliminating harmful ROS (Tomofuji et al., 2014;McCarty, 2015). In a double-blinded, placebo-controlled study, 4 weeks administration of hydrogenrich water (HRW) helped reduce and prevent accumulated oxidative stress in the brain, thereby improving mood, anxiety, and autonomic function in adult volunteers (Mizuno et al., 2017). Recently, several studies have arisen to explore the potential anti-fatigue effects of H 2 (Table 1) in healthy cohorts who performed either acute or chronic exercise, and shown the promise of intaking H 2 either before or after the exercise may help alleviate fatigue (Aoki et al., 2012;Da Ponte et al., 2018;Botek et al., 2019;LeBaron et al., 2019;Mikami et al., 2019;Dobashi et al., 2020;Hori et al., 2020;Shibayama et al., 2020;Timon Andrada et al., 2020;Dong et al., 2022). ...
Full-text available
Objective: In this study, we examined the effects of pre-exercise H 2 gas inhalation on physical fatigue (PF) and prefrontal cortex (PFC) activation during and after high-intensity cycling exercise. Methods: Twenty-four young men completed four study visits. On the first two visits, the maximum workload (W max ) of cycling exercise of each participant was determined. On each of the other two visits, participants inhaled 20 min of either H 2 gas or placebo gas after a baseline test of maximal voluntary isometric contraction (MVIC) of thigh. Then participants performed cycling exercise under their maximum workload. Ratings of perceived exertion (RPE), heart rate (HR) and the PFC activation by using functional near-infrared spectroscopy (fNIRS) was measured throughout cycling exercise. The MVIC was measured again after the cycling. Results: It was observed that compared to control, after inhaling H 2 gas, participants had significantly lower RPE at each workload phase ( p < 0.032) and lower HR at 50% W max , 75% W max , and 100% W max during cycling exercise ( p < 0.037); the PFC activation was also significantly increased at 75 and 100% W max ( p < 0.011). Moreover, the H 2 -induced changes in PF were significantly associated with that in PFC activation, that is, those who had higher PFC activation had lower RPE at 75% W max ( p = 0.010) and lower HR at 100% W ma x ( p = 0.016), respectively. Conclusion: This study demonstrated that pre-exercise inhalation of H 2 gas can alleviate PF, potentially by maintaining high PFC activation during high-intensity exercise in healthy young adults.
... Hydrogen sulfide (H2S) and methane (CH4) are important gas transfer molecules in many physiological and developmental processes, including adventitious root development, postharvest preservation of horticultural products, stomatal movement, seedling growth, and seed germination [1]. In recent years, it has been discovered that hydrogen, as a novel beneficial gas signaling molecule, can respond to physiological processes [2]. Hydrogen (H2) has an unmistakable color and taste and is the simplest gas in nature. ...
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Hydrogen gas (H2) is considered as a signaling molecule and plays multiple roles in plant growth. However, the effect of H2 on postharvest physiology in lily scales during storage has not been reported. In this study, the regulatory roles of hydrogen-rich water (HRW, a H2 donor, a concentration of 0.45 mM for 100% HRW) in water status, ion balance, and nutrients in Lanzhou lily (Lilium davidii var. unicolor) scales were investigated. The scales were soaked in HRW for 12 d, and sampling was performed every 3 d for a total of 5 times. The results show that HRW (0, 10, 50, and 100%) increased the fresh weight, dry weight, relative water content, and water loss rate in lily scales, with maximum biological response at 50% HRW. Treatment with 50% HRW significantly increased the K+ content and K+/Na+ ratio in lily scales and decreased Na+ content. The Na+ K+-ATPase, and PM H+-ATPase activities were also increased by 50% HRW treatment. Meanwhile, 50% HRW up-regulated the expression of AKT1 and HA3 genes and down-regulated the expression of NHX2 and SOS1 genes. In addition, 50% HRW treatment significantly increased the expression level of PIP1;5, PIP2A, TIP1;3, and TIP2;2 genes. Treatment with 50% HRW significantly increased the content of water-soluble carbohydrate, sucrose, glucose, and fructose in lily scales, and decreased the content of starch. In addition, 50% HRW treatment significantly increased the activity of α-amylase, β-amylase, total amylase, sucrose synthase, and sucrose phosphate synthase. Collectively, H2 might enhance the water retention capacity and nutrient content in lily scales by maintaining ion balance, regulating aquaporin, and increasing sugar-metabolizing enzyme activity, thereby prolonging the storage period of postharvest scales of Lanzhou lily.
... Other studies have also shown the anti-inflammatory responses induced by H2 through inhibiting pro-inflammatory cytokines, for instance, interleukins IL-1β, IL-4, IL-5, and IL-13, among others [27,28]. In the last years, the potential antidepressant and/or anxiolytic effects of H2 have also been shown in animals with unpredictable mild stress [29] and in healthy patients [30]. All these attributes suggested that H2 might be a good candidate for treating chronic pain and the linked affective disorders. ...
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Chronic inflammatory pain is manifested in many diseases. The potential use of molecular hydrogen (H2) as a new therapy for neurological disorders has been demonstrated. Recent studies prove its analgesic properties in animals with neuropathic pain, but the possible antinociceptive, antidepressant, and/or anxiolytic actions of H2 during persistent inflammatory pain have not been investigated. Therefore, using male mice with chronic inflammatory pain incited by the subplantar injection of complete Freud’s adjuvant (CFA), we assessed the actions of hydrogen-rich water (HRW) systemically administered on: (1) the nociceptive responses and affective disorders associated and (2) the oxidative (4-hydroxy-2-nonenal; 4-HNE), inflammatory (phosphorylated-NF-kB inhibitor alpha; p-IKBα), and apoptotic (Bcl-2-like protein 4; BAX) changes provoked by CFA in the paws and amygdala. The role of the antioxidant system in the analgesia induced by HRW systemically and locally administered was also determined. Our results revealed that the intraperitoneal administration of HRW, besides reducing inflammatory pain, also inhibited the depressive- and anxiolytic-like behaviors associated and the over expression of 4-HNE, p-IKBα, and BAX in paws and amygdala. The contribution of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 and NAD(P)H: quinone oxidoreductase 1 pathway in the analgesic activities of HRW, systemically or locally administered, was also shown. These data revealed the analgesic, antidepressant, and anxiolytic actions of HRW. The protective, anti-inflammatory, and antioxidant qualities of this treatment during inflammatory pain were also demonstrated. Therefore, this study proposes the usage of HRW as a potential therapy for chronic inflammatory pain and linked comorbidities.
... 2 A study postulated that drinking hydrogenrich water is associated with reinforcement of the central nervous system function comprising mood, autonomic nervous system, and anxiety. 18 A considerable amount of work has been carried out on medical students to figure out anxiety and its risk factors. It is therefore the need of the hour to find out simple intervention strategies to cope with the stress and anxiety among this population. ...
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p> Background and Objective: A high incidence of burnout, depression, and anxiety is found among medical undergraduate and postgraduate students worldwide with the increasing prevalence of stress. The objective of this study was to analyze the correlation between water intake and the risk of anxiety among medical undergraduates of a public sector medical college in Pakistan. Method: This cross-sectional study was conducted on 375 medical undergraduates of Khawaja Muhammad Safdar Medical College, Sialkot, Pakistan. To assess the level of anxiety, the Generalized Anxiety Disorder Assessment Scale 7 (GAD-7) was used. Points 3-0 were assigned to response categories of “nearly every day,” “more than half the days,” “several days,” and “not at all,” respectively. GAD-7 score was calculated by adding together the scores for seven questions. Scores of 15, 10, and 5 were taken as cut-off points for severe, moderate, and mild anxiety, respectively. Calculation of water consumption was carried out based on the number of water glasses intake per day. It was classified into <4, 4-7, and >7 of water/day. Result: Out of 110 male medical students, 58.2% were suffering from normal to mild anxiety and 41.8% from moderate to severe anxiety. A total of 40.0% and 60.0% of female medical students were suffering from normal-mild and moderate-severe anxiety, respectively. The risk of anxiety was more among female than male students. Logistic regression indicated a correlation between decreased anxiety and female gender and water intake of 4-7 or >7 glasses/day. Conclusion: The findings of the current study showed lesser anxiety levels in male students and an inverse relationship between water intake and level of anxiety. Therefore, increasing the intake of water can be beneficial in reducing stress and anxiety thus improving the quality of life.</p
... parts per million (0.4-0.6 mM) H2, for four weeks showed that sympathetic nerve activity during the resting state was significantly reduced, suggesting that HRW may support homeostatic function in parts of the central nervous system that control temperament, anxiety levels, and autonomic nerve function. 105 In laboratory models, consumption of H2 was demonstrated to positively affect neurons in the hippocampus, effectively reducing learning impairments and memory loss through decreased expression of pro-apoptotic proteins (e.g., caspase-3). 40 However, as mild cognitive impairment is an emerging symptom of post-COVID-19 syndrome, specific studies assessing the efficacy of H2 to ameliorate COVID-19-related cerebral deterioration are warranted. ...
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Coronavirus Infectious Disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) that emerged as a novel pathogen of global concern in the latter stages of 2019. COVID-19 is a highly contagious disease which can be transmitted through aerosol droplets and surface-to-host contact. Both symptomology and the severity of disease can vary wildly between individuals, from asymptomatic but infectious, to those that require critical care. Due to the neoteric emergence of SARS-CoV-2, current treatment strategies are not yet well developed and rely on the repurposing of such medications as antiviral, corticosteroid, immunosuppressant and oxygen (O2) therapies. However, the minimal efficacy of these interventions is concerning. In addition to the acute infection that prevails, it is estimated that up to 30% of adults who contract COVID-19 develop chronic symptoms lasting longer than 12 weeks. It is also estimated that 15% of children aged 2-16 years have developed long-lasting sequelae associated with SARS-CoV-2 infection. According to recent clinical data, molecular hydrogen (H2) and oxy-hydrogen (H2/O2) therapies successfully remediated the debilitating effects of SARS-CoV-2 infection in adults. By acting as an effective anti-inflammatory and antioxidative agent, it is reported that H2 administration can improve recovery through abatement of the hyperinflammatory cytokine cascade and reduction of inhalation resistance in patients with mild-moderate disease symptoms. In this review, the authors investigate the clinical and empirical evidence relating to treating the symptoms of both acute and chronic COVID-19 with H2-containing therapeutics.
... To further improve the effect, the combined use of inhalation of hydrogen during sleep may also prove effective. H 2 has been reported as a novel potential therapeutic strategy for the prevention and treatment of chronic neurological diseases, including AD 45,46 , cognitive dysfunction 47 , mood disorders 48,49 , and PD 50 . We hope that H 2 will play a similar role for RP. ...
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Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders involving the progressive dysfunction of photoreceptors and the retinal pigment epithelium, for which there is currently no treatment. The rd6 mouse is a natural model of autosomal recessive retinal degeneration. Given the known contributions of oxidative stress caused by reactive oxygen species (ROS) and selective inhibition of potent ROS peroxynitrite and OH·by H2 gas we have previously demonstrated, we hypothesized that ingestion of H2 water may delay the progression of photoreceptor death in rd6 mice. H2 mice showed significantly higher retinal thickness as compared to controls on optical coherence tomography. Histopathological and morphometric analyses revealed higher thickness of the outer nuclear layer for H2 mice than controls, as well as higher counts of opsin red/green-positive cells. RNA sequencing (RNA-seq) analysis of differentially expressed genes in the H2 group versus control group revealed 1996 genes with significantly different expressions. Gene and pathway ontology analysis showed substantial upregulation of genes responsible for phototransduction in H2 mice. Our results show that drinking water high in H2 (1.2–1.6 ppm) had neuroprotective effects and inhibited photoreceptor death in mice, and suggest the potential of H2 for the treatment of RP.
... Data were analyzed using Memfmcc software (Fatigue Science Institute, Osaka, Japan) [34]. The VM302 can simultaneously perform electrocardiography (ECG) and photoelectric volumetric pulse waves from the fingertip and has been used in several clinical trials [38,39]. By monitoring HRV with ECG and photoplethysmography, 90 s of cardiac autonomic function data were collected at a sampling rate of 600 Hz [34]. ...
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The gut microbiota has become a significant factor associated with health and disease. Although many studies have reported the implications of changes in the gut microbiota on cardiovascular diseases, there are no reports on the relationship between heart rate variability (HRV) and the gut microbiota. Therefore, we investigated the association between gut microbiota abundance and HRV parameters in this cross-sectional study of the general Japanese population. This study included 950 participants of the Iwaki Health Promotion Project who underwent a medical examination in 2019 that included HRV and gut microbiota measurements. At the genus level, multivariate regression analysis showed that higher gut microbial diversity was associated with a higher standard deviation of RR intervals (SDNN). Moreover, a higher SDNN was associated with a higher relative count of Lachnospiraceae incertae sedis. L. incertae sedis abundance was associated with higher HRV parameters such as SDNN, coefficient of variation of RR intervals, low-frequency component power (LF)/high-frequency component power, and LF. In the general Japanese population, higher gut microbial diversity and L. incertae sedis abundance were associated with higher HRV parameters.
Methamphetamine (METH) is a potent and highly addictive psychostimulant and one of the most widely used illicit drugs, the abuse of which has become a severe public health problem worldwide. A growing amount of evidence has indicated potential connections between gut microbiota and mental disorders induced by METH and associations with neural and metabolic pathways. The present study aimed to explore the relationship between fecal microbial alterations and neuropsychiatric diseases in METH addictions. Thus, mental disorders and gut microbial alterations were analyzed by self-rating depression (SDS) and anxiety (SAS) scales and 16 S rRNA gene sequencing, respectively. Our results showed that increased SDS and SAS indices and decreased alpha diversity indicated more serious mental disorders and lower bacterial diversity in METH users than in the age-matched healthy control group. The gut microbial composition in female METH users was also significantly altered, with reductions in hydrogen-producing bacteria, including Bacteroides and Roseburia. Molecular hydrogen (H2) is spontaneously produced by intestinal bacteria in the process of anaerobic metabolism, which is the main pathway for H2 production in vivo. Numerous studies have shown that hydrogen intervention can significantly improve neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease. Our results showed that hydrogen intervention, including drinking and inhaling, significantly alleviated mental disorders induced by METH abuse, and the inhalation of hydrogen also altered gut microbiota profiles in the METH abusers. These results suggest that hydrogen intervention has potential therapeutic applicability in the treatment of mental disorders in METH abusers.
Objective: We conducted a two-way crossover trial to investigate the effects of a personal air-conditioning system on fatigue induced by mental load. Design: Sixteen healthy volunteers performed mental fatigue-inducing tasks that consisted of a 2-back task for 30 min and the A, B, and C tasks of the advanced trail making test (ATMT) for 30 min on four occasions (4-hour mental load) with or without the personal air-conditioning system with a 1-week interval. We evaluated work performance by mean reaction time, number of errors, total trial number, and reaction time from the previous task to the next task in the ATMT and subjective fatigue sensation by the visual analogue scale (VAS). Results: The mean reaction time, the number of errors, and reaction time from the previous task to the next task were significantly lower, and the total trial number was significantly higher when the personal air-conditioning system was used. On the other hand, the personal air-conditioning system did not affect fatigue sensation in VAS. Conclusion: We found that the personal air-conditioning system attenuated mental fatigue and increased the subjects’ motivation.
We conducted a group comparison study using a VDT in one of three conditions: 1)solid wood, 2)veneer, 3)wood look sheet vinyl to investigate the effects of recognition of wall material wooden interior space on physiology, psychology response and impression evaluations. The subjects who recognized the wood look sheet vinyl space had a longer mean error counts and shift time between the tasks in the ATMT and more mean of instability and uneasiness in the Subjective Fatigue Questionnaire. Analytical result suggested that VDT workers' recognition of wall material can effect on fatigue, motivation, physiology, psychology response and impression.
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It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (ΔHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low-frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with ΔHR and changes in LF/HF (ΔLF/HF), increases and decreases in ΔHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension–Security/Relaxation, whereas those in ΔLF/HF were related to the feeling axes of Sleepiness–Wakefulness and Gloomy–Refreshed. This indicated that listening to music improved the participants' feelings of fatigue and decreased their heart rates. However, it did not reduce the cardiac LF/HF, suggesting that cardiac LF/HF might show a delayed response to fatigue. Thus, we demonstrated changes in cardiac autonomic nervous functions based on feelings of fatigue.
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This study aims to investigate the protective effects and underlying mechanisms of hydrogen-rich saline on the cognitive functions of elder mice with partial hepatectomy-induced postoperative cognitive dysfunction (POCD). Ninety-six old male Kunming mice were randomly divided into 4 groups (n = 24 each): control group (group C), hydrogen-rich saline group (group H), POCD group (group P), and POCD + hydrogen-rich saline group (group PH). Cognitive function was subsequently assessed using Morris water-maze (MWM) test. TNF-α and IL-1β levels were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, along with NF-κB activity determined by ELISA. The morphology of hippocampal tissues were further observed by HE staining. Learning and memory abilities of mice were significantly impaired at day 10 and day 14 post-surgery, as partial hepatectomy significantly prolonged the escape latency, decreased time at the original platform quadrant and frequency of crossing in group P when compared to group C (p < 0.05). The surgery also increased the contents of TNF-α, IL-1β, and NF-κB activity at all time points after surgery (p < 0.05). The introduction of hydrogen-rich saline (group PH) partially rescued spatial memory and learning as it shortened escape latency and increased time and crossing frequency of original platform compared to group P (p < 0.05). Moreover, such treatment also decreased TNF-α and IL-1β levels and NF-κB activity (p < 0.05). In addition, cell necrosis in the hippocampus induced by hepatectomy was also rescued by hydrogen-rich saline. Hydrogen-rich saline can alleviate POCD via inhibiting NF-κB activity in the hippocampus and reducing inflammatory response.
We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions. We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls. Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease. Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls. BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls. Thus, measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.
The objective of our study was to develop a new fatigue scale for the assessment of patients with chronic fatigue syndrome (CFS) as well as people who feel they are chronically fatigued but do not meet the diagnostic criteria for CFS. A new fatigue scale was developed by one psychiatrist and two physicians who specialize in CFS. This scale consists of various psychosomatic symptoms, psychiatric symptoms, and diagnostic criteria for CFS. It was completed by 325 patients with CFS, 311 fatigue patients who did not fulfill the diagnostic criteria for CFS, 92 healthy workers, and 80 university students. The Chalder fatigue scale, the profile of mood states (POMS), the performance status (PS), which is included in the Japanese diagnostic criteria for CFS, and the visual analogue scale (VAS) for fatigue were also assessed with the agreement of patients who consulted our center from December 2004 to April 2006. Seventy-two university students also completed the questionnaire, including this new scale, the Chalder fatigue scale, and other lifestyle factors, and we reconfirmed the effectiveness of the new scale among fatigue patients with and without CFS and normal controls. There was a high degree of internal consistency in the results, and principal components analysis supported the notion of an 8-factor solution (42 items covering fatigue, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection). Only anxiety and depression, pain, and infection factors were able to distinguish CFS from not CFS. The sensitivity and specificity of CFS were 67.7 and 64.4, respectively, using a cut-off score of 25 points for this subscore. We concluded that the new fatigue scale used in this study was useful for differentiating CFS patients from not CFS patients and fatigued people from a healthy sample.
If a method for the qualitative and quantitative evaluation of fatigue can be developed, it will be useful not only as a means of self-monitoring by individuals and improving occupational health, but also for facilitating the development and commercialization of antifatigue medications and food supplements. Although it is difficult to determine with precision the economic loss caused by fatigue, there is no question that the successful suppression of chronic fatigue (which is one factor responsible for the onset or exacerbation of lifestyle-related chronic diseases) will greatly contribute to decreasing medical expenditure. It is known that major signs of fatigue, which appear in the form of compromised physical and mental function, are closely related to the function of the frontal lobes (which may be the center for fatigue recognition) and of the autonomic nervous system. For this reason, the quantification of fatigue requires the development of biomarkers capable of objectively and sensitively evaluating changes in frontal lobe function (working memory, etc.) and autonomic nervous system function (pulse waves, etc.). Qualitative and quantitative evaluations of fatigue will be possible by meta-analyses of changes in biochemical, immunological, and physiological markers in blood, saliva, and urine, as well as changes in brain function imaging in the presence of mental or physical stress.
Symptoms of autonomic dysfunction are one of the characteristic features of the clinical condition known as chronic fatigue syndrome (CFS). In this study we examined the autonomic nerve functions in 1,099 patients with CFS and in 361 normal healthy controls. The autonomic nerve functions were studied in terms of heart rate variability and spectral analysis, and by using the maximal Lyapunov exponent (MLE) and chaotic analysis. The heart rate variability analysis revealed that both the logarithmic low-frequency power (Log LF) and logarithmic high-frequency power (Log HF) were reduced significantly with age in healthy subjects (p < 0.005). When we compared these parameters between the CFS patients and healthy controls according to age groups, there was no significant difference in Log LF between CFS and control except in the case of the 40's age group. However, Log HF decreased significantly in moderate and severe fatigue CFS groups in all age groups. All of the severe fatigue CFS age groups had a significant increase in the ratio of Log LF/HF as compared with that of the healthy controls. When we studied the change in these power values during sleep as compared with that during awake time, the HF power rose 3.03-fold in the controls and 1.86-fold in the CFS group during sleep as compared with that during the awake time; and this difference in fold increase during sleep between the CFS and control groups was significant (p < 0.05). Furthermore, the MLE for both the moderate and severe fatigue CFS groups was decreased significantly as compared with that of the healthy control group (p < 0.01). It is well known that autonomic nervous function differs greatly in individuals, but our present large research study indicates that there is no doubt that parasympathetic nervous dysfunction is involved in the pathophysiology of CFS patients with severe fatigue. We incorporated the evaluation of autonomic function into the Japanese CFS diagnostic criteria in 2012, because this evaluation might be a useful objective diagnostic tool for CFS.
Spectral analysis of spontaneous heart rate fluctuations were assessed by use of autonomic blocking agents and changes in posture. Low-frequency fluctuations (below 0.12 Hz) in the supine position are mediated entirely by the parasympathetic nervous system. On standing, the low-frequency fluctuations increase and are jointly mediated by the sympathetic and parasympathetic nervous systems. High-frequency fluctuations, at the respiratory frequency, are decreased by standing and are mediated solely by the parasympathetic system. Heart rate spectral analysis is a powerful noninvasive tool for quantifying autonomic nervous system activity.