Brain Mental health Patient stories Sunnybrook Magazine – Fall 2018

Investigating use of focused ultrasound to treat major depression


(Photography by Kevin Van Paassen)

Sunnybrook researchers are investigating exciting new techniques to harness the power of ultrasound waves to treat depression

For as long as she can remember, Linda Bohnen has suffered from debilitating anxiety and depression. Despite trying talk therapy, numerous medications and even electroconvulsive therapy, nothing worked for long. Her feelings of hopelessness, overwhelming sadness and numbness always returned.

“It was really limiting my life. It was hard on my husband, on my daughter and on me,” says Linda.

The anxiety also made it difficult to leave the house. The only exception was taking her Siberian husky mix, Stoli, out for a walk.

Then Dr. Anthony Levitt, chief of Sunnybrook’s Hurvitz Brain Sciences Program and Linda’s psychiatrist for the past 30 years, told her about an intriguing new medical trial he was leading.

For the first time, Sunnybrook researchers were analyzing the safety and effectiveness of using MRI-guided focused ultrasound to help patients with treatment-resistant major depression.

As someone with highly resistant mood disorders – something that 2 per cent of the Canadian population suffers from – Linda seemed like a good candidate.

She would be the first-ever patient in North America to receive this game-changing procedure for treatment-resistant major depression – incision-free brain surgery done in real time (the only other case took place in South Korea).

“I felt that I had nothing to lose,” says Linda. “I had tried everything else, so why not?”

Same but different

The fundamentals of the procedure have actually been around for more than 50 years and have a long history of success.

“In the old days, it used to be done neurosurgically,” notes Dr. Levitt. Surgeons would create an incision in the scalp and skull, he explains, before drilling a hole in order to reach the area of the brain that would then be cauterized. Unfortunately, that meant destroying some healthy brain tissue along the way, too.

“And if you got it wrong, you’d have to go back and get it right,” he says. “There was no way of checking at the moment you were doing it.”

With MRI-guided focused ultrasound, however, a special helmet trains beams of ultrasound on one specific region of the brain called the anterior limb of the internal capsule – a pathway known to be active in depression. This “highway” connects the frontal lobes to the emotional centres of the brain, including the amygdala and hippocampus.

Fortunately, individual ultrasound waves pass through living tissue quite harmlessly. Where they converge, however, the beams create heat and form a lesion on a precisely targeted area of the brain.

“There’s no incision,” Dr. Levitt points out. “We don’t destroy healthy tissue on the way to the lesion because the beams of ultrasound don’t destroy anything except where they meet.”

Dr. Nir Lipsman – a neurosurgeon and principal investigator of the trial and director of the Harquail Centre for Neuromodulation at Sunnybrook – likens the technique to using a magnifying glass to concentrate light and create a pinprick point of heat “except we’re using this ultrasound system to concentrate sound energy,” he explains. “This is an old procedure done in a new way.”

Can focused ultrasound open a therapeutic window to treat ALS?

The disease

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a devastating neurodegenerative ailment that progresses rapidly and is fatal. “It’s definitely up there as one of the worst diseases to afflict humans,” says neurologist Dr. Lorne Zinman, director of Sunnybrook’s ALS clinic – the largest of its kind in Canada – and an associate scientist in the Hurvitz Brain Sciences Research Program.

“Patients gradually lose their ability to move their arms and legs, to speak, swallow and breathe – all while their minds remain sharp,” says Dr. Zinman. ALS is relentless in its attack on the approximately 3,000 Canadians with the disease. “Patients with ALS witness a progressive loss of motor function and, although we do not yet have any medications to stop the disease, hope is on the horizon,” says Dr. Zinman.

The research

In a world-first, Dr. Zinman and a team of Sunnybrook researchers are investigating the safety, tolerability and feasibility of opening the blood- brain barrier using low-intensity focused ultrasound in patients with ALS. This barrier naturally protects the brain by limiting the passage of molecules. This keeps the brain safe, but it also keeps out potentially beneficial therapeutic agents.

In this phase 1 trial, eight patients will have their blood-brain barriers temporarily opened over the motor cortex. This is the part of the brain that controls movement and where ALS may start. The patients will be injected with micro-bubbles – think minuscule balloons floating around in the bloodstream – and when focused ultrasound waves hit the bubbles, they expand and contract, temporarily opening the blood-brain barrier.

The takeaway

By safely opening the blood-brain barrier of the motor cortex, Sunnybrook researchers are creating a unique therapeutic window for medications and biotherapeutics, like antibodies, viruses and stem cells, to pass through.

These novel interventions may help to protect the damaged motor neurons of patients with ALS and slow the progression of this terminal disease. The first patient underwent the procedure in April 2018.

Surgery at the click of a button

There are other benefits of guided ultrasound. Because the procedure is done inside an MRI scanner, Dr. Lipsman can see exactly where he wants to create the lesion, using computer-generated algorithms to create 3-D images in real time. He can even extend and change the shape of the lesion if needed, right then and there – all with the click of a button.

Or, as Dr. Levitt calls it, “surgery by mouse.”

What’s more, the risk of bleeding is quite low. Because the surgeons actually control the heat, they can test a specific area of the brain first at a lower heat to be sure only that portion is affected without any movement or sensation issues. “With ultrasound, we can do a test beforehand to make sure we have the right area,” says Dr. Levitt.

Once they have the all clear from the patient, the surgeons can go ahead and increase the temperature.

Two decades of development

This particular phase 1 trial was possible because of the work of Dr. Kullervo Hynynen, director of physical sciences at Sunnybrook Research Institute.

For almost two decades, Dr. Hynynen worked with industry partner INSIGHTEC to develop the technology.

On the day of her procedure, Linda wore Dr. Hynynen’s special focused ultrasound technology helmet, which looks a bit like an old-fashioned hairdryer. It actually contains 1,000 transducers, which convert electrical energy into sound energy. It also has a membrane that fits tightly against Linda’s now-shaved head, with a space where water circulates between the transducers and her skull to reduce the sensation of heat.

This isn’t the first time the game-changing helmet has been used.

Focused ultrasound was successfully tested in a world-first trial at Sunnybrook and other medical centres for patients with essential tremor, a nervous system disorder causing involuntary shaking. This success led to Health Canada and FDA approvals in 2016.

Dr. Hynynen recalls seeing a dramatic decrease inpatients’ tremors and shakes once the ultrasound hit the right location. Even so, his team of engineers and clinicians faced many obstacles on the way to success. “For about 50 years, people thought it was impossible to use ultrasound in the brain,” he says.

Tell that to Linda. Other than experiencing some heat in her head during the procedure, and minor headaches for several weeks following the procedure, she considers herself very lucky. Slowly, she noticed her mood was lifting.

“There have been more good days than bad,” explains Linda. Overall, she’s also noticed that she is more talkative and energetic. While Linda continues to take medication for her depression, some dosages have been reduced for the first time in decades.

“They had good experiences using ultrasound on patients with other [conditions],” she says. “I had a lot of hope.”

One piece of the puzzle

Dr. Levitt knows that addressing treatment-resistant depression – experienced by people who have been ill for at least five years and have had multiple treatments fail – is not as simple as flipping a switch on an ultrasound machine and hoping for the best.

Patients like Linda and the nine others who will be part of the trial will likely continue to take their medication even after the procedure. Some will also continue to get counselling.

In addition, trial participants will be assessed for the severity of depression and level of functioning at various checkpoints over the course of the year after treatment.

While the overall hope is for patients with depression to feel better, the goal is to make sure that the focused ultrasound procedure is safe and effective. Although researchers are in the early stages of the trial, they say focused ultrasound has the potential to be another treatment option for patients with major depression who aren’t responding to existing standard treatments, “It’s an adjunct. It’s an additional treatment,” he says, explaining that focused ultrasound is unlikely to control all symptoms but will make a difference for some, including extreme anxiety that keeps people like Linda housebound.

Besides, talk therapy will be needed for another reason after successful procedures: “These people have often had years where the symptoms have dominated their lives,” Dr. Levitt points out “Now they’ve got to figure out what they’re going to do with their lives,”

Dr. Lipsman agrees. In addition to follow-up appointments at the one-, three-, six- and twelve-month marks, patients who are part of the trial will be monitored for years, “This is a procedure where it’s incredibly important to maintain close contact and continue treating patients for the long run,” he says. That kind of commitment and moral support has helped Linda cope during recovery. Wearing scarves and turbans while her hair grows back, she’s now looking forward to hopping on a plane to see her daughter in Seattle, and hopefully feeling less anxious about travelling now than she has in the past.

As the first person in North America to undergo an innovative trial procedure to treat depression, she knows anything is possible, “I’m proud of myself for having done the procedure,” Linda says, “This past week, my mood has been very good. I’m just hoping that I continue to improve.”

Beating bone pain with ultrasound

When Kendra Dunlop was first diagnosed with metastatic breast cancer, she could barely reach for a book on her bedside table without gasping in pain. Kendra, a mother of four who lives in Toronto, had developed a lesion on her eighth right rib, and movement hurt – a lot.

Her oncologist referred her to Dr. Edward Chow at Sunnybrook, a radiation oncologist who leads the Bone Metastases Site Group. There, Kendra was asked whether she would like to take part in a new clinical trial that would use high-intensity focused ultrasound to treat her pain.

She agreed, knowing that by using ultrasound early, she could put off using radiation therapy until it was needed later. Eventually there would be a limit on how many rounds of radiation she would be permitted, and she wanted to make them count. Kendra underwent the procedure in early 2018 and is happy with her decision.

“I have zero pain now,” says Kendra. “I could whack my rib and it doesn’t hurt.”

It’s the kind of response to treatment Dr. Chow likes to see. When cancer spreads to the bone, it’s very painful. Although using focused ultrasound does not cure cancer, when the sound waves converge at the bone metastases and damage the nerves, it stops the pain. The trial is being performed for palliative treatment only – and is intended for patients who have already reached their radiation limit – but it offers more pain-free days. The trial is also open to patients like Kendra with bone metastases who have yet to be treated with radiation treatment.

As principal investigator, Dr. Chow helps refer people like Kendra to the study, which will eventually enroll 20 patients. He hopes that the research will eventually lead to the creation of mobile ultrasound units that can be moved into areas with poor access to major radiation centres.

“The portable ultrasound machine is small and easy to move. You can imagine a mobile unit going everywhere and treating patients in the rural areas,” he says.

It’s a vision also shared by Dr. Elizabeth David, the interventional radiologist at Sunnybrook who actually performs the procedure. Although ultrasound ablation of bone has been around for years, the Sunnybrook Research Institute’s engineers have made modifications to the way the energy is applied. In a more typical setting, the patients are on an MRI table and need to contort their bodies to adjust to the device that sits fixed under the table. The new device has an articulated arm, which allows Dr. David to focus the ultrasound beam on smaller areas of the body, such as Kendra’s right rib.

The patient can sit comfortably while the machine is moved to treat the painful site. And the treatment is guided by real-time ultrasound images, which allows Dr. David to see that the target precisely.

“It can be repeated at the same spot over and over again,” says Dr. David. “As long as the bone isn’t weight bearing, there’s no real limitation to it.”

Kendra reports experiencing a “tumour flare” initially – a brief period of increased discomfort – but it went away within weeks. She says she would undergo the procedure again, if she could.

“I’m thrilled to have been able to participate in this trial and [I] feel very fortunate that I was at a hospital that allowed me to do it. I just hope it does prove successful in more patients.”