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Neurological Applications of Focused Ultrasound
Nishanth Khanna MD, Victor Frenkel PhD, Andrew Steven MD, Dheeraj Gandhi MD, Elias
Melhem MD
Department of Radiology and Nuclear Medicine,University of Maryland School of Medicine
ASNR 53rd Annual MeetingChicago, Il
eEdE#: eEdE-81 (Shared Display)
Disclosures
The authors declare no financial disclosures
Objectives
• Discussion of promising clinical applications
• Discussion of the physical principles of focused ultrasound (FUS)
• Familiarization with the FUS apparatus used in neurological applications
• Illustration of the variety of biological effects generated by varying FUS energy deposition
Focused Ultrasound
A single element US transducer
can focus acoustic wave
propagation at a specific point
The structure of the transducer depends on the
target tissue
The therapeutic benefit of FUS
relies on energy deposition via acoustic wave
propagation to a focal point
Focused Ultrasound
Acoustic energy can be deposited in multiple layers of tissue in multiple dimensions within a targeted volume by steering the focal
point
Focused Ultrasound (FUS) Applications
Rate of Energy Deposition
NeuromodulationLow IntensityPulsed FUS
Enhanced Drug Delivery
High IntensityPulsed FUS
Thermal AblationHigh IntensityContinuous
FUS
Destructive /Irreversible
Biological Effects
‘Visible’ /Reversible
‘Invisible’ /Reversible
FUS for Thermal Ablation
Lou et al 2007 J Ultrasound Med
treated
untreated
Thermal ablation with FUS has high resolution with a sharp line of demarcation (approx. 8-10 cell diameters) between treated and untreated tissues
FUS offers the added benefit of no radiation deposition when compared to other therapeutic systems (i.e. gamma knife)
Extra-neurological FUS applications
Also approved for use in ablation of uterine fibroids via an MR-guided extracorporeal
transducer
Initially used in US-guided treatment of prostate cancer via a transrectal transducer
Noninvasive MR Thermometry
Ranjan et al 2012 J Control Release
Near real-time
temperature
measurement of FUS induced
heat generation is possible
via MR thermometr
y
Brain – The Focused Ultrasound Apparatus
MRI offers guidance
and monitoring
of treatment
The FUS apparat
us
A multi element,
hemi-spherical, phased
array FUS transducer
Brain – The Focused Ultrasound Apparatus
Degassed water circulates in a “bladder” around the patient’s head for efficient acoustic
wave propagation
High resolution,
high energy
deposition with one
focal point
Multiple focal points - larger area of relative
hyperthermia to enhance radiotherapy
Individual US elements can be steered to
correct aberrations (i.e. at soft tissue-bone interfaces)
A multi-element, phased array transducer offers versatility
Konofagou 2012 TheranosticsClement 2012 J Acoust Soc Am
Transcranial FUS Exposures
•energy loss/heating•reflection/refraction•phase alteration
the variable thickness of the skull further exacerbates the
problem
Impedance mismatch at soft tissue/bone & bone/soft tissue interface results in:
Hynynen et al 2006 Euro J Radiol
Transcranial FUS Exposures
X-ray computed tomography (CT) images are used to predict and correct longitudinal wave distortion created by
the skull by steering individual ultrasound elements
Clinical Applications of High Intensity FUS – Essential Tremor
A clinical trial performed in 2011 and published in 2013, enrolled 15 patients with refractory essential tremor to
evaluate the role of MR-guided focused ultrasound
Before
Clinical Assessment of Tremor Suppression
After(same day)
Elias et al 2013 NEJM
Clinical Assessment of Tremor Suppression
Elias et al 2013 NEJM
All but one of the patients experienced significant improvement in symptoms lasting at least one year after therapy
Unilateral Thalamotomy of the Ventral Intermediate Nucleus – MRI Findings
Clinical benefit persisted well after resolution of MRI findings without evidence of non-target intracranial injury
Elias et al 2013 NEJM
Other Clinical Applications of High Intensity FUS
Early clinical trials suggest utility in thermal ablation of solid intracranial tumors
Other Clinical Applications of High Intensity FUS
Jolesz 2014 Annu Rev Med
continuous, high
intensityheat coagulative
necrosis
uterine fibroids,solid tumors,
thalamus
I
t
FUS Duty Cycle and Mechanisms
continuous, high
intensityheat coagulative
necrosis
uterine fibroids,solid tumors,
thalamus
pulsed,high
intensity
acoustic cavitation, acousticrad force
increased permeabilit
y
enhanced drug/genedelivery
I
t
I
t
FUS Duty Cycle and Mechanisms
When applied in a pulsed, high intensity manner, cooling between the pulses and lower average temporal intensity result in lower temperature elevations. Mechanical effects
of FUS will predominate
FUS with Ultrasound Contrast Agents
Ultrasound Contrast Agents
Without With
Varying pressure field of the FUS acoustic wave causes oscillation
of the bubbles of US-contrast agents
Blood Brain Barrier Opening - Mechanisms
Liu et al 2014 Theranostics
Various interactions of the US-contrast bubbles with the endothelial wall creates transient increase
in permeability
Enhanced Drug Delivery in the Treatment of Glioblastoma
Wei 2011 PloS One
Visualization of BBB opening
Post-gadolinium enhancement serves as a surrogate for visualization of BBB opening
Monitoring Tumor Growth
A T2 sequence was used to monitor growth and decide the initiation of treatment (Day 10). After achievement of
adequate tumor burden, treatment was initiated and tumor response was assessed (Day 17).
The FUS + Temozolomide group demonstrated lower rate of tumor growth
Wei 2011 PloS One
Tumor Growth and Survival Benefit
Importantly, improved outcomes were also demonstrated in the FUS + treatment group
Wei 2011 PloS One
Temozolomide Wei et al 2013 PloS One
Doxil Treat et al 2011 Ultrasound Med Biol
Herceptin Konoshita et al 2006 Proc Natl Acad Sci
boronophenylalanine-fructose (BPA-f) Yang et al 2014 PloS One
Ab - amyloid-β peptides Jordao et al 2013 Exp Neurol
Glial cell line-derived neurotrophic factor (GDNF) Wang et al 2012 Plos One
Stealth, brain-penetrating nanoparticles Nance et al 2014 J Control Release
Neural Stem Cells Burgess et al 2011 Plos One
NK-92 cells Alkins et al 2013 Cancer Res
Other Examples of FUS Enhanced Delivery in Preclinical Trials
continuous, high
intensityheat coagulative
necrosis
uterine fibroids,solid tumors,
thalamus
pulsed,high
intensity
acoustic cavitation, acousticrad force
increased permeabilit
y
enhanced drug/genedelivery
I
t
I
t
HIFU Duty Cycle and Mechanisms
continuous, high
intensityheat coagulative
necrosis
uterine fibroids,solid tumors,
thalamus
pulsed,high
intensity
acoustic cavitation, acousticrad force
increased permeabilit
y
enhanced drug/genedelivery
pulsed,low
intensity
bilayer sonophores
?acoustic
rad force?
mechanical perturbatio
n
neuromodulation:- stimulation- suppression
I
t
I
t
I
t
HIFU Duty Cycle and Mechanisms
Pulsed, low intensity application can generate neuromodulation; although, the exact mechanisms
remain unclear.
FUS Induced Neuromodulation
Reproducible in vivo neurostimulation of the mouse
somatomotor response measured via EMG in the corresponding limb
FUS Induced Neuromodulation
Selective in vivo neurostimulation of the mouse somatomotor cortex shows increased probability of muscle contraction and
contraction strength at acoustic intensity ≥ 1.1 W/cm^2. Above this level, contraction duration and strength peaks and stabilizes,
an “all or none” phenomenon
HIFU-induced in vivo neurostimulation and suppression of rabbit
eloquent cortex
Reproducible, FUS-induced neurostimulation confirmed
by functional MRI and electrophysiological
recordings
FUS Suppression of VEPs
Suppression of visual evoked potentials (VEPs) after focused ultrasound application confirms neuromodulation
After experimentation, excision and histologic examination of the brain parenchyma demonstrated no evident injury
Potential Clinical Applications of Neuromodulation
• Functional evaluation when used in conjunction with functional imaging techniques
• Expanding on understanding of psychiatric illness and other neuropathologies
• Therapeutic tool in disorders that may benefit from neuroexcitation/suppression, i.e. epilepsy, obsessive compulsive disorder
Summary• Neurological FUS has the potential to be a
transformative technology in neuroscience and therapeutics
• Neurological applications include thermal ablation, enhanced drug delivery and neuromodulation in the context of noninvasive therapies or neuroconnectivity studies
• FUS is the only system that offers noninvasive, localized and transient permeability of the blood brain barrier
• Unique benefits of FUS over other therapeutic systems include noninvasiveness, lack of radiation and high tissue resolution
ReferencesRanjan A, Jacobs G, Woods DL, et al. Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model. Journal of Controlled Release. 2012;158(3):487-494.
Konofagou EE. Optimization of the Ultrasound-Induced Blood-Brain Barrier Opening. Theranostics. 2012;2(12):1223-1237.
Hynynen, K., McDannold, N., Clement, G., Jolesz, F. A., Zadicario, E., Killiany, R., ... & Rosen, D. (2006). Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain—a primate study.European journal of radiology, 59(2), 149-156.
Elias, W. J., Huss, D., Voss, T., Loomba, J., Khaled, M., Zadicario, E., ... & Wintermark, M. (2013). A pilot study of focused ultrasound thalamotomy for essential tremor. New England Journal of Medicine, 369(7), 640-648.
Jolesz, F. A. (2009). MRI-guided focused ultrasound surgery. Annual review of medicine, 60, 417.
ExAblate Neuro: Focused Ultrasound Transcranial Neurosurgery. http://www.insightec.com/contentManagment/uploadedFiles/fileGallery/Brochure_ExAblateNeuro.pdf Accessed March 2, 2015
Foster RS, Bihrle R, Sanghvi N, et al. High-intensity focused ultrasound in the treatment of prostatic disease. European urology 1992;23:29-33
Tyler WJ, Tufail Y, Finsterwald M, et al. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PloS one 2008;3:e3511
Yoo SS, Bystritsky A, Lee JH, et al. Focused ultrasound modulates region-specific brain activity. NeuroImage 2011;56:1267-1275