Translational Research of Sleep Medicine
睡眠醫學之轉譯研究
Terry B.J. Kuo, MD, PhD (郭博昭)
Professor and Director
Institute of Brain Science
National Yang-Ming University
Cheryl C.H. Yang, PhD (楊靜修)
Professor and Director
Sleep Research Center
National Yang-Ming University
Hypertension
Essential Hypertension > 90%
Secondary Hypertension < 10%
Renal hypertension
Endocrine hypertension
Others
Possible Mechanisms of “Essential Hypertension”
Heredity
Environment
Heart and Vessels
ventricular hypertrophy, atherosclerosis...
Nerve
Impairment of autonomic nervous system...
BP = CO * TPR
Autonomic Nervous System
Measurement of autonomic function is difficult
in free moving subjects.
Non-invasive Technique
Heart Rate Variability
HF:
Parasympathetic (Vagal) activity
Akselrod et al (1981) Science
LF/HF, LF%:
Cardiac sympathetic modulation
Sympathovagal balance
Arterial Pressure Variability
Sympathetic blockade
Kuo et al (1997) Am J Physiol
LF (BLF):
Vascular sympathetic modulation
Heart Rate Variability in Humans
Sympathetic
Sympathetic
Lucini et al (2002) Circulation
Arterial Pressure Variability in Rats
WKY SHR
WKY SHR
Stauss et al (1995) J Auton Nerv Syst
WKY SHR
Most of the previous controversial results were
obtained without a detailed classification of the
sleep-wake states
Hypothesis
The changes in autonomic functions
accompanied with hypertension are
consciousness state dependent.
Aims
To determine whether the cardiovascular
autonomic functions have specific pathological
changes in spontaneously hypertensive rats
during sleep time
Polysomnographic Analysis in Rats:
Electroencephalogram(EEG), Electromyogram (EMG),
and Electrocardiogram (ECG)
Shaw et al (2002) J Neuroscei Meth
K&Y Lab’s Polysomnography
Data Acquisition and Analysis
Software
Free moving rat
Electrophysiologic
Amplifiers
Digital Video Recorder
Shaw et al (2002) J Neurosci Meth
K&Y Lab’s Polysomnography (II)
Kuo and Yang (2004) Taiwan Patent
K&Y Lab’s Wireless BP Recorder
K&Y Lab’s Sleep Scoring System
• Step 1:
Power spectral analysis of EEG, EMG, and HRV
• Step 2:
Classification of Sleep Stage
• Step 3:
Determination of Sleep Structure
Kuo et al (2004) Sleep
Power Spectral Analysis
Power = 3
MPF = 7
Power = 7
MPF = 4
MPF: Mean Power Frequency
Power: Amplitude or Magnitude
Classification of Sleep Stage
EMG Power
AW
AW: active waking
QS: quiet sleep
PS: paradoxical sleep
EEG Frequency
QS
PS
Kuo et al (2004) Sleep
Determination of Sleep Structure
EMG Power
AW
EEG MPF
QS
PS
Mature AW, QS, and PS:
persist unchanged for  56 s
Transient Interruptions:
fail to last for 56 s
Kuo et al (2004) Sleep
AW
QS
PS
QS
PS
QS
SWA
P
S
a normal rat
Yang et al (2003) Neurosci Lett
In Normal Rats
During QS..
P
P
S
S
Yang et al (2003) Neurosci Lett
SWA
QS
QS
QS
QS
QS
SWA
P
S
a normal human
Yang et al (2002) Neurosci Lett
In Normal Humans
During QS..
P
P
S
S
Yang et al (2002) Neurosci Lett
SWA
Sleep and autonomic functions
Vagal
Function
AW
QS
PS
Sleep Depth
AW
QS REM
Sleep Depth
Sympathetic
Function
interaction between cerebral cortical and autonomic functions
Normotensive Rats (WKY) and
Spontaneously Hypertensive Rats (SHR)
WKY
Vascular
Sympathetic
Cardiac
Vagal
Cardiac
Sympathetic
Kuo and Yang (2005) Circulation
SHR
Vascular
Sympathetic
Cardiac
Vagal
Cardiac
Sympathetic
Kuo and Yang (2005) Circulation
Kuo and Yang (2005) Circulation
Cardiac
Vagal
Cardiac
Sympathetic
Vascular
Sympathetic
Baroreflex
Sensitivities
Kuo and Yang (2005) Circulation
Editorial (Circulation 2005:112:786-788)
Differences in Sleep Patterns
between WKY and SHR
Kuo et al (2004) Sleep
Summary
1 During quiet sleep (slow wave sleep), the sympathetic function
should rest in normal condition: the deeper sleep, the lower
sympathetic modulation.
2 During quiet sleep, the vagal function should activate. But the
increase magnitude is not related with the sleep depth.
3 The baroreflex function should activate during quiet sleep.
Summary
4 The changes of autonomic functions during quiet sleep are
reversed during paradoxical sleep (rapid eye movement sleep).
5 The cardiovascular sympathetic function does not rest during quiet
sleep in SHR.
6 The baroreflex function does not activate during quiet sleep in
SHR.
7 The changes in autonomic functions in SHR may be related to the
changes in sleep quantity and quality.
失眠會造成哪些後遺症
精神疾病
心臟血管疾病
意外傷害
行為障礙
影響工作表現
消耗醫療資源
Limitations
Human study
For the fixed polysomnography
The size is too large, users must sleep in an
unfamiliar environment. This may affect the accuracy
of the collected data.
For the ambulatory polysomnography
The device is still large, and too expensive.
Animal study
The wires may cause some interference, including
electrical noise and psychological stress
Research Motivation
To develop the best equipment for the best
sleep research
For the human study
accurate, miniature, wireless, low cost
For the animal study
accurate, miniature, wireless, low cost
The Introduction of Low-power,
Digital Radio Frequency Technique
Try to use the
new technique
Button-type
wireless recording system
K&Y’s Wireless Electrocardiography
Receiver
Sensor
Receiver
Electrocardiogram
Sensor
K&Y’s Wireless
Electrocardiography
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•
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Radio Frequency: 2.4 GHz
Data transmition mode: digital, bi-directional, acknowledged
Sampling resolution: 8-12 bits, 125-1000 samples/s
Power: 1.9 V, 1 mA (on), <10 uA (off)
One tiny button-type battery (CR1620: 3 V, 70 mAH) can operate
continuously over 2 days.
Target to the smallest digital, wireless ECG sensor
Implemented with a specially designed RF protocol, more efficient to
Bluetooth, Zigbee protocols
Applied with other sensor techniques, including body temperature, EEG,
EOG, EMG
A prototype of disposable tiny wireless medical instrument
Patent pending
K&Y’s Wireless Polysomnography
K&Y’s Wireless Polysomnography
• Continuous recording of
multiple physiological signals
over 24 hours
• Completely wireless
• ECG, EMG, EOG, EEG
• 3-D acceleration,
Body temperature,
• Telemetric signal transmission
• Easy to use
• Sleep recorder, Holter monitor,
Actimeter, Body temperature
recorder
K&Y’s Wireless Polysomnography for
Rats
AW
QS
PS
K&Y’s Wireless Polysomnography
for Rats
2.3 cm
Connector
Signal relayed by Wires
0.6 cm
Battery
Microcontroller
& RF tranciver
Amplifiers &
Accelerometer
• Continuous recording of multiple
physiological signals over 24 hours
• Partially wireless
• ECG, EMG, EEG
• 3-D acceleration,
Body temperature,
• Telemetric signal transmission
• Easy to use
• Sleep recorder, ECG recorder,
Actimeter, Body temperature
recorder
K&Y’s Wireless Polysomnography
for Mice
Classical Sleep Instrument
Traditional Data Logger for
Electrocardiogram
Big size
External AC power
Expensive
Noisy
Silicon Laboratories C8051F410
System-on-a-chip MCU
MCU
(US$ 8)
256 MB Flash
(US$ 12)
Powered by 2.0 V
Low Power, Miniature Data Logger
Firmware
Power consumption
as low as possible
Analog-digital conversion
as accurate as possible
Flash memory storage
as large as possible
PC compatible
Ambulatory ECG Recorder
Power Consumption: 2.0 V, 3 mA
Recording Time: > 24 hours
Voltage Resolution: 8-12 bit
Time Resolution: 2500 sample/second
Maximal Recording Channel: 8
Type of Signals:
ECG, EMG, EOG, EEG
Temperature, 3-D acceleration
Data Storage:
256 MB Flash memory, FAT format
AW
NREM-Sleep
REM-Sleep
Eye movement correlates to
neural control of heart rate
AW
QS
REM
Miniature Ethernet Server
Firmware programmed by
Guo-She Lee,MD, PhD
(李國熙 醫師)
TCP, UDT...
C8051F340
System-on-a-chip MCU
(US$ 10)
CP2201
Ethernet Controller
(US$ 6)
KY-2 Web Server
• Tiny web server for monitoring
biomedical signals
• TCP, UDP, HTTP, FTP, e-mail
• Clinical application, Nursing home,
home care
Digital Diagnosis Technique
(DDT)
Electrode
Heart
sound
AI
Computer
Mic
DSP
Computer
Web
Server
ECG
Breathing
sound
Terminal
Computer
User
Voice
DSP
Computer
Camera
DSP
Computer
Digital Signal Processing (DSP)
Artificial Intelligence (AI)
Network
Others
Image
Others
Prospective
• Using the new research
instrument to explore the new
sleep-related issues
• The are still a lot of questions
which warrant further
explorations
• To answer why I can sleep and
why I can not sleep
致謝
賴其萬 教授
蕭光明 教授
慈濟大學
行政院國家科學
委員會
教育部
KY-1 Ambulatory Sleep Recorder
• Continuous recording of multiple
physiological signals over 24 hours
• ECG, EMG, EOG, EEG
• Temperature, 3-D acceleration
• Flash memory  256 MB, FAT format
• Telemetric signal transmission
• Remote control
• Easy to use
• Sleep recorder, Holter monitor, Actimeter,
Body temperature recorder