Focused Ultrasound and the Blood-Brain Barrier

When does a barrier protect and when does it hinder? This question is central to the challenge of delivering therapeutics to the brain. For many neuropathologies, the answer is clear: there is a critical need for strategies that can allow clinicians to effectively deliver drugs to the brain. We believe focused ultrasound (FUS) has the potential to be a powerful tool in this quest.

Part of this challenge lies in the unique nature of the blood vessels in the brain. The cells that line these vessels are tightly linked together, creating a complex obstacle—called the blood-brain barrier (BBB)—that prevents the vast majority of drugs from entering the brain from the bloodstream. Throughout the years, several strategies of bypassing the BBB have been used, with limited success and many adverse effects. These range from directly inserting a needle into the brain for injections, to the administration of hyperosmotic solutions, which create gaps between cells in the BBB throughout a large volume.

In 1956, Bakay et al successfully ablated brain tumors using high-intensity FUS. In doing so, he observed that the permeability of the BBB was enhanced in the periphery of the ablated tissue. While this was exciting news for BBB enthusiasts, the necessity of damaging tissue in the process of opening the BBB was clearly unacceptable. Several decades later, this approach was successfully modified by administering microbubbles, an ultrasound contrast agent, before sonicating (Hynynen et al 2001). This made it possible to use much lower power levels to produce the desired increase in BBB permeability, thereby avoiding brain damage. By adjusting where the ultrasound energy is focused, specific brain regions can be targeted. For a few hours after treatment, drugs can be administered intravenously, bypass the BBB, and enter the neural tissue in the targeted areas.

Over the past 16 years, many preclinical studies have used FUS to increase the permeability of the BBB, delivering a wide range of therapeutic agents to the brain, from chemotherapeutics and viruses, to antibodies and stem cells. Efficacy has been demonstrated in models of Alzheimer’s disease, Parkinson’s, brain tumors, and others. Moreover, the safety of using FUS to increase BBB permeability has been tested in every commonly used laboratory animal.

The flexibility of FUS as a tool for treating neuropathologies may go beyond the delivery of drugs to the brain. Recently, FUS was shown to reduce the amount of β-amyloid plaques and improve memory deficits in the brains of transgenic mice (Burgess et al 2014, Leinenga and Gotz 2015, Jordao et al 2013).

The success of these preclinical trials has led to the initiation of 3 human trials. Two of these trials are testing the safety of increasing the permeability of the BBB in brain tumors for chemotherapy delivery, and the third is evaluating the safety and initial effectiveness of FUS in patients with early stage Alzheimer’s disease. The rapid movement towards clinical testing has been accompanied by impressive technological advancements in the equipment used to focus ultrasound through the human skull. Arrays of thousands of ultrasound transducers can be controlled to produce sound waves that travel through bone and brain, and arrive at precisely the same time in the targeted location. The sound produced by vibrating microbubbles can be detected and used to ensure the treatment is progressing as planned.

If the barrier to drug delivery to the brain can be bridged by FUS, the development of effective treatment strategies for a wide range of neuropathologies will expand. Given the clear need for such treatments and the flexibility of FUS, the recent push toward clinical testing is encouraging. The coming years will be critical in demonstrating the safety of the technique and spreading awareness. Success in these regards will go a long way in establishing FUS as an impactful tool in the fight against inflictions of the central nervous system.

 

If you deliver drugs to the brain, how do you do so? Have you found a way to permeate the blood-brain barrier using ultrasound? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Charissa Poon and Dallan McMahon are PhD students at the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and the department of Medical Biophysics, University of Toronto, respectively.

Kullervo Hynynen, PhD, is professor at the department of Medical Biophysics and the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and a senior scientist at Sunnybrook Research Institute in Toronto, Canada.

The National Ultrasound Interest Group (NUSIG)

The National Ultrasound Interest Group (NUSIG) is a student-led organization founded in 2014 to promote ultrasound in undergraduate medical education. You may know us as the force behind planning national level events like SonoSlam. The bulk of NUSIG’s work, however, is sharing education and leadership resources between Ultrasound Interest Groups (USIGs) across the country. Each of the five regional representatives contact medical schools in their areas to exchange ideas, plan co-sponsored events, and see how NUSIG can assist them in evangelizing ultrasound.

SonoSlam_organizers

NUSIG provides everything from information on getting equipment and funding, to original educational content. Our podcast on iTunes (quickly closing on the 1,000 download mark) currently features a journal club series. Each episode is hosted by a different school evaluating an ultrasound-related article.

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Our next series is how to plan an Ultrafest, where we interview schools experienced in putting on these events. Our hope is that these USIGs can learn from each other, and other schools might be inspired to start their own UltraFest once it’s been laid out how. In the future, we aim to collect medical student level ultrasound lectures from across the country and publish them for anyone to view. Our vision is to serve as a central repository for the best medical student educational content available. Lastly, our twitter feed regularly features current ultrasound research articles, and retweets outstanding free open access medical education content.

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If you want to learn more about us or get involved, check out our website at www.nationalusig.com, and follow us on twitter and Facebook @NtlUSIG. You can find us on iTunes by searching for “NUSIG podcast.”

Are you a member of the National Ultrasound Interest Group? Did you attend this year’s SonoSlam? If so, share your thoughts and feedback. Comment below or let us know on Twitter: @AIUM_Ultrasound.

Mat Goebel is in charge of Social Media for the National Ultrasound Interest Group and is a medical student at University of California at San Diego.

Why SonoStuff.com?

Three reasons:

As a co-director of technology enabled active learning (TEAL) at the UC Davis school of medicine I incorporate important technologies into the medical curriculum, which has primarily been point of care ultrasound (POCUS). Ultrasound is an incredible medical education tool and curriculum integration tool. It can be used to teach, reinforce, and expand lessons in anatomy, physiology, pathology, physical exam, and the list goes on.

I knew there was a better way to teach medical students thaschick_photo_1n standing in front of the classroom and giving a lecture. Student’s need to learn hands-on, spatial reasoning, and critical thinking skills to become excellent physicians. Teaching clinically relevant topics with ultrasound in small groups with individualized instruction
is the best strategy. I needed to flip the classroom.

I started by creating online lectures for an introduction to ultrasound lecture, thoracic anatomy, and abdominal anatomy:

Introduction to Ultrasound, POCUS

FAST Focused Assessment of Sonography in Trauma Part 1

FAST Focused Assessment of Sonography in Trauma Part 2

Aorta Exam AAA POCUS

Introduction in Cardiac Ultrasound POCUS

Topics quickly grew in scope and depth. I initially housed my lectures on YouTube and emailed them out to students before the ultrasound laboratory sessions. However, I wanted a platform that allowed for improved organization and showcasing. I needed a single oschick_photo_2nline resource they could go to to find those materials I was making specific to their medical curriculum.

https://www.youtube.com/channel/UCOhSjAZJnKpo8pP7ypvKDsw

Around the same time, during a weekly ultrasound quality assurance session in my emergency department I realized we were reviewing hundreds of scans each month and the reviewers were the only ones benefiting educationally from the process. Many cases were unique and important for education and patient care.

We began providing more feedback to our emergency sonographers and I decided I could use the same software I was using to develop material for the school of schick_photo_3medicine to highlight the most significant contributions to POCUS in our department every week. I quickly realized I needed a resource to house all these videos, one that anyone in my department could refer to when needed. The most efficient and creative method was to start a blog. I was discussing the project and possible names for the blog with colleagues and Dr. Sarah Medeiros said, “sounds like it’s a bunch of ultrasound stuff”. https://sonostuff.com was born.

I owe a great deal to free and open access to medical education or FOAMed. I was hungry for more POCUS education in residency and the ultrasoundpodcast.com came to the rescue. I became a local expert as a resident and even traveled to Tanzania to teach POCUS.

schick_photo_4I primarily began www.SonoStuff.com to organize and share with my department of emergency medicine and school of medicine, but it grew into a contribution to the growing body of amazing education resources that is FOAMed. I now use it as a resource in my global development work along with the many other FOAMed resources.

The work we all do in FOAMed, including AIUM’s the Scan, are an incredible and necessary resource. I have read the textbooks and attended the lectures, but I would not be where I am without FOAMed. I know all or most of those contributing to FOAMed do it out of love for education and patient care, without reimbursement or time off. Thank you to the many high-quality contributors and I am proud to play a small part in the FOAMed movement.schick_photo_5

Michael Schick, DO, MA, is Assistant Professor of Emergency Medicine at UC Davis Medical Center and Co-Director of Technology Enabled Active Learning, UC Davis School of Medicine. He is creator of www.sonostuff.com and can be reached on Twitter: ultrasoundstuff.

16 Years and Counting

Every year I look forward to February for a number of reasons. One is that I know spring in North Carolina is just around the corner. Another is that I know I will be escaping to Florida for a long weekend to attend my favorite ultrasound course, the AIUM Advanced Ultrasound Seminar: OB/GYN.

NC spring

Spring in North Carolina from http://www.visitnc.com.

I am a general OB/GYN and have been in practice in Durham, North Carolina, since 1998. I chose my current position because of its location, my family, and the chance to continue teaching OB/GYN residents.

In my early years as a resident educator, it was easy to teach the residents. But as time has passed and I have gotten busier, it seems that the residents have gotten smarter. They know about changes in protocols, new medications, new technology, and more. Therefore it is important for me to continue to educate myself through reading, listening, and attending courses.

I have always had an interest in ultrasound and received a great introduction to scanning as a resident at the Medial University of South Carolina in Charleston. My program directors put a strong emphasis on using ultrasound as a tool for caring for OB and GYN patients. So I probably have an interest in ultrasound beyond most generalists and I have enjoyed coming to the AIUM course since 1999.

One of the great things about the course is that it has adapted so well with the times. I remember the first 3D and 4D imaging that this course covered and how many questions people had about how they would be used. I remember discussions about whether an anatomy scan would be worthwhile and if insurance carriers would pay for it.

In the early years of the course there would be many long lectures about the frequency of X, the p values of certain markers, the RR of this thing or that thing, unreadable tables and presentations, and more. Recently, however, the course has become more evidence-based and clinically relevant for all participants. This has made the course even more worthwhile and shows that the enthusiastic and collegial faculty have dedicated their lives to medical ultrasound.

As we begin to move into fall and then winter, I start to long for February—for obvious reasons. I hope to see you in Florida.

Is there anything you have attended for more than a decade? What made it special? Have questions about the AIUM OB Course? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Frank Frenduto, M.D., is a managing partner and a board member for the Women’s Health Alliance in Durham, NC. His special interests are high-risk pregnancies, laparoscopic surgery, and gynecologic ultrasound.