Keywords
circadian rhythm - sleep - rectal temperature - patch-type sensor
Introduction
The circadian rhythm of the core body temperature (CBT) is closely associated with
diurnal changes in physiological and cognitive functions. This CBT rhythm is regulated
by a central circadian pacemaker located in the suprachiasmatic nucleus (SCN).[1] Assessing the circadian phase of the core body temperature (CBT) is important for
adjusting an individual's circadian rhythm by exposure to a timed bright light, so-called
bright-light therapy. The human circadian system comprises two distinct circadian
oscillators that separately regulate the circadian rhythm of rectal temperature and
the sleep-wake cycle.[2]
[3] Thus, the phase difference between the circadian phase of the CBT, as well as the
sleep-wake cycle of these two oscillators, provides valuable information. Patients
with circadian rhythm sleep disorders, such as non-24-hour sleep-wake disorder and
delayed sleep-wake disorder, have altered phase relationships between the circadian
rhythms of their CBT and the sleep-wake cycle.[4] Moreover, misalignment between the circadian rhythm and sleep-wake cycle increases
the incidence of various diseases.[5] Thus, assessing the circadian phase of CBT could allow us to evaluate the internal
phase relationship between the circadian pacemaker in the SCN and the sleep-wake cycle.
Rectal temperature is commonly used as a marker to assess the circadian phase of CBT
in the research and clinical fields of sleep and chronobiology.[3]
[6]
[7] The rectal temperature is often measured once per minute by using a flexible wired
rectal probe. Recently, some noninvasive temperature sensors, such as ingestible capsule
sensors[8] and ear canal sensors[9] have been used for monitoring CBT. In addition, a patch-type wearable temperature
sensor has been developed and used for monitoring the CBT during sleep periods,[10] exercise conditions,[11] and when in a hot environment.[12]
[13]
[14] Regarding the accuracy of the wearable temperature sensor, some studies reported
relatively low accuracy for CBT values.[11]
[12]
[13]
[14] In human sleep and circadian rhythm research, patch-type wearable temperature sensors
would have been expected to easily assess the circadian phase of the CBT and provide
a surrogate for a rectal probe. However, there is still a lack of research focused
on assessing the circadian phase of the CBT using the patch-type wearable temperature
sensor in participants in the real world. In the present study, we performed comparative
measurements of CBT using the patch-type wearable temperature sensor and a rectal
probe from healthy adults in the real world. Here, we demonstrated that a wearable
temperature sensor could be a useful tool for reasonably estimating the circadian
phase of the rhythm sleep disorders, such as CBTtrough and provide a surrogate for a rectal probe.
Materials and Methods
Participants
A total of 16 (8 males and 8 females) participants aged 19–45 years participated in
the present study as paid volunteers. None of the participants worked early in the
morning, late at night, or on rotating night shifts. None of the participants had
any history of psychiatric, endocrine, or sleep disorders. All participants provided
written informed consent before participating in the study and were able to withdraw
from the experiment at any time. This study was approved by the Ethics Committee of
the Hokkaido University Graduate School of Education (#19–10) and conducted by the
Declaration of Helsinki.
Experimental Protocols
To estimate sleep and wakefulness, all participants were asked to use an actigraph
worn on the wrist. The participants were also asked to complete a sleep diary. In
addition, the participants were instructed to wear the CALERA Research sensor outside
of bathing to measure CBT. Moreover, rectal temperature was measured intermittently
from 3–4 hours before bedtime to 1–3 hours after waking up each day. The participants
were prohibited from exercising and taking showers and/or baths during rectal temperature
measurements. All data were measured for the participants under free-living activities
for 3–5 days. [Fig. 1A] illustrates location of the sensors on a participant's body and the example of experimental
protocol ([Fig. 1B]).
Fig. 1 Location of the sensors on a participant's body and example of experimental schedule.
The left figure (A) indicates the location of the sensors on a participant's body.
An actigraphy device (ActTrust2) was worn on the non-dominant wrist. The wearable
temperature sensor (CALERA Research sensor) was attached to the torso at ∼20 cm below
the armpit, and the rectal probe was inserted into the rectum from the anal sphincter.
Right figure (B) shows an example of an experimental schedule for 3 days. Each arrow
shows the recording periods of each sensor.
Measurements
Sleep-wake Cycle
Wrist activity was recorded every minute using an actigraph worn on the nondominant
wrist (ActTrust2; Condor Instruments, São Paulo, Brazil). We used the activity count
measured by the wrist actigraph to estimate the participants' sleep and waking states.
The activity count was automatically scored using the built-in Cole–Kripke algorithm[15] in Act Studio software ver. 1.0.24 (Condor Instruments).
Patch-type Wearable Temperature Sensor
A patch-type, wearable, and commercially available temperature sensor, CALERA Research
sensor (greenTEG), was used in the present study to estimate the circadian phase of
the CBT. The CALERA Research sensor assesses skin temperature and heat flux and employs
machine learning technology with an AI algorithm to estimate the CBT. The CBT data
estimated using the CALERA Research sensor were automatically transmitted and stored
on a web server (CORE cloud). Original body temperature data (1-minute bins) were
downloaded to a computer as .csv files and were used to analyze the circadian phases
of the CBT. The participants were instructed to wear a CALERA Research sensor attached
to the torso at ∼20 cm below the armpit by the manufacturer's recommendations. The
CALERA Research sensor was worn on the skin using a medical-grade adhesive patch (A-165210,
green TEG).
Rectal Temperature Probe
A rectal probe (401J; Yellow Springs Instrument Co., Inc. USA) was used for measurements.
Rectal temperature data (1-minute bins) were measured and stored using a data logger
(NT-logger N543R; Nikkiso Thermo). The participants were instructed to insert the
rectal probe 15 cm beyond the anal sphincter by themselves.
Data Analysis
The trough phase of the CBT was defined as the midpoint of nocturnal decrease in CBT
(CBTtrough) and used as the circadian phase markers, as already established.[16]
[17] The CBTtrough was determined by a geometric method as previously published[16]
[17] with slight modification, as below. Briefly, the original temperature data for every
1-minute bin were averaged at 10-minute intervals and smoothed using a three-point
moving average method. The CBTtrough was then defined as the middle of two points where a line on the middle level between
the temperature at the point more than 0.2°C higher from the minimum values of body
temperature crossed the descending and ascending parts of the temperature rhythm ([Fig. 2]). In the above analysis, two of the 16 participants were excluded because of missing
temperature data (e.g., the rectal probe slipped out and/or a nocturnal drop in body
temperature was not observed). Therefore, temperature data from 14 participants were
used in the analysis. We successfully collected 34,537 data points (1-minute bins)
and 60 circadian phases of the CBTtrough measured using the CALERA Research sensor and rectal probe. To evaluate actual temperature
values between the two devices, body temperatures during the nocturnal sleep period
were averaged and compared between the CALERA Research sensor and rectal probe.
Fig. 2 Geographic method to determine the circadian phase of CBT. The left panels indicate
representative recordings of CBT measured by the CALERA Research sensor (grayed line)
and rectal probe (solid line) before, during, and after the nocturnal sleep period
in the participant (male, 22 years). The geographic method used to determine the CBTtrough phase (dashed lines and arrows) is illustrated. The gray areas show the actigraphy-based
sleep periods. CBT: core body temperature.
Statistical Analysis
The reliability of the CBTtrough measured by the CALERA Research sensor was analyzed by the intraclass correlation
coefficient (ICC) of the CBTtrough in a rectal probe. The ICC is a value between 0 and 1, where a value less than 0.5,
between 0.5 and 0.75, between 0.75 and 0.9, and greater than 0.90 indicate poor, moderate,
good, and excellent reliability.[18] Lin's concordance correlation coefficient (CCC)[19] was used to evaluate the agreement and reliability between the CBTtrough measured by the CALERA Research sensor and rectal probe. A CCC value less than 0.90,
between 0.90 and 0.95, between 0.95 and 0.99, and greater than 0.99 indicates poor,
moderate, substantial, and almost perfect agreement, respectively.[20] Furthermore, the Bland-Altman plot[21] was used to compare the CBTtrough between the CALERA Research sensor and rectal probe and calculate the mean difference
and 95% limits of agreement (95% LoA). Statistical analyses were performed using StatView
software (version 5.0, SAS Institute, Cary, NC, USA) and R software (version 4.4.0,
The R Foundation for Statistical Computing, Vienna, Austria).
Results
The participants' characteristics and the number of circadian phases used in the present
analysis are shown in [Table 1]. [Fig. 3] shows representative recordings of wrist activity and body temperature measured
by the CALERA Research sensor and rectal probe. The ICC value of 0.96 (95%CI: 0.93
to 0.98) value indicated excellent agreement,[18] whereas the CCC value of 0.96 (95%CI: 0.93 to 0.97) values indicated substantial
agreement[20] between the two devices. The Bland-Altman analysis found the mean bias of CBTtrough between the two devices was 0.16 hour (95%LoA: -0.76 hour to 1.07 hour) ([Fig. 4]). The mean of the CBTtrough was 5.9 ± 1.6 hour in CALERA Research sensor and 5.8 ± 1.7 hour in rectal probe,
respectively. During the nocturnal sleep period, the mean body temperature measured
by the CALERA Research sensor was 36.69 ± 0.16°C, while the rectal probe measured
36.59 ± 0.25°C, indicating that the CALERA Research sensor overestimated the body
temperature by ∼0.10°C (95% CI: 0.06 to 0.14°C) as compared with a rectal probe. The
differences in the mean temperature values between the two devices were not consistent
in the 60 records. The mean temperature values in the CALERA Research sensor were
higher than those in the rectal probe (46 of 60 records, 77%). In contrast, the other
14 records (23%) showed lower temperature values in the CALERA Research sensor as
compared with the rectal probe. In addition, the difference in the temperature value
between the two devices showed inter- and intra-individual differences. Six of 14
participants (43%) showed higher temperature values in the CALERA Research sensor
as compared with the rectal probe, and the other 8 participants (57%) showed higher
or lower temperature values in the CALERA Research as compared with the rectal probe.
Fig. 3 Representative recording of CBT measured by the CALERA Research sensor and rectal
probe with simultaneous recording of wrist activity in the real world for 3 days.
The top panel indicates a representative recording of CBT measured with the CALERA
Research sensor (grayed line) and rectal probe (solid line). The lower panel indicates
wrist activity measured using wrist actigraphy. The gray areas show the actigraphy-based
sleep periods.
Fig. 4 Bland—Altman plot comparison for the CBTtrough phase determined by the CALERA Research sensor and rectal probe. The solid line indicates
the mean difference between the CBTtrough phase determined by the CALERA Research sensor and rectal probe. The dotted lines
indicate 95% confidence intervals.
Table 1
Participants' demographic characteristics, recording period, and number of CBT phases
|
Participants
|
Age (yrs.)
|
Sex
|
BMI (kg/m2)
|
Recording period (dd/mm/yy)
|
Number of CBT phases
|
Sleep onset (h, local time)
|
Sleep offset (h, local time)
|
|
1
|
42
|
M
|
24.0
|
11/8/22
|
−
|
28/8/22
|
5
|
0.1 ± 2.7
|
6.9 ± 0.5
|
|
2
|
45
|
F
|
19.3
|
28/10/22
|
−
|
13/11/22
|
4
|
2.8 ± 0.4
|
8.5 ± 0.9
|
|
3
|
43
|
F
|
24.0
|
7/12/22
|
−
|
14/12/22
|
5
|
2.0 ± 1.0
|
7.5 ± 0.7
|
|
4
|
19
|
F
|
19.7
|
13/12/22
|
−
|
20/12/22
|
4
|
2.0 ± 0.6
|
7.8 ± 0.4
|
|
5
|
22
|
M
|
19.7
|
12/12/22
|
−
|
17/12/22
|
4
|
1.2 ± 0.2
|
8.6 ± 0.4
|
|
6
|
48
|
M
|
19.4
|
3/1/23
|
−
|
8/1/23
|
5
|
23.7 ± 0.3
|
6.5 ± 0.8
|
|
7
|
22
|
M
|
18.3
|
6/1/23
|
−
|
10/1/23
|
3
|
2.4 ± 1.4
|
9.2 ± 2.4
|
|
8
|
22
|
F
|
17.2
|
9/1/23
|
−
|
16/1/23
|
3
|
2.4 ± 1.2
|
11.4 ± 0.4
|
|
9
|
21
|
F
|
19.1
|
27/12/22
|
−
|
2/1/23
|
5
|
0.4 ± 1.1
|
8.1 ± 0.5
|
|
10
|
19
|
F
|
22.7
|
28/12/22
|
−
|
2/1/23
|
N/A
|
|
|
|
11
|
21
|
F
|
24.5
|
10/1/23
|
−
|
15/1/23
|
5
|
2.9 ± 1.1
|
9.4 ± 1.2
|
|
12
|
25
|
F
|
23.1
|
10/1/23
|
−
|
21/1/23
|
N/A
|
|
|
|
13
|
23
|
M
|
21.1
|
8/7/23
|
−
|
3/9/23
|
4
|
1.0 ± 1.0
|
8.3 ± 1.7
|
|
14
|
21
|
M
|
17.7
|
28/6/23
|
−
|
29/7/23
|
4
|
2.3 ± 1.0
|
9.1 ± 0.8
|
|
15
|
21
|
M
|
20.6
|
9/7/23
|
−
|
5/9/23
|
4
|
0.6 ± 0.2
|
8.7 ± 1.0
|
|
16
|
20
|
M
|
22.4
|
9/7/23
|
−
|
13/7/23
|
5
|
2.2 ± 0.3
|
9.9 ± 0.9
|
|
Mean
|
27.1
|
|
20.8
|
|
|
1.0
|
8.5
|
|
SD
|
10.5
|
|
2.4
|
|
|
1.4
|
1.4
|
Abbreviations: BMI, body mass index; CBT, core body temperature; N/A, not applicable.
Data from 2 (#10 and #12) of 16 participants who did not assess the phases of core
body temperature were excluded from the analysis.
Discussion
The present study aimed to evaluate whether a patch-type wearable temperature sensor
could be used to assess the circadian phase of CBT, like the use of a wired rectal
probe from healthy adult participants in the real world. Although the absolute temperature
value during the sleep period was different between the two devices, body temperature
at the same time points was similar enough to use for circadian determination. Thus,
the geometric method could be applied to determine the circadian phase of the CBT
measured by both devices. The ICC and CCC values indicated the agreement of the CBTtrough estimated by the CALERA Research sensor and rectal probe was excellent and substantial
agreement, respectively. The result of the Bland-Altman analysis demonstrated that
the 95% LoA of the mean difference ranged between the CBTtrough of CALERA Research sensor and rectal probe was -0.76 hour to 1.07 hour, indicating
that there was about ± 1 hour difference in the CBTtrough between the CALERA Research sensor and rectal probe. The mean temperature values
during the sleep period were higher in the CALERA Research sensor by 0.1°C on average
as compared with the rectal probe.
In humans, the candidates for physiological functions (melatonin, cortisol, and CBT)
reflect the phase of the central circadian pacemaker in the SCN.[22] Assessing the circadian phase of SCN pacemakers in circadian rhythm and sleep research
in clinical settings usually relies on circadian rhythms of melatonin and/or CBT.
The most reliable marker of the circadian pacemaker in humans is melatonin levels
in blood (plasma or serum) or saliva. Although the circadian rhythm of melatonin is
the most reliable circadian phase marker for assessing the circadian rhythms in humans,
sample collection (every 30–60 minutes) from subjects under dim light conditions is
required.[23]
[24] In contrast to measuring the circadian rhythm of melatonin, measuring CBT remains
useful for assessing the phase of circadian rhythms in humans.[22] However, the measurement of the CBT by using a wired rectal probe is sometimes difficult
for some subjects such as children and unconscious patients under the real world or
clinical settings. In contrast to a wired rectal probe, a wireless wearable temperature
sensor patched on the skin surface could allow us to assess the CBTtrough regardless of the participant's age and disease. Under clinical and practical conditions,
bright-light therapy is an effective treatment for seasonal affective disorders and
circadian rhythm-related sleep disorders. Appropriate timings for bright-light exposure
are commonly determined using the circadian phase of the CBT and the phase response
curve to a single bright-light.[25]
[26] The reported phase response curve to a single bright-light has an advanced (delay)
portion of 6 hours after (before) showing the CBTtrough. In the present analysis, the CBTtrough estimated by the CALERA Research sensor was about ± 1 hour different from the CBTtrough measured by the rectal probe. Therefore, the CALERA Research sensor would be useful
to provide the circadian phase marker to determine the optimum time of day of light
exposure when conducting not only bright-light therapy but also exogenous melatonin
ingestion.
Of note, it has been demonstrated that circadian rhythms in CBT are attenuated or
occasionally disappear in subjects showing internal desynchronization between the
circadian pacemaker in the SCN and the sleep-wake cycle in the real world.[27] Therefore, it has been recommended that the circadian rhythm of plasma melatonin
or cortisol levels, rather than the CBT, is used to assess the circadian phase more
precisely in participants undergoing internal desynchronization.[22]
[27]
The present study had some methodological limitations. First, it should be noted that
the temperature value measured by the CALERA Research sensor still requires validation,
and the accuracy and reliability need to be improved.[11]
[12]
[13]
[14] Second, the means of CBT values during the sleep period was higher in the CALERA
Research sensor by 0.10°C as compared with the CBT in the rectal probe. This discrepancy
in the CBT values between the rectal temperature and the CALERA Research sensor was
not consistent and showed inter- and intra-individual differences. It is necessary
to examine various environmental and physiological factors to influence the temperature
value in the CALERA Research sensor. Lastly, the data was obtained from a relatively
small number of participants. Further studies should confirm our results in a larger
group of healthy participants and patients such as those with the circadian rhythm
sleep or seasonal affective disorders.
Conclusion
This study demonstrates that a patch-type, heat-flux-based wearable temperature sensor
could be an alternative method for assessing the circadian phase of CBT in healthy
adult participants in the real world.
