While completing his doctoral thesis in a deep brain stimulation project at the University of Toronto, Dr. Nir Lipsman began his work in focused ultrasound at Sunnybrook Health Sciences Centre. The overlapping theme at that time – and one that continues in his work today – is applying the latest technological advances to difficult-to-treat brain disorders. An early adopter of focused ultrasound, this neurosurgeon is looking to bring non-invasive solutions to patients as quickly and as safely as possible. He intends to lead the way by collaborating with experts in neurodegenerative disease, psychiatric disorders, and oncology. This approach led him to become the first physician to use focused ultrasound to open the blood-brain barrier in a patient with Alzheimer’s disease as part of a clinical trial.
Read our Q & A with Dr. Lipsman to learn about his background, his research, and his clinical work.
When and how did you become interested in focused ultrasound?
In 2010, I learned of exciting work that was happening at Sunnybrook, where Kullervo Hynynen, a pioneer in focused ultrasound research, was based. The prospect of an image-guided therapy that would allow us to directly interface with brain pathology really piqued my interest, and we started working in earnest on a proof of concept trial in essential tremor. I worked closely with Michael Schwartz, a neurosurgeon at Sunnybrook, to launch the ablative program there, and we continue to work closely today.
Was your PhD thesis in focused ultrasound?
No. I finished medical school and started my neurosurgery residency in 2007. In 2010, I took a break from my training to pursue a PhD. The University of Toronto’s Department of Surgery, under the leadership of James Rutka, is quite unique in its support of residents interested in pursuing academic research. My supervisor was Dr. Andres Lozano, a world leader in functional neurosurgery, and working with him was a major reason I decided to pursue neurosurgery and research training in Toronto. My thesis was about using deep brain stimulation (DBS) to treat refractory anorexia nervosa.
What are your areas of interest in focused ultrasound?
Because the bar to intervene in the brain needs to be appropriately high; there are risks we try to minimize and outcomes we try to optimize. I’ve always been interested in new ways to interface directly with brain pathology, especially in disorders that are not always visible on MRI or CT scans. Focused ultrasound merges the latest in diagnostic and therapeutic technologies and could offer a safer approach to conventional therapies. The prospect also of directly tackling the pathology that drives brain circuit disorders, and maybe influence their natural history, is an exciting one.
What mechanisms and clinical indications do you study?
We are investigating both ablative and non-ablative applications of focused ultrasound for a broad range of conditions. We have clinical trials at various stages for thermal ablation in essential tremor, obsessive-compulsive disorder (OCD), depression, and movement disorder symptoms that are amenable to lesioning, like some of the symptoms of Parkinson’s disease. In Alzheimer’s disease and brain tumors, we are investigating the safety of blood-brain barrier (BBB) opening. Neuromodulation is another potentially exciting field, and we are in the early stages of investigating this non-lesional approach to influencing brain circuitry.
What is the goal of your work?
We are motivated by our pursuit of safe and effective treatments for patients. There is a movement in neurosurgery toward less invasive treatment options, and this is true for spinal, vascular, and tumor surgery, among others. The hope is that focused ultrasound would help us minimize risk without sacrificing efficacy or durability. The BBB applications are entirely novel; here, focused ultrasound has the potential to specifically address some of the major obstacles to getting medications and other compounds across the BBB (size limitations).
What are your funding sources?
The Sunnybrook Foundation funds much of my work through the generosity of philanthropic gifts to my research program and the focused ultrasound program at Sunnybrook. The Focused Ultrasound Foundation has supported our tremor and brain tumour work, and is now supporting our Alzheimer’s and OCD trials.
Who are your team members?
This work is impossible without a large team full of excellent, dedicated professionals. Dr. Kullervo Hynynen, the physicist behind all of our work and a pioneer of focused ultrasound technology, is based at Sunnybrook, and his partnership has been the key to advancing all of these trials. My team currently has three research coordinators and managers and five graduate students, post-docs, and undergrads. We are very fortunate to have the technical expertise of Dr. Hynynen and his team of physicists and technicians, and we operate in a center with extensive expertise in the conditions that we treat. We are also grateful to the strong support we receive from our hospital and research institute and the myriad members of the technical and clinical support staff on whom we rely heavily.
Q. Who are your internal and external collaborators?
Our clinical partners for each of the disciplines are:
- Neurosurgery: Michael Schwartz, Todd Mainprize, Andres Lozano, James Drake, James Rutka, and Clement Hamani
- Neurology: Sandra Black, Lorne Zinman, Jennifer Jain, Benjamin Lam, and Agessandro Abrahao
- Oncology: James Perry, Maureen Trudeau, and Arjun Sahgal
- Psychiatry: Anthony Levitt, Peggy Richter, Anthony Feinstein, and Peter Giacobbe
Our scientific collaborators at Sunnybrook Research Institute are:
- Kullervo Hynynen, PhD, pioneering focused ultrasound medical physicist
- Isabelle Aubert, PhD, preclinical scientist and Alzheimer’s expert
Outside of Sunnybrook, we have ongoing collaborations with several clinician-scientists, including Rees Cosgrove, MD, at Brigham and Women’s Hospital, and Travis Tierney, MD, at Miami Children’s Hospital.
What are your greatest achievements?
My children! I have a daughter who is 5 years old, a son who is 3 years old, and an amazing, understanding wife, who is a visual artist in her own right. Professionally, so far, I would say these three: 1) being a part of the essential tremor pivotal trial, from publishing the paper on our initial experience all the way to helping obtain Health Canada approval; 2) launching the Alzheimer’s trial and treating the first patient; and 3) having Sunnybrook recognized as a focused ultrasound Center of Excellence by the Focused Ultrasound Foundation.
Any major disappointments?
It’s been an incredibly rewarding experience and I’m grateful that aside from some hiccups here and there, there have not been major disappointments. Most importantly, the patients we’ve treated and enrolled so far have done well. Occasional frustrations along the way are usually related to the limitations of growth and wanting to expand our scope—like recruitment challenges for studies. With essential tremor, we have many more patients than we can treat. Although we are treating two to three patients each month, we have at least 20 on a one-year waiting list.
What do you see as impediments to your success?
Funding. Now that we have Health Canada approval to treat tremor, we want to provide this clinical service to as many patients as possible. There are major funding limitations, though, because although focused ultrasound for tremor is approved, it’s not publicly funded by the Ontario government. This needs to change, and we are in active discussions with the government, who is undertaking a review of the economic benefit of focused ultrasound thalamotomy. We are hopeful that this will change in the next 12-18 months.
What is on your research wish list?
Many things! A major priority now is investigating whether focused ultrasound can be used in neurodegenerative diseases like Alzheimer’s and Parkinson’s. In addition, I’m interested in using focused ultrasound to modulate brain function, as this could potentially give us a better understanding of the brain and teach us what focused ultrasound is doing at a basic neuronal level. It would answer questions like, “Can we stimulate or inhibit key nodes in the brain that are not functioning properly and do this in a way that is noninvasive, safe, and effective?” Neuromodulation could also be used to make other neurosurgical procedures safer and more predictable and it could aid DBS programming.
Did the Foundation play a role in your work?
Besides funding several of our studies, I have chaired two steering committees dealing with psychiatric disorders and Alzheimer’s disease. I have attended several Foundation-organized workshops for Alzheimer’s and essential tremor and have forged rewarding collaborations with researchers in the field. I’ve been privileged to work with the Foundation; they are outstanding in their support of us and of Sunnybrook. A key turning point was being designated a Center of Excellence. It was a real validation of our clinical projects, and the support has been amazing.
Do you have a memorable clinical story or highlight to share?
With essential tremor, the treatments never get old because the result is so immediate. To see the patients go back to their hospital beds and eat and drink without shaking is incredibly rewarding. The patients in the Alzheimer’s study—and their caregivers—are also very inspiring. Their hope and courage in taking on a journey with many unknowns is very inspirational for us as a team.
What comes next?
We are intensely interested in Alzheimer’s disease. We want to finish the phase 1 study, look carefully at the data, and then plan the phase II study if warranted. We continue to enroll patients in our brain tumor study, and OCD will start soon. We want to expand the indications and lead in phase I trials in a rigorous way and translate the preclinical results that we are seeing into clinical tools.
- First Alzheimer’s Trial for Focused Ultrasound Begins May 2017
- Sunnybrook Designated Centre of Excellence November 2016
- News Flash – Prestigious Journal Publishes ET Results August 2016
- OCD/Depression Steering Committee Begins Clinical Study Protocol Design April 2016
- Neurosurgery Meeting Spotlights Transcranial Focused Ultrasound June 2013
- FUSF Funding Two Clinical Trials at Sunnybrook Health Sciences Centre July 2011