8/17/2011
CT CALVARIA IMAGE
BRAIN THERAPY BY FUS
Meaghan O’Reilly, Alison Burgess, Aki Pulkkinen,
Yuexi Huang, Nazanin Hosseinkhah
and Kullervo Hynynen
Imaging Research and
Centre for Research in Image-Guided Therapeutics
Sunnybrook Research Institute
Department of Medical Biophysics and
Institute of Biomaterials & Biomedical Engineering
University of Toronto
ULTRASOUND PROPAGATION IN SOFT TISSUE/BONE
SPEED OF SOUND IN HUMAN SKULL BONE
Soft Tissue Bone
270 kHz
Transducer
1.402 MHz
Normalized Absorbd Power
1.965 MHz
836 kHz
7
Bone:
high ultrasound absorption
=> hot spot
6
5
4
2.526 MHz
3
2
1
0
1 MHz
0
50
100
Depth (mm)
150
200
Pichardo et al., Phys Med Biol. 2011;56(1):219-250
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TRANS-SKULL SONICATIONS
NON-INVASIVE FOCUSED ULTRASOUND
BRAIN SURGERY
PROBLEMS:
Ultrasound
Absorption in Skull
•10-20x higher than in brain
Variable Skull
Thickness
•ultrasound focus destroyed
•skull heating
•reduced power in brain
Ultrasound
Transducer
It was believed that FUS was not possible in the brain
HYPERTHERMIA & RT/CT
SKULL HEATING PROBLEM:
LARGE HEMISPHERICAL TRANSDUCER
Brain
Skull
Tumor
Skull-window
Water
Skin
US Transducer
Guthkelch et al. J Neurooncol., 1991;10(8):271-284
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PROTOTYPE HEMISPHERICAL ARRAYS
64 elements
Clement et al., Phys.Med.Biol.
2000;45:3707-3719
200 elements, F-number = 0.67
“High power transcranial beam steering for ultrasonic brain therapy.”
Phys Med Biol. 2003;48(16):2577-89.
Pernot M, Aubry JF, Tanter M, Thomas JL, Fink M
1372 elements
Song and Hynynen. IEEE Trans
Biomed Eng. 2010;57(1):124-33
SONICATION THROUGH AN EX VIVO HUMAN SKULL:
NO PHASE CORRECTION
Phase Correction
to compensate for
the skull thickness
-4
z (mm)
SKULL DEFOCUSING PROBLEM:
A PHASED ARRAY AND PROPAGATION PREDICTION
Transducer
Elements
Skull
0
RF-signals
4
-4
0
x (mm)
4 -4
0
y (mm)
4
Clement and Hynynen, Phys Med Biol. 2002;47:1219-1236
Aubry, et al. J. Acoust Soc Am. 2003;113(1):84-93
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SONICATION THROUGH AN EX VIVO HUMAN SKULL:
MODEL CORRECTED
ATTENUATION IN HUMAN SKULL BONE
-4
z (mm)
1.402 MHz
0
835 kHz
4
-4
0
x (mm)
4 -4
0
y (mm)
4
Clement and Hynynen. Phys. Med. Biol. 2002;47(8):1219-1236
270 kHz
Pichardo et al.,Phys Med Biol. 2011;56(1):219-50
AMPLITUDE CORRECTION
White et al., IEEE UFFC. 2005;52:1518-1522
White et al., IEEE UFFC. 2005;52:1518-1522
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MRI GUIDANCE AND MONITORING OF THERMAL
SURGERY OF THE BRAIN
EXABLATE 4000: DUAL FREQUENCY SYSTEM
Targeting
Monitoring: Temperature Map
Temperature Rise (°C)
5.1
3.3
1.6
-0.2
*
Frequency:
220 kHz and 650 kHz
Number of Channels:
Head Fixation:
-2
pins
1000
*Martin et al., Annals of Neurology 2009
Courtesy University Children's Hospital, Zurich
MR-THERMOMETRY DURING BRAIN TREATMENTS:
3 TUMOR PATIENTS
Brigham and Women’s Hospital, Boston, MA, USA, 2005
McDannold et al, J. Neurosurgery 2010
THERMAL ABLATION FOR PAIN TREATMENT
MRI thermometry
McDannold et al, J. Neurosurgery 2010
T2w 48h after treatment
Martin et al., Annals of Neurology 2009
Courtesy University Children's Hospital, Zurich
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TREATMENT PLANNING
Pressure
TREATMENT PLANNING COMPARED WITH
CLINICAL SONICATIONS
Temperature
SKULL BASE HEATING:
THERMAL TREATMENTS CLOSE TO THE SKULL BASE
230 KHZ
Temperature
treatable
un-treatable
skull base
temperature
Time
focal temperature = 42C
Huang et al. ISMRM 2010
Pulkkinen et al ., ISTU10
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SIMULATIONS: TEMPERATURE ELEVATION INDUCED BY
MICROBUBBLES & FUS
MICROBUBBLES IN CAPILLARY BLOOD VESSELS
T2w
y (µm)
Temperature Rise (°C)
CE-T1w
x (µm)
Sonication Duration 5 min
Burst Length
Frequency
PRF
Peak Power
0.55 MHz
10ms
1Hz
0.47W
Klotz et al. Phys. Med. Biol. 2010
HISTOLOGY 24H:
ISCHEMIC NECROSIS
50 mm
MRI-HIFU TREATMENTS FOR ISCHEMIC STROKE
Sonication Duration 5 min
MRI:
Frequency
0.55 MHz
•used to detect blood clot
Peak Power
0.47W
•take precise coordinates
to target the HIFU system
Burst Length
10ms
PRF
1Hz
Iron loaded blood clot
prior to treatment
Autolysis - formation of a semi-liquid mass of dead cells
Vykhotdseva et al., ISTU10
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MRI-HIFU TREATMENTS FOR ISCHEMIC STROKE
FOCAL AND NON-INVASIVE METHOD FOR DRUG
DELIVERY: CENTRAL NERVOUS SYSTEM
Twice as many people suffer from central
nervous system diseases such as:
Prior to Treatment:
•The middle cerebral
artery (MCA) is blocked
•epilepsy
•Alzheimer’s disease
•schizophrenia
than from diseases of the blood vessels
and heart.
Following HIFU:
•vessel intact
•blood flow re-established
• HIFU has disrupted the
blood clot
HOWEVER,
>95 % of all known CNS drugs have a MW >500 Da
and do not penetrate into the brain tissue
due to the Blood-Brain barrier (BBB)
SIMULATIONS OF A MICROBUBBLE IN A CAPILLARY
Microbubble Effects:
•Acoustic microstreaming =>
shear stress on vessel wall
• Expansion and invagination
of the vessel
2 µm bubble
5 µm vessel
350 kPa
1 MHz
AGENTS DELIVERED ACROSS THE BBB BY FUS
Agent
Size
Citation
1,3-bis(2-chloroethyl)-1-nitrosourea
(BNCU)
~ 214 Da
Liu et al., 2010 (Radiology)
Methotrexate
~450 Da
Mei et al., 2009 (J. Ultrasound Med)
Doxorubicin
~ 550 Da
Treat et. al., 2007 (Int. J. Cancer)
Fluorescent-tagged dextrans
3 kDa, 70 kDa
Choi et al., 2010 (UMB)
Herceptin
~ 150 kDa
Kinoshita et al., 2006 (PNAS)
Amyloid-β antibodies
~ 150 kDa
Jordão et al., 2010, (PLoS One)
Raymond et al., 2008 (PLoS One)
Dopamine D4 receptor-targeting
antibodies
~ 150 kDa
Kinoshita et al., 2006
(Biophys Res Commun)
Polyethylene glycol coated
Au-nanoparticles
50 nm
Etame et al., 2011 (CCNS)
Stem Cells
7-10 µm
Park et al., 2011 (ISTU11)
Burgess et al., 2011 (Submitted)
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CONCLUSIONS
ACKNOWLEDGEMENTS
•Transcranial FUS is a promising modality for non-invasive brain
therapy that has being clinically investigated for treatment chronic
pain and glioblastoma
•Current research shows promise for treatment of stroke and for
targeted circumvention of the blood-brain barrier
•The skull bone remains a limiting factor in treatments, which can
be addressed through careful treatment planning
•Future work will investigate additional means of monitoring
transcranial FUS to improve safety, reduce costs and improve
treatment accessibility
Funding:
CRC
Terry Fox Foundation
Ontario Research Fund
OICR
Canada Foundation for Innovation
National Institutes of Health
Industry:
General Electric
InSightec
Philips
Celsion
Artenga
Fus Instruments
Collaborators:
I. Aubert, PhD
S. Black, MD
P. Burns, PhD
R. Chopra, PhD
G. Czarnota, MD,PhD
E. David, MD
D. Dumond, PhD
D. Goertz, PhD
R. Kerbel, PhD
J. McLaurin, PhD
B. Stefanovic, PhD
BWH
N. McDannold
G. Clement
N. Vykhotdseva
THANK YOU!
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