University of Oulu
Teemu Myllylä
Optoelectronics and Measurement Techniques Unit, University of Oulu
Finland
6/21/20171
Towards continuous monitoring of the glymphaticsystem of the human brain
University of Oulu
Outline ‒ Glymphatic system
- Blood brain barrier (BBB) and brain clearance
‒ Multimodal human brain monitoring in Oulu
- BBB disruption monitoring
- Multimodal human imaging in Magnetic Resonance Imaging (MRI)
‒ Towards wearable monitoring
- A combined opto-capacitive-microwave imaging device
- Sensing method
- Validation experiments
6/21/20172
Towards continuous monitoring of the glymphaticsystem of the human brain
University of Oulu
(G)lymphatic system
‒ Lymphatic vessels are present throughout the body
‒ Density of lymph vessels correlates with the rate of tissue
metabolism
‒ Lymphatic flow is responsible for flushing out harmful
fluids from the body system, such as
- toxins
- metabolic waste products
- soluble proteins
6/21/20173
Source: https://www.extremetech.com/
University of Oulu
Glymphatic system
‒ The Glymphatic system is the counterpart of the
lymphatic system elsewhere in the body.
‒ As a whole, it is responsible for flushing out toxins,
metabolic waste products, soluble proteins and
other harmful fluids from the body system into the
CSF drainage
Raper, Daniel, Antoine Louveau, and Jonathan Kipnis. "How Do Meningeal
Lymphatic Vessels Drain the CNS?." Trends in Neurosciences 39.9 (2016): 581-
586.
6/21/20174 Source: http://www.samanthamonarch.com/
University of Oulu
Glymphatic system
‒ CSF flows from perivascular space via
astroglial cell aquaporin channels (AQP4),
through brain tissue.
6/21/20175
Source: http://biofoundations.org/
University of Oulu
Focused ultra sound (FUS) Alzheimer diseace therapy, 2014
BBB and Brain clearance
University of Oulu
Sham SUS
No.
of p
laqu
es/s
ectio
n
Sham SUS
Pla
que
burd
en
(% s
urfa
ce a
rea)
E
B
D
Sha
mS
US
Striatal section Hippocampal section
Sham SUS
C
Pla
que
burd
en
(% s
urfa
ce a
rea)
F
G
55 60 65 75
2.0
1.5
1.0
0.5
0.0
7050
SUS
Sham
Baseline
Age (weeks)
A
DC
3–mer/CTFb
9–mer*56
HMW
GAPDH
Sham SUS Sham SUS
A B
250
75
50
25
15
10
250
75
50
25
15
10
E
Rat
io o
f Ab/
GA
PD
H
HMW *56 3–mer/CTFb HMW *56 3–mer/CTFb Sham SUS
pg A
b42/
mg
tota
l pro
tein
MWM
*56
3–mer/CTFb
HMW
9–mer
GAPDH
1–mer
MWM
Sham
SUS
Rat
io o
f Ab/
GA
PD
H
Fig. 2. SUSreduces Ab plaques in an AD mouse
model. (A and B) Representative images of free-
floating coronal sections from APP23 transgenic
mice (first cohort) with and without SUStreatment.
Campbell-Switzer silver staining revealed compact,mature plaques (amber) and more diffuse Ab de-
posits (black). A stained section at a higher magnifi-
cation isshown in panel (B).(Cand D)Quantification
of amyloid plaquesrevealed a56%reduction in the
area of cortex occupied by plaques (unpaired t test,
P= 0.017) and a 52% reduction in plaque number
per section (t test, P= 0.014) in SUS-treated com-pared to sham-treated APP23mice(n= 10pergroup).
(E and F) Representative sections of SUS-treated
brains versus control brains stained with Thioflavin
S(E)and 4G8(F).(G)Plaqueload plotted asafunctionof age confirmed that the SUS-treated group had
significantly lower plaqueload than thesham-treated
group.Baseline plaque load at the onset of treatment
is indicated by open circles. Scale bars, 1 mm (panel
A) and 200 mm (panel B).
Fig. 3. SUStreatment reduces different Ab spe-
cies. (A to D) Western blotting of extracellular-
enriched (A) and Triton-soluble (B) fractions of thebrains of the first cohort of APP23 mice with 6E10
and 4G8 anti-Ab antibodies revealed a reduction in
distinct Ab species in both fractions in SUS-treated
compared to sham-treated mice. These data arequantified in (C) and (D), respectively. The Western
blots show significant reductions of HMW spe-
cies, the 56-kD oligomeric Ab*56 (*56) and trimeric
Ab (3-mer)/CTFb, in the extracellular-enriched
fraction and of *56 and 3-mer/CTFb in the Triton-
soluble fraction (unpaired t tests, P< 0.05). GAPDH
(glyceraldehyde 3-phosphate dehydrogenase) wasused for normalization. MWM, molecular weight
marker.(E)ELISA for Ab42 in the Triton-soluble frac-
tion revealed asignificant reduction in SUS-treated
compared to sham-treated mousebrains(unpairedt test, P< 0.05; n = 10 per group).
RESEARCH ARTICLE
www.ScienceTranslationalMedicine .org 11 March 2015 Vol 7 Issue 278 278ra33 3
on May 3, 2016
http://stm.sciencem
ag.org/D
ownloaded from
BBB and Brain clearance
University of Oulu
Outline ‒ Glymphatic system
- Blood brain barrier (BBB) and brain clearance
‒ Multimodal human brain monitoring in Oulu
- BBB disruption monitoring
- Multimodal human imaging in Magnetic Resonance Imaging (MRI)
‒ Towards wearable monitoring
- A combined opto-capacitive-microwave imaging device
- Sensing method
- Validation experiments
6/21/20178
Towards continuous monitoring of the glymphaticsystem of the human brain
University of Oulu
BBB disruption monitoring
The BBB forms a major obstacle for brain drug delivery, especially in the treatment of brain tumours. A method involving BBB disruption (BBBD) induced with intra-arterial mannitol infusion, developed at the University of Portland, is exploited at the Oulu University Hospital to treat CNS lymphoma.
9
Myllylä T. et al. ”Studies for drug delivery
detection during blood brain barrier
disruption therapy”, 7th Imaging in Drug
Discovery Conference, October 7-8, 2014 in
Dublin, Ireland, (2014).
University of Oulu
Grand average DC-EEG and average NIRS traces illustrating characteristic responses
evoked by intra-arterial mannitol infusion
V. Kiviniemi, V. Korhonen, J. Kortelainen, S. Rytky, T. Keinänen, T. Tuovinen, M. Isokangas, E. Sonkajärvi, T. Siniluoto, J. Nikkinen, S.
Alahuhta, O. Tervonen, T. Turpeenniemi-Hujanen, T. Myllylä, O. Kuittinen, J.Voipio,”Real-time monitoring of human blood-brain barrier
disruption”, PLOS ONE (2017).10
BBB disruption monitoring
University of Oulu
‒ Drivers of lymphatic and CSF flow
- Body movements, muscle contractions
- Cardiovascular system, arterial and cardiac pulsations
- Blood pressure, which indirectly maintains force of pressure in the lymphatic channels
- Respiratory pulsations induce counter pulsations probably cleaning the perivenulous accumulations
- Very low frequency (VLF) waves modulate CSF convection
=> simultaneous measurement of brain and physiological signals are of interest
Multimodal imaging in MRI- Towards continuous monitoring of the glymphatic system
University of Oulu
A. Zienkiewicz, N. Huotari, L. Raitamaa, V. Raatikainen, H. Ferdinando, E. Vihriälä,
V. Korhonen, T. Myllylä, V. Kiviniemi, “Continuous blood pressure recordings
simultaneously with functional brain imaging - studies of the glymphatic system,
SPIE proceeding, PhotonicsWest (2017).
Korhonen, V., Hiltunen, T., Myllylä, T., Wang, X., Kantola, J., Nikkinen, J., Zang, Y.,
LeVan, P. and Kiviniemi, V. , "Synchronous Multiscale Neuroimaging Environment
for Critically Sampled Physiological Analysis of Brain Function: Hepta-Scan
Concept," Brain connectivity 4(9), 677-689 (2014)
Functional ultrafast MRI, NIRS, blood pressure, EEG, ECG, CO2
expiration and oxygen saturation (SpO2) recordings simultaneously.
A collaboration project in Oulu
- Oulu University Hospital
- Medical Research Center
(Oulu Neuroimaging group, OFNI)
- Oulu Biocenter
- University of Oulu
(Optoelectronics and Measurement
Techniques Unit)
Multimodal imaging in MRI- Towards continuous monitoring of the glymphatic system
University of Oulu
The glymphatic system is more active during sleep [Xie L. et al. "Sleep drives metabolite clearance from the adult brain." science 342.6156 (2013): 373-377]
=> For sleep studies, a wearable, over-night monitoring method needed
Requirements:
- easy to use (small)- suitable for long-term measurements- doesn’t affect sleep quality- completely safe method
6/21/201713
Continuous monitoring of the glymphatic system
University of Oulu
Outline ‒ Glymphatic system
- Blood brain barrier (BBB) and brain clearance
‒ Multimodal human brain monitoring in Oulu
- BBB disruption monitoring
- Multimodal human imaging in Magnetic Resonance Imaging (MRI)
‒ Towards wearable monitoring
- A combined opto-capacitive-microwave imaging device
- Sensing method
- Validation experiments
6/21/201714
Towards continuous monitoring of the glymphaticsystem of the human brain
University of Oulu
Dynamics of CSF volume and flow in subarachnoid space
reflect dynamics of the glymphatic system?
‒ CSF acts as a cushion behind the skull, providing basic mechanical
as well as immunological protection to the brain.
‒ Cerebrospinal fluid (CSF) is a clear, colourless liquid including water
(H2O) approximately with a concentration of 99 %.
6/21/201715
Raper, Daniel, Antoine Louveau, and Jonathan Kipnis.
"How Do Meningeal Lymphatic Vessels Drain the
CNS?." Trends in Neurosciences 39.9 (2016): 581-586.
Continuous monitoring of the glymphatic dynamics- By measuring of CSF in the subarachnoid space
University of Oulu
NIRS sensing
‒ Near Infra-red Spectroscopy
(NIRS)
6/21/201716
Monte Carlo simulation of a multilayered brain. Photon trajectory maps for 830 nm
for source-detector separations of 30 mm (left) and 40 mm (right).
Korhonen, V. O., Myllyla, T. S., Kirillin, M. Y., Popov, A.
P., Bykov, A. V., Gorshkov, A. V., Sergeeva, E.,
Kinnunen, M. and Kiviniemi, V. , "Light propagation in
NIR spectroscopy of the human brain," Selected
Topics in Quantum Electronics, IEEE Journal of 20(2),
289-298 (2014).
University of Oulu
NIRS sensing
6/21/201717
Isosbestic point for oxy- and deoxy Hb
The Beer-Lambert law
Isosbestic point for oxy Hb and water
University of Oulu
Capacitive sensing
‒ Dielectric properties of tissue are well studied,
however, utilization of a capacitive sensor for
non-invasive CSF sensing are not reported
• Capacitors are sensitive to change in
volume of fluid, and even flow
• Can measure total water volume (in blood
and CSF)
• Low manufacturing costs
• Skin (electrical) conductance not needed
6/21/201718
University of Oulu
Capacitive sensor
‒ Basic operation principle: creating step
excitations to the unknown capacitance CX by
using a fixed resistor RC with known voltage
values and measuring the time interval of each
charge time constant which is dependent on CX
‒ The exact value of the unknown CX, which is the
capacitive field over the sensor plates, can be
determined with the obtained results
6/21/201719
Cref: 220 pF Cx
Rc: 4,7 Mohm
Trig
Tresh
Out
TimerLMC555
DAQNI USB-6212
Counter in
The basic construction of the capacitance measuring device.
University of Oulu
Capacitive sensor
‒ The time of high and low periods of the square wave
(charging and discharging sequences), shown in Fig
below, is read by a counter using 80 Mhz clock
frequency.
‒ the value of Cx can be determined using the equation
on left if a reference capacitor is in parallel with Cx.
6/21/201720
Vcap: voltage over the unknown capacitance.
Vout
Vouth: 3,1 V
Voutl: 0,2 V
Vtrig: 1,14 V
Vtresh: 2,27 V
Vout: timers output (charging) voltage.
Vcap
T = time periods of the square wave. T is 0,34 ms when Cx is not connected which corresponds frequency of 2,9 kHz.
Fig. Signals and voltages of the capacitance measuring device.
University of Oulu
Capacitive sensor
‒ In addition, the device uses a multiplexer (Texas Instruments CD4051) which enables selecting Cx from eight different sources
6/21/201721
Capacitance measurement device connected to a multiplexer. Cx can be selected from eight different sources (channels 0 i/o - 7 i/o).
Capacitance measurement device (fig.1)
MultiplexerCom o/i
0 i/o
1 i/o
2 i/o
3 i/0
4 i/o
5 i/o
6 i/o
7 i/0
CD4051
University of Oulu
Microwave imaging technique
‒ One recent example is wideband microwave head imaging system for on-the-spot detection of intracranial hemorrhage. The dielectric contrast between healthy brain tissues and a hemorrhage that causes a strong microwave scattering.*
‒ The system uses a compact sensing antenna with directional radiation, and a portable, compact microwave transceiver for signal transmission and data acquisition
‒ System operates from 0.75–2.55 GHz
‒ The collected data is processed to create a clear image of the brain using an improved back projection algorithm
6/21/201722
*Mobashsher, Ahmed Toaha; Mahmoud, A.; Abbosh, A. M. Portable
wideband microwave imaging system for intracranial hemorrhage detection
using improved back-projection algorithm with model of effective head
permittivity. Scientific reports, 2016, 6.
University of Oulu
Validation of sensitivity
‒ 3D simulations using
- COMSOL Multiphysics for capacitive technique
- Cone-Shaped Distribution (CSD) for microwave technique
- Monte Carlo for optical technique
‒ Multilayered phantom measurements
- Mimicking both optical and dielectric properties of brain tissues
- In vivo measurements in MRI
6/21/201723
University of Oulu
Simulations
‒ Geometric setup: a capacitor is placed on top of a human head with layers of skin, skull and
cerebrospinal fluid
6/21/201724
Geometric setup (left). The change in volume of the CSF is plotted against the change in capacitance for different configurations of the capacitor (right).
University of Oulu
‒ Capacitive sensor test and simulation was done using the same geometric setup and method
‒ Both simulation and real measurement show that small changes in water volume can be detected.
6/21/201725
Average response of the capacitive sensor (right) and the simulation result (left). The thickness of the layer of water was varied from 1 mm to 10 mm.
Phantom experiments
Myllylä T, Vihriälä E, Pedone M, Korhonen V, Surazynski L, Wróbel M, Zienkiewicz A, Hakala J, Sorvoja H, Lauri J, Fabritius T, Jędrzejewska-Szczerskae M,
Kiviniemi V, Meglinski I (2017) Prototype of an opto-capacitive probe for non-invasive sensing cerebrospinal fluid circulation, Invited Paper, Proc. SPIE 10063.
University of Oulu
@1900 MHz
Tissue Source Permittivity Elec. Cond. (S/m)
Skin Skin (Dry) 38.71429860635464 1.224532125743767
Skull Cancellous Bone Cancellous 19.213035781740164 0.6199036157247495
Skull Cortical Bone (Cortical) 11.716472852861365 0.2924341961945009
Cerebrospinal Fluid Cerebrospinal Fluid 67.05564806810452 2.9972739179098724
Brain Cerebellum 45.884888803827074 1.7652286689074284
Brain (Grey Matter) Brain (Grey Matter) 49.88159397536683 1.4502995498876796
Brain (White Matter) Brain (White Matter) 36.8683967651613 0.9575054584828246
Source
https://www.itis.ethz.ch/virtual-population/tissue-properties/database/dielectric-properties/
Human Skull Electrical and Mechanical Parameters
Phantom experiments
University of Oulu
- Oulu Functional Neuro-Imaging group (OFNI)
- Health & Wellness Measurements group (HWM)
Alexander Bykov, Jaakko Hakala, Markus Harju, Vesa Kiviniemi, Vesa Korhonen, JanneLauri, Igor Meglinski, Matteo Pedone, Lukasz Surazynski, Marko Tuhkala, Erkki Vihriälä, Aleksandra Zienkiewicz
Thank you!
Contact: [email protected]
6/21/201727
Acknowledgement