Beyond Imaging: The Amazing Power of Ultrasound: from Destroying Tumors to Healing the Brain, and More!

By Victor Frenkel

When most of us hear the word ultrasound, we typically think of
diagnostic imaging; especially in regard to its use in obstetrics.
Ultrasound, however, can also be used for a wide variety of
therapeutic applications, which the author has chosen as the
theme of this book.
The book begins with a primer on sound waves, which are followed
with some basics on imaging. Next are descriptions of the evolving
technology, with a specific emphasis on medical applications.
Examples are given of the different procedures that are carried
out using sophisticated, non-invasive, image-guided devices. Each
procedure is carefully explained with the help of many detailed
illustrations. Examples of these include the destruction of tumors
deep within the body using highly focused ultrasound beams.
Especially impressive are the treatments that are guided with realtime
MRI. One in particular is employed for opening barriers in
the brain to facilitate the delivery of a range of agents for treating
conditions such as Alzheimer’s disease.
For almost thirty years, Victor Frenkel has worked as a teacher,
mentor, and research scientist at medical schools, engineering
departments, and government institutions. Along the way he made
his own contributions in the field of therapeutic ultrasound. These
include the development of novel treatment protocols, and also
designing and building the devices used to carry them out. Told
with easy-to-follow language, including key historical and cultural
perspectives, this book is meant for anyone who loves cutting edge
technology, especially pertaining to medical treatments.

• Language: English
• Publisher: Archway Publishing
• Release date: Jun 24, 2024
• ISBN: 9781665760270

Victor Frenkel

Victor Frenkel, PhD (Author) was born in Montreal, Canada in 1960. After receiving an associate degree in physics, he moved to Israel. For many years, he lived on a kibbutz in the southern desert, served in the military, and completed his undergraduate and graduate studies. He first began working with ultrasound during his dissertation research at the Technion, Israel Institute of Technology. He came to Baltimore for a postdoctoral fellowship in 1999 at the University of Maryland Biotechnology Institute. He then moved on to work as a staff scientist at the National Institutes of Health, applying his expertise and knowledge for translational applications in human health. For three years, he taught biomedical engineering to undergraduate and graduate students at Catholic University of America in Washington, DC. After that, he accepted a position as Associate Professor of Radiology at the University of Maryland School of Medicine in Baltimore and took on the role of founding director of the Translational Focused Ultrasound Research program. He is currently on the faculty at the Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine. For almost thirty years, he has investigated how ultrasound can be used to enhance the delivery of therapeutics in various treatment applications. He has published over one hundred peer-reviewed original research articles, invited review papers, conference proceedings, editorials, book chapters, and books. He lives in central Maryland with his two teenage sons and his twelve-year-old rescue lab, Grover.

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Copyright © 2024 Victor Frenkel.

All rights reserved. No part of this book may be used or reproduced by any means, graphic, electronic, or mechanical, including photocopying, recording, taping or by any information storage retrieval system without the written permission of the author except in the case of brief quotations embodied in critical articles and reviews.

This book is a work of non-fiction. Unless otherwise noted, the author and the publisher make no explicit guarantees as to the accuracy of the information contained in this book and in some cases, names of people and places have been altered to protect their privacy.

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Because of the dynamic nature of the Internet, any web addresses or links contained in this book may have changed since publication and may no longer be valid. The views expressed in this work are solely those of the author and do not necessarily reflect the views of the publisher, and the publisher hereby disclaims any responsibility for them.

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ISBN: 978-1-6657-6026-3 (sc)

ISBN: 978-1-6657-6027-0 (e)

Library of Congress Control Number: 2024910175

Archway Publishing rev. date: 06/12/2024

CONTENTS

Introduction

1Hey, Stop, What’s That Sound?

2Dolphins, Bats, and Other Creatures That Use Echoes To See

3From Sound Waves to Electrical Signals and Back Again

4How Fast Was That Fastball?

5Using Sound to Peer inside Your Body

6Healing with Sound

7Things Are Definitely Heating Up!

8Seek and Destroy

9Tiny Bubbles…in Your Brain?

10You’re Bursting My Bubble

11On Your Nerves

12Sterilization, Catalyzation, and Testing of

Auto Parts

13Closing Thoughts

Acknowledgments

Glossary

Further Reading

The Team

This book is

dedicated to the memory of

Rao Gullapalli

a mentor and friend, and one of the kindest and

most generous individuals I have ever known.

Also by Victor Frenkel

Therapeutic Ultrasound: Mechanisms to Applications

Walks with Grover: Treks in the Neighborhood with Our Loveable Lab Rescue

Not everything is black and white.

And there are more than fifty shades of gray.

Just ask a sonographer.

—Anonymous

Author’s Note

As I worked on the manuscript for this book, I would occasionally recall the earliest days with my dissertation advisor, Eitan Kimmel (Professor Emeritus of Biomedical Engineering at the Technion, Israel Institute of Technology), who guided me as I began my career as a research scientist in the exciting and emerging field of therapeutic ultrasound. Of all the memories I have of Eitan, few are more pleasant than the two of us sitting outside at a café, enjoying a meal or perhaps just having coffee, in one of the many picturesque neighborhoods of the coastal city of Haifa. It was in venues like these where Eitan would typically insist on meeting to review my newest data and discuss the approach we should take for my next experiment. Sometimes we’d change the setting and instead partake in a beer (or two) down at the beach on a pleasant afternoon, with the shimmering waters of the Mediterranean extending endlessly away from us. Those were some happy and rewarding times, where we forged new inroads into understanding how ultrasound was generating the effects we were observing.

Over the years, Eitan went on to propose novel mechanisms for ultrasound-induced biological effects, important for applications in drug delivery, neuromodulation, and mechanotransduction, among others. His ideas on these topics were often bold; he stubbornly refused to accept long-standing conventions—ultimately refuting a number of these to redefine our understanding of previously reported phenomena. Eitan and I did not always agree, but ultimately, we understood each other. Most importantly, we always enjoyed each other’s company. In the end, I think we did some really good work together. I owe him much gratitude for taking me on as a graduate student in his lab, my lack of a formal engineering background notwithstanding. My work with Eitan kick started my career in ultrasound research, which I’m happy to say that I continue to enjoy. Three decades later, I am no less grateful to him.

INTRODUCTION

A man arrives at a university hospital. He suffers from essential tremor (ET), a debilitating neurological disorder characterized by involuntary and rhythmic shaking during voluntary movements, such as lifting a cup to drink. The MRI scanner in which he is placed looks like any other scanner you’d find in a hospital or clinical setting. There is, however, one major difference. At the end of the patient table, closer to the bore, is a device that looks like an oversized helmet. The inside surface of the device is lined with a sophisticated array of ultrasound transducers. As he gets up on the table, a technologist places the device over his shaven head, and couples it to his scalp with a flexible water jacket.

The incisionless surgical procedure that this patient is about to undergo is not science fiction. It is also not a depiction of what visionaries are saying is inevitable for medical science in the near or distant future. Our patient is about to undergo a revolutionary procedure that has been in development for almost a century.

Back to our device, which admittedly looks more like something you would see in a B-rated science fiction movie. One of the unique features of the ultrasound beams created by each of the more than 1000 individual miniature transducers is that they’re incapable of creating any meaningful effects on their own. At the treatment target in the patient’s brain, however, where the beams all meet, the concentration of acoustic energy is so great that it can raise the temperature of the tissue and accurately destroy it within just a few seconds. This focal point, just millimeters in diameter, can also be electronically steered and accurately positioned at almost any location within the brain. In this particular treatment, the target is the ventral intermediate nucleus (or VIM), a discrete region within the thalamus, deep inside the center of the brain. Destroying the VIM with ultrasound-induced heat will effectively eliminate the brain signals that are the source of the patient’s tremor.

The patient is now inside the scanner. After a sequence of well-performed safety checks, he will soon be treated. What truly can be characterized as nothing short of amazing is that the only instrument the neurosurgeon employs to perform this noninvasive surgery is a computer mouse, which he uses at a modified MRI console. Also remarkable is that the surgeon is sitting in an adjacent room, about fifteen feet or so away from the patient and the scanner. The door between them is hermetically sealed and they communicate through a live-feed video.

After a routine MRI scan is performed to identify the target, the patient is ready to be treated. A number of final adjustments are made on the graphic user interface, and then these are followed by a click of the mouse. Hundreds of the miniature ultrasound transducers are simultaneously activated, creating a well-focused ultrasound (FUS) beam at the VIM. Within seconds, the tissue begins to heat up.

The overall procedure involves a series of short duration treatments (typically ten to fifteen seconds), where each time a greater amount of energy is applied. The goal is to keep treating until all the neurons in the VIM are destroyed. This occurs by coagulative necrosis, where the proteins are denatured by the heating process.¹ Throughout the treatments, a second, specialized MRI scan is employed which enables the temperature at the target to be monitored. This informs the neurosurgeon that an effective thermal dose² has been applied.

The treatments are supervised by a neuroradiologist as well as a neurologist³ who specializes in movement disorders. Whereas the former ensures that the treatments are performed accurately and safely, it is the neurologist who ultimately validates their success. Following each successive FUS treatment, he enters the scanner room and performs a series of simple evaluations. He asks the patient to hold a cup of water and also to trace a line on a spiral maze. Once these are done, he hands the results of the current maze test to one of the techs, who then posts it with the preceding ones on the back wall of the console room. I have personally witnessed a number of these treatments, and each time I am amazed as if seeing them for the first time. Following the maze results in chronological order, you can easily observe the gradual mitigation in the patient’s tremor with each successive treatment. Once the treatment has been completed, where no further improvement is detected (this typically takes an hour or so), the patient is taken out of the scanner and, after a short post-op monitoring period, she or he is free to go home.

001_a_lbj23.jpg

A representative example of the stark improvement in an ET patient’s ability to complete the spiral maze test after receiving a complete noninvasive FUS treatment.

Another one of the debilitating manifestations of ET that affects a patient’s quality of life is the inability to write in a legible manner. In order to further evaluate the immediate benefits of the FUS treatment, our patient was asked to write a simple sentence before and after receiving the treatment. The stark difference in improvement in his handwriting afterward—essentially now rendering his writing legible (and in addition to the clearly less visible extent of his tremor)—is an undeniable testament to the success of the procedure.

The FUS treatments for ET, which represent the pinnacle of the many therapeutic ultrasound (TUS) procedures available today, were first performed more than a decade ago. They were FDA-approved in 2016 and have since been adapted for a number of other neurological disorders where, similar to ET, the target for treatment can be accurately defined. This includes Parkinson’s disease and other indications, both in and outside of the brain.⁴ The ability to effectively perform these treatments arose from combining two separate but equally important technologies: high-resolution, soft tissue imaging with MRI, and the sophisticated arrays of ultrasound transducers for accurately and noninvasively focusing an ultrasound beam inside the body.

Today, you can receive a FUS treatment for ET in almost every state in the United States and also be reimbursed by most health care plans. Within the first two years since the first procedure was performed, more than 1,000 patients were treated for ET. That number only continues to grow as more treatment locations are established all around the world. Currently, at the time of writing this book, the number of patients who have been treated is closer to 10,000.

The use of MRI, as you just learned, is a mainstay of many of the existing FUS applications employed today. It is currently the gold standard for guidance and for validating the safety and efficacy of these high-tech treatments. MRI and other technologies (including sophisticated arrays of ultrasound transducers), as well as the applications that they are used for, are the theme of this book. I have humbly endeavored to document and describe them in a way that I hope makes them both interesting and also easy to understand, and without having to dumb down the science too much.

Throughout the chapters, and after a primer on sound waves, I describe the emergence of ultrasound, and then follow its development over a wide range of medical (and some non-medical) applications. This book is not intended to be an authoritative text on ultrasound, but instead an introduction for those of you who have always been more than a little curious about the technology. This curiosity may have been sparked when seeing the first sonogram of your soon-to-be born daughter or son. Or perhaps when reading Tom Clancy’s fabulous first novel, The Hunt for Red October—one of my favorites, by the way, in that particular genre. The story often circles back to the savvy sonar tech, Petty Officer Jones, aboard the US naval submarine Dallas. I personally was fascinated by his descriptions of the sounds emanating from a new class of Russian submarine. He listens to them with some very sophisticated ultrasound technology (some of which you’ll learn about in this book) as he attempts to decipher those odd sounds and noises and how they’re created.

As you make your way through this book, you’ll learn about the impressive advancements still being made in therapeutic ultrasound. Many of these, I should note, have taken place during the last few decades since I, myself, began working in the field. In the first few chapters, I get some basic theory out of the way, using simple, linear equations and figures to explain easy and straightforward concepts. The majority of the book, you’ll be glad to hear, is about the very cool applications and the cutting-edge devices used to carry them out for treating some very important diseases and conditions.

If, by chance, when you’re done reading this book, you’re ready to learn even more about ultrasound, I’ve provided some additional references for peer-reviewed journal articles at the end of this book. I have also included a detailed glossary to help you keep track of all the terms and nerdy acronyms.

Overall, I would like to say that I sincerely hope you’ll enjoy reading this book at least as much as I did getting it into print.

One

HEY, STOP, WHAT’S THAT SOUND?

⁵

Most of us have heard the centuries old question posed by philosophers: if a tree falls in the forest and no one is there to hear it, does it still make a sound?

According to the physical definition of what sound is, it would seem that it doesn’t really matter whether someone heard it or not. Sound, in the pure physical sense, is defined as the compression and rarefaction (opposite of compression; see Figure 1.1) in a medium (in this case, air) resulting from a physical disturbance. In the above case, this would be the tree in the forest hitting the ground. If the sound wave propagates in the frequency range of 20 Hz to 20,000 Hz⁶ (the average range discernable or audible to humans),⁷ then the answer is indeed easy: yes, it did.

The term sound, according to this definition, is a pure and objective physical phenomenon. The philosophical argument becomes relevant if we then consider the ear as a device that measures, or senses, these mechanical changes, which are then interpreted in our brains as sound.⁸ If that is the case, and no