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

Questions?

nkhanna1@umm.edu