Dr. Shahnawaz Alam
Resident; MCh-Neurosurgery
Moderated by:
Dr. V. C. Jha
HOD, Dept. of Neurosurgery
HIGH-INTENSITY FOCUSED
ULTRASOUND AND MR THERMAL
ABLATION: APPLICATION IN
NEUROSURGERY

INTRODUCTION
• Ultrasonic waves are sound waves that propagate through matter, and their
frequencies are above the hearing range of human ears (> 20,000 Hz). Typical
US frequencies from therapeutic equipment are between 1 to 3 MHz.
• Sonic intensity (SI) can be defined as a average rate of sonic energy-flow
through a unit area (SI unit: W/cm2).
• High-intensity US generally refers to US with an intensity higher than 5 W/cm2.
This type of US can transfer enough energy to cause coagulation necrosis of
tissue and is usually used for ultrasonic surgery.
• Low-intensity US (0.125-3 W/cm2) causes non-destructive heating, therefore, it
stimulates or accelerates normal physiological responses to an injury. This
range of US is usually used for physiotherapy.

• In the modern era of minimal invasiveness, high-intensity focused ultrasound
(HIFU) promises therapeutic utility for multiple neurosurgical pathologies.
• The use of focused ultrasound (FUS) waves for intracerebral ablation was first
described by Lynn et al. in 1942.
• Later, the Fry brothers designed a complex device with 4 piezoelectric
transducers that had the ability to focus pinpoint lesions and used HIFU for
safe ablation of intracranial tumors by performing craniectomy to create a
window for the transmission of acoustic waves.
• With intraoperative MRI, the magnetic resonance-guided focused ultrasound
(MRgFUS) is more precise than ultrasound or a surgeon’s direct visualization.

PRINCIPLES AND MECHANISMS OF ACTION OF HIFU
• In the MRgFUS procedure, a small target is heated with ultrasound rays, a technique
called sonication.
• The pre-sonication volume target is identified by MRI, post-sonication temperature is
measured by proton resonance frequency shift by means of fast GRE sequences, and
the ablated volume is identified by means of T2-weighted fast spin-echo sequences.
• Primary goal: to maximize energy accumulation at the target area to induce significant
biological reactions (coagulation necrosis) without instigating harm to surrounding
tissues.
• The “focal zone” can be defined as the area where the ultrasound intensity (energy/unit
area) is high enough to create a lesion. These lesions are ellipsoidal, 8–15 mm in length,
and have a diameter of 1–2 mm.
• In HIFU treatment, FUS is applied for local ablation therapy of various types of tumors in
the body using an intensity of 100-10,000 W/cm2 .

• HIFU exposure can be either constant (thermal) or pulsed (acoustic cavitation).
 Thermal Mechanisms of Action
• Ultrasound produces frictional heat by causing vibration of molecules in tissue;
a temperature of > 56°C maintained for 2 seconds or more leads to coagulative
necrosis. The thermal damage leads to unplanned cell death.
• The targeted cells retain their outline, their proteins coagulate, and their
metabolic activity halts.

HIFU transducer with focused
beam on a tumor. HIFU
produces a focused ultrasound
beam that passes through the
overlying skin and tissues to
necrose a localized region
(tumor), which may lie deep
within the tissues. The affected
area at the focal point of the
beam leads to lesion
coagulative necrosis and is
shown in red.

 Nonthermal (Mechanical) Mechanisms of Action
• The pulsed method of HIFU exposure can cause fast changes in the targeted
tissue pressure, known as the peak rarefaction pressure amplitude (PRPA).
• There is a threshold for PRPA for each tissue at which acoustic cavitation
(formation of gas- or liquid-filled cavities) occurs, generally at points of
“weakness,” such as the interfaces between different layers of tissue or fluid-
filled structures.
• These acoustic cavitation bubbles oscillate at large displacement amplitudes
and exert shear stresses on the surrounding tissue, causing mechanical tearing;
k/a histotripsy.

 ACOUSTIC STREAMING is described as a small scale eddying of fluids near a
vibrating structure such as the surface of stable cavitation gas bubble. This
phenomenon is known to affect diffusion rates & membrane permeability.
 Sodium ion permeability is altered resulting in changes in the cell membrane
potential. Calcium ion transport is modified which in turn leads to an
alteration in the enzyme control mechanisms of various metabolic processes,
especially concerning protein synthesis & cellular secretions.

 There are 2 types of cavitation:
1. STABLE CAVITATION does seem to occur at therapeutic doses of US. This is
the formation & growth of gas bubbles by accumulation of dissolved gas in
the medium. They take approx. 1000 cycles to reach their maximum size.
The `cavity' acts to enhance the acoustic streaming phenomena & as such
would appear to be beneficial.
2. UNSTABLE (TRANSIENT) CAVITATION is the formation of bubbles at the
low pressure part of the US cycle. These bubbles then collapse very quickly
releasing a large amount of energy which is detrimental to tissue viability.
Forms of stable and inertial cavitation

Schematic of tcMRgHIFU setup
MRgHIFU setup consists of a positioning system, a transducer, and a stereotactic
head frame, which is placed for patient immobilization during the procedure.

A: Noninvasive setup of HIFU transducer with transducer tracker, head-motion tracker, and degassed
water. B: HIFU transducer converging noninvasive transcranial ultrasonic energy at the ellipsoidal
focal zone to produce tissue lesions at depth.

INITIAL CHALLENGES WITH TRANSCRANIAL MRgHIFU
 Bone: relatively high attenuation coefficient, absorbs and reflects ultrasound energy;
Also its acoustic impedance higher than that of the soft tissues, inferior efficacy of
energy transfer and unwanted heating of the skull in transcranial HIFU therapy.
 To overcome this, transducers with a large number of high-energy sources; An
external cooling system that circulates chilled water around the scalp.
 To distribute the heat as widely as possible, the active area has been maximized
through a hemispheric design, known as a piezoelectric component arrangement.
 Severe aberration of FUS waves d/t Irregularity in skull thickness, result in the
defocusing of ultrasound beams.
 A computerized multichannel hemispheric phased-array transducer (ExAblate
Neuro, InSightec Ltd.).

An ExAblate Neuro MRgFUS transducer helmet on an MRI table

CURRENT APPLICATIONS IN NEUROSURGERY
• A silicone diaphragm is fitted to the scalp, and the transducer is filled with
degassed water (dissolved oxygen below 1.2 ppm). The cooled degassed
water (between 15°- 20°C) is circulated between sonications to prevent
unwarranted heating and lower the skull temperature.
• GBM is MC & most aggrassive; the center of attention for multiple HIFU trials.
 According to Medel et al. HGG are not an ideal pathology for HIFU, and the
technique might be more effective for well-circumscribed lesions, such as
metastases or benign tumors, inaccessible to surgery.

Functional Neurosurgery Transcranial MRgHIFU
• Precise ablation of the focused targets in the thalamus, subthalamus, or basal ganglia;
These locations are centers to many pathological conditions, namely neuropathic pain,
Parkinson’s disease (PD), and essential tremor (ET).
 In 2009, Martin et al. reported the first successful application of tcMRgHIFU for
functional neurosurgery. They treated 9 patients with chronic neuropathic pain with
medial thalamotomies. The ablations were precisely located within a diameter of 4 mm
according to MRI. There were no neurological deficits on follow-up.
 Jung et al. were the first to describe the use of MRgFUS for the treatment of medically
refractory obsessive-compulsive disorder (OCD). They performed bilateral thermal
anterior limb capsulotomy in 4 patients and reported favorable results. Similarly, a
clinical trial of 10 patients evaluated the feasibility, safety, and initial efficacy of
MRgFUS in the treatment of major depressive disorder.

 Enhancing Drug Delivery Across the Blood-Brain Barrier: Several studies have
demonstrated the potential of FUS to deliver chemotherapeutic agents, antibodies,
growth factors, or genes to the desired area of the brain.
 By modifying the sonication parameters from those used for ablation, a
controlled, reversible, and reproducible opening of the BBB can be achieved,
allowing for the delivery of targeted drugs, such as liposomal doxorubicin;
nanoparticles; fluorophores; and naked DNA injected systemically to locally
sonicated tissue in vivo.
 Targeting ligands can also be conjugated to microbubbles, enabling the
microbubble complex to accumulate selectively in areas of interest. When these
microbubbles are destroyed with low-frequency, high-power ultrasound, the
microvessel walls become permeable, allowing for the drugs or genes contained
within microbubbles to be released into the bloodstream and then delivered to
tissue by convective forces.

Schematic illustration of transient BBB opening. MRgFUS in conjunction with
microbubbles leads to open the BBB by separating the endothelial tight junction,
allowing enhanced delivery of therapeutic agents.

• Several preclinical studies have also demonstrated the successful delivery of anti-
amyloid antibodies and other disease-modifying drugs across the BBB using FUS therapy
for the treatment of Alzheimer’s disease (AD).
 Sonothrombolysis in Ischemic Stroke: As evident from several preclinical studies, HIFU
based thrombolysis has recently emerged as a promising drug-free treatment option.
FUS causes microbubble oscillation, leading to mechanical disruption of the ischemic
clot and improving rates of recanalization.
 The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound
and Systemic tPA (CLOTBUST) trial and the Transcranial Low-Frequency
Ultrasound-Mediated Thrombolysis in Brain Ischemia (TRUMBI) trial with
unfocused, low-frequency (300 kHz) ultrasound have shown some promise, but
with complications such as increased hemorrhage rates.

HIFU-Induced Immunomodulation and Antitumor Immunity
• The release of tumor antigens from necrotic cells and a diverse array of
endogenous signals from HIFU-damaged tumor cells can enhance an
antitumor immune response.
• A HIFU-induced strong antitumor immune response could help to combat
residual tumor cells at the primary lesion site and suppress metastasis.
• Future Applications of tcMRgFUS: Trigeminal Neuralgia and Refractory
seizure.

MRgHIFU parameters in various intracranial disease applications

• MRI-guided laser interstitial thermal therapy (LITT) is the selective ablation of a
lesion or a structure using heat liberated from a laser.
• The laser is selectively applied to the region of the tumor using optical fibers.
LITT uses an Nd:YAG laser with a wavelength of 1064 nm. The tissue penetration
ranges from 2 to 10 mm.
• During 1976-1979, Asher and Heppner performed more than 250 central nervous
system (CNS) lesion ablations after modifying the CO2 laser. In addition, they
coupled the laser to an operating microscope to increase precision.
• A neodymium-doped yttrium aluminum garnet (Nd: YAG) laser was also used
but lacked the precision required for most neurosurgical procedures owing to
poor absorption by CNS tissue, leading to extensive collateral damage.

• Because the Nd:YAG laser is selectively absorbed by blood and blood vessels,
it can be used to occlude small blood vessels.
• The Nd:YAG laser penetrated deeper than the CO2 laser; the depth of
penetration is predictable, and its effect on vascularized tissues is greater than
that of the CO2 laser.
• Recent advances in MRI equipment, thermal imaging sequences, software,
and laser delivery techniques and equipment enabled the prediction and
accurate control of tissue temperatures which renewed the use of the Nd:YAG
laser.

• When the laser hits the tumor, the tumor tissue interacts by absorbing the laser
photons, which are then transformed into thermal energy insider the tumor
tissue. When the temperature of the tissue is between 43-45 °C for more than
10 min, the cancer cells are sensitized to chemotherapy and radiation therapy.
• When the temperatures ranges between 50-80 °C for a shorter amount of time,
tumor necrosis occurs through protein denaturation.
• The damage can be quantified using the Arrhenius thermal dose model; Using
this model, MRI software can generate thermal maps to visualize thermal
changes and monitor tumor necrosis.

• The LITT system comprises a laser system, workstation, and MRI. There are
two clinically U.S.FDA approved LITT systems: Visualase (Visualase, Inc.) and
NeuroBlate (Monteris Medical, Inc.).
• The main differences between the two systems are the laser wavelength,
cooling method, heat production, and distribution pattern.
1. The NeuroBlate system, approved by FDA in 2009, has a 1064nm diode
pulsed laser with a CO2 cooled side firing probe or diffusing tip probe.
2. The Visualase system, approved by the FDA in 2007, has a 980nm diode
continuous laser with a saline cooled diffusing applicator tip. Laser The
laser system comprises a laser light source, laser fibers, applicator, sheath
and diffusion tip.

• MRI images obtained before and during the LITT procedure are sent from
the MRI scanner to a linked workstation.
• It provides real-time thermal maps for monitoring the procedure and
estimates tissue necrosis (c/a magnetic resonance thermometry).
• It also identify the lesion and plan the trajectory for the laser probe.
Navigation software is used for registration and trajectory planning.
• The laser shuts off automatically if the valid temperature range at the tip is
exceeded.

MRI of laser-ablated lesion: Immediate and early stage (0 to 3 months post procedures)
MRI of laser-ablated lesion: Delayed stage (2 weeks to 6 months post procedure)

Immediately after and in the early stages after LITT (0 to 3 months post
procedure). The treated lesion shows a distinct central zone and peripheral
zone surrounded by vasogenic edema.

Summary of studies reporting clinical application of LITT in neurosurgery

Summary of common complications of LITT and recommendation to avoid

Conclusions
 MRgFUS is an emerging technique allowing non-invasive, incision-free transcranial
treatment for a variety of intracranial diseases via thermal and non-thermal
mechanisms.
 Despite improvements that have overcome the initial technical challenges, only very
few clinical trials have thus far been carried out.
 Accurate thermal ablation via MRgHIFU-mediated stereotactic lesioning can be
confirmed with real-time visualization of the target volume with MRI thermometry.
 Emerging preclinical evidence suggests that MRgFUS-mediated BBB opening has
potential to revolutionize the targeted treatment of selected brain diseases, including
brain tumors and neurogenerative disease.

 The principle of LITT is selective ablation of tumor cells by heat and is monitored by
real-time MRI thermometry.
 LITT has a range of applications, such as treatment of glioma, metastases, radiation
necrosis, chronic pain, and epilepsy.
 LITT is used for selected lesions and in selected patients as a safer alternative treatment
option for patients in whom the lesion is not accessible by surgery, in patients who are
not surgical candidates, or in those in whom other standard treatment options have
failed.
 Complications of LITT include hemorrhage, brain edema, thermal injury of adjacent
structures, and treatment failure.

References:
• Rhoton's Cranial Anatomy and Surgical Approaches
• Schmidek and Sweet: Operative Neurosurgical Techniques 6th edition
• Youmans and Winn neurological surgery 8th edition
• Ramamurthi & Tandon's textbook of neurosurgery 3rd edition
• Internet
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