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.

A Personal Vignette From the ’60s and ’70s

In the mid to late 1960s, neurologic sonography at the Neurological Institute at Columbia Presbyterian Medical Center was being performed by Lewis B. Grossman, MD, and Georgina Wodraska within the Neuroradiology section. I had developed a friendship with Dr Grossman in part due to a similarity in our family medical histories of early demise due to coronary artery disease. We had discussed this one evening and the following morning Dr Grossman did not show up for work and had died of a heart attack.

Two other life changing events happened later that day. First, Georgina Wodraska informed me that I was to be the new head of Neurologic Sonography, much to my astonishment and with significant doubt as my exposure to sonography was extremely limited and I had significant doubt regarding its capabilities beyond that of detecting midline displacements of the brain. Second, that afternoon I started on a physical activity regimen that progressed over time from walking to long distance running (and now in my 80s back to walking).

20170521_191539

Dr Tenner and his daughter, Sallye,
wrapped in mylar while waiting out a flash storm
in a Utah canyon alcove in May 2017.
Sallye, ARDMSRVT, is a sonographer at
Bay Pines Veterans Health Center in St. Petersburg, Florida.

In the mid to late ’60s, the neuroradiologists’ armamentarium consisted of an x-ray tube for radiographs and a needle. The needle was placed directly into an artery (carotid, vertebral, brachial) or into the subarachnoid space to perform arteriography or pneumoencephalography, respectively. To better understand the source of brain echo reflections, ultrasound using a 1.5-mhz transducer using the thin squamosa of the temporal bone as a window was done while vigorously flushing the carotid needle with a bolus of normal saline, which caused an amplification of the echo reflections within the intracerebral arterial vasculature. We also realized that lesions within the brain that were within the field of view of insonation may also be seen. Although the acoustic impedance of normal brain tissue and brain tumors have little difference ex vivo, there are significant differences in vivo due to 1) the basic angio architecture of the tumor, which is distended in vivo and collapsed ex vivo, and 2) surrounding brain edema and areas of liquefaction necrosis and cyst formation within the tumor. Hydrocephalus, arterio-venous malformations, giant aneurysms, intra and extra axial tumors, and some congenital malformations were also detectable.

A mode neurosonography is heavily operator-dependent and required an in-depth knowledge of neuroanatomy and neuropathology. Training a sonographer required a dedicated teacher and a highly motivated and dedicated student.

In 1971 I headed the section of Neuroradiology at SUNY Downstate Medical Center where a sonography school was formed and we were able to attract a student, Larry Waldroup, who had a keen interest in neurosonography. He subsequently took a position with Barry Goldberg, MD, and had a most productive and distinguished career.

Our experience with neurosonography resulted in the publication of a textbook “Diagnostic Ultrasound in Neurology” in 1975. This was also the time that computer tomography was becoming widely available. Needless to say the timing of the publication and the introduction of computed tomography, a main stay of diagnostic radiology, did not bode well for the sales of the textbook. Although, the Preface of the textbook states “in recent years there has been striking progress in the scope and pace of ultrasonic examinations and methodology,” which is still true today. Ultrasound of the brain has now also found a mainstay nitch in neonatal, intraoperative neurosonography, and transcranial Doppler.

 

Do you have any stories to tell of the evolution of ultrasound? Who are your mentors? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Dr Michael Tenner is a Professor of Radiology and Neurosurgery and Professor and Director of Neuroradiology at New York Medical College in Valhalla, New York.