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Sunnybrook doctor first to perform blood-brain barrier procedure using focused ultrasound waves

Wency Leung

Dr. Todd Mainprize leaned over and peered through his wire-rim glasses at a computer screen showing the brain scan of his brain cancer patient, Bonny Hall, who lay in a magnetic resonance imaging machine (MRI) in the adjacent room.

“This has gone exactly the way we hoped,” the neurosurgeon said, crossing his arms.

He smiled and nodded. His experimental procedure had been a success.

Here in the S-wing of Toronto’s Sunnybrook Hospital, Mainprize and his research team accomplished on Thursday what no one in the world has ever done before: Using focused ultrasound waves, they have opened the human blood-brain barrier, paving the way for future treatment of an array of currently impossible or hard-to cure-illnesses – from brain cancer to certain forms of depression, stroke, Parkinson’s disease and Alzheimer’s disease.

The blood-brain barrier is an extremely selective filter that Mainprize likens to cling film, which coats the blood vessels in the brain, preventing harmful substances in the bloodstream from passing through. Though its function is to protect the brain, this barrier has limited doctors’ ability to treat diseases, such as tumours, using drugs like chemotherapy to target specific areas of the brain.

By successfully opening the blood-brain barrier, “that will allow us to use many, many more medications in the brain than we can currently use,” said Dr. Kullervo Hynynen, director of physical sciences at Sunnybrook Health Sciences Centre, who developed the technology used in the experimental procedure.

Hynynen said about 98 per cent of molecules that could potentially be used for brain treatments cannot currently be used because they cannot get through the blood-brain barrier. This includes antibodies, which in animal studies have been shown to remove brain plaques involved in Alzheimer’s disease, or stem cells, which could be used to treat stroke patients. Thus, he says, the ability to penetrate the blood-brain barrier will “revolutionize” brain medicine.

Previous methods of circumventing this cling film-like coating have been inconsistent and difficult to control, or invasive, such as inserting microcatheters through the skull to inject drugs directly into the brain. But by using focused ultrasound, the Toronto researchers have demonstrated a way of breaching the blood-brain barrier that is non-invasive, selective (or contained within a specific area), reversible and, the researchers believe, safe.

Here’s how it works: Medication is first introduced into a patient’s bloodstream – in this case, a chemotherapy drug called liposomal doxorubicin. Next, microbubbles, or tiny air bubbles, which are typically used as a contrast medium to enhance visibility in ultrasound imaging, are intravenously delivered into the bloodstream. Using MRI to locate their target area, doctors then send focused ultrasound waves, causing the microbubbles in the brain’s capillaries to expand and contract. This expansion and contraction creates little tears in the cling film-like layer of endothelial cells of the blood-brain barrier, allowing the drug molecules to pass through into the brain to the targeted areas.

The microbubbles themselves do not cross the barrier and disappear within minutes, passing through the lungs. Meanwhile, the tiny tears in the blood-brain barrier close up again between an estimated eight to 12 hours.

The appearance of bright spots, the size of pinkie fingerprints, on the MRI images of Bonny Hall’s brain allowed Mainprize to immediately see that he had accomplished what he set out to do.

“This white spot and this white spot is where we opened the blood-brain barrier,” he said, pointing to the computer screen.

In the days previous, Hall, 56, of Tiny, Ont., was anxious yet eager to be the first patient to undergo the procedure.

“I think that someone has to go first,” Hall said, noting she empathized with the first patient to be treated with penicillin. “I kind of feel that way.”

Hall discovered her brain tumour eight years ago, though doctors at the time found it was benign. About five months ago, however, they found it had become cancerous and had grown to about five centimetres by three centimetres – about the size of a miniature candy bar – on the right side of her head, just above her ear.

Although the tumour caused no pain, Hall experienced what she described as “little blips,” or small 10– to 20-second seizures during which she would feel “spaced out.”

On the morning of the procedure, as the chemotherapy drug dripped into her arm, Hall said she was looking forward to getting her life back to normal.

“Seeing people here really suffer,” she said of the other patients at the hospital’s cancer centre, “I really do hope this will work for them some day.”

The following morning, after determining it possible to open the blood-brain barrier, Mainprize performed traditional surgery to remove Hall’s tumour. He carefully cut open a hand-sized flap of skin and muscle and removed part of her skull, extracting a white mass of tissue. The tumour will be analyzed over the next week to determine how much of the chemotherapy effectively passed through the blood-brain barrier.

The next step for the research team will be to repeat the focused ultrasound procedure on nine additional patients to show it can be replicated safely.

The possibilities for future research, Mainprize said, are enormous. “With … this technique, you can selectively open almost anywhere in the brain and deliver whatever you want,” he said. “Essentially, whatever you can think of is a potential study that may help in the future.”