Researchers from the Krembil Brain Institute have shed light on the long-term effects of deep brain stimulation on neuronal activity in a brain region involved in Parkinson disease.
A hallmark feature of Parkinson disease is an increase in a type of neuronal activity—known as beta oscillations—in the basal ganglia region of the brain. Previous studies suggest that deep brain stimulation applied to this region reduces motor symptoms of the disease by disrupting this form of patterned neuronal activity.
According to Krembil Senior Scientist Dr. Robert Chen, however, beta oscillations are only one piece of the puzzle.
“When measuring the activity of large groups of neurons, the signals that we acquire are made up of oscillations, or patterned activity, as well as non–patterned, or aperiodic, activity, which is often viewed as background activity,” says Dr. Chen. “To understand precisely how deep brain stimulation treats disease symptoms, we need to consider its long-term effects on patterned and non-patterned forms of neuronal activity.”
To determine the long-term effects of deep brain stimulation in the basal ganglia, Dr. Chen’s team recorded local neuronal activity in patients with Parkinson disease during six study visits over 18 months. They then applied computational methods to separate the oscillatory and aperiodic components of the signals.
“It has previously been very challenging to study the long-term effects of deep brain stimulation on brain activity because we were limited to recording from neurons over a short period while surgically implanting the electrodes,” explains Dr. Ghazaleh Darmani, a postdoctoral researcher in Dr. Chen’s lab and the first author of the study. “In this study, we were able to assess neural signals over a longer period because our patients had specialized devices that can record local activity throughout the study period.”
The team discovered that deep brain stimulation increased aperiodic beta activity over time. In contrast, beta oscillations were stable over time.
These findings call into question the traditional view that deep brain stimulation treats Parkinson symptoms by reducing beta oscillations in the basal ganglia, and highlight the need to consider different forms of neuronal activity when studying the disease and developing therapies.
The researchers also found that dopaminergic medications that are commonly used to treat the disease affect these two types of brain activity differently. These medications did not affect aperiodic beta activity but did suppress beta oscillations.
“Our findings suggest that beta oscillations and aperiodic activity represent distinct but complementary neural processes in Parkinson disease,” says Dr. Darmani. “Clarifying how each type of activity contributes to disease symptoms is an important step towards developing more targeted and effective deep brain stimulation treatments.”
This work was supported by the Canadian Institutes of Health Research, Medtronic Inc. and the UHN Foundation. Dr. Robert Chen is a Professor in the Division of Neurology, Department of Medicine at the University of Toronto.
Darmani G, Drummond NM, Ramezanpour H, Saha U, Hoque T, Udupa K, Sarica C, Zeng K, Cortez Grippe T, Nankoo JF, Bergmann TO, Hodaie M, Kalia SK, Lozano AM, Hutchison WD, Fasano A, Chen R. Long-Term Recording of Subthalamic Aperiodic Activities and Beta Bursts in Parkinson's Disease. Mov Disord. 2023 Feb. doi: 10.1002/mds.29276.
On March 21, 2023, tune in for Season 2 of the Krembil Brain Institute’s podcast Your Complex Brain.
Hosted by Heather Sherman, Manager of Communications for the Krembil Brain Institute, this educational podcast is geared towards a general audience and is freely available on all major podcast platforms, including Apple Podcasts, Spotify and Google Podcasts. New episodes will air every other Tuesday.
Listeners will enjoy in-depth interviews with leading neuroscientists and clinicians from the Krembil Brain Institute, as well as moving personal accounts of brain injury, disease and recovery from patients and dedicated care teams.
The podcast will also shine a light on some of the Institute’s talented trainees and its collaborations with national and international researchers and advocacy organizations that enable world-class discoveries and clinical innovations.
Season 2 will explore a wide range of brain-related topics, including:
● a new theory of Alzheimer disease;
● how the brain responds to pain;
● how gender affects the diagnosis of brain disease; and
● the future of deep brain stimulation
To learn more, watch the Season 2 trailer here.
“This podcast is such a great way to connect with our community partners and members of the public, to let them know about the amazing science happening at the Krembil Brain Institute, and what makes us a world leader in brain research and care,” says Krembil Director Dr. Jaideep Bains.
With more than 14,000 downloads for its first season, Your Complex Brain was a finalist for the Canadian Online Publishing Awards 2022 Best Podcast award.
The Krembil Brain Institute is home to one of the world’s largest and most comprehensive teams of scientists and clinicians dedicated to developing treatments for diseases of the brain and spine. This podcast celebrates the work of this exceptional multidisciplinary team and breaks down barriers between scientists and the public.
For more information about the podcast, visit https://www.uhn.ca/Krembil.
Imagine you found a gene that can be targeted to treat a specific type of disease. Shortly, you discover that a pharmaceutical company developed a drug for the disease that works on the same gene you found. Can you connect these two events together to guide your next step of research, and possibly make a breakthrough discovery?
This is exactly what happened to Dr. Steven Chan during his postdoctoral research at Stanford University. The disease that he was studying was acute myeloid leukemia (AML), and his focus was on a form of the disease that has a mutation in a gene known as IDH, which codes for the isocitrate dehydrogenase protein. At that time, the mutation was newly identified and there was no targeted treatment for this form of AML. To overcome this challenge, he performed a genetic screen to search other genes that when inactivated, led to the death of AML cells with IDH mutations. Soon, a gene called BCL2 caught his eyes—it codes for a protein that helps AML cells survive, and AML cells with IDH mutations appear to be highly dependent on it. Therefore, he hypothesized that inhibiting BCL2 might be a way to target this form of AML.
Coincidentally, a scientific paper came out in 2014 that described a drug called ABT199 that can inhibit BCL2. At that time, the pharmaceutical company AbbVie was investigating its efficacy in other types of cancer. Steven found this interesting—suddenly there was a very specific drug that can inhibit the target that he found. He tested the drug on AML cells with and without the IDH mutation to compare the effects. After years of laboratory experiments, it turned out that cells carrying the mutation were indeed more sensitive to the drug, while those without the mutation were less sensitive. This discovery led to a major publication in Nature Medicine, and more importantly, identified a specific patient subgroup that could benefit from this drug.
ABT199 is now known as venetoclax. It was approved by the U.S. Food and Drug Administration in 2016 and became a game changer in current leukemia treatment. Looking back, Steven is amazed at how the timing worked out—enabling him to leverage new findings that unlocked the clinical potential of his discoveries. “While luck does play a part in science, I do think that if your mind is prepared, you are more likely to connect the dots and make unexpected discoveries when these fortunate coincidences happen,” says Steven.
While Steven was working on a BCL2 inhibitor, another group of scientists, led by Dr. Tak Mak, who is also a Senior Scientist at Princess Margaret, developed the first set of IDH inhibitors. Dr. Chan realized that if both therapies target IDH-mutated cells, they might work even better when combined. Using experimental models, his lab found that the combination of the two inhibitors was indeed more effective at killing IDH-mutated AML cells than each drug alone. Given the promising preclinical results, Dr. Chan launched a clinical trial in November 2020 to test the drug combination in patients.
“Getting the clinical trial started was a lot more challenging than I thought it would be,” says Steven, “but it’s all worth it when you see patients benefiting from it.”
Steven found it immensely gratifying to be a part of a journey where research discoveries were translated to the clinic. It has been the proudest moment of his career thus far and is one of his strongest motivations to continue doing bench science experiments. “My role in this journey was to make the connection between the mutation and the drugs. It has been inspiring for me to witness the drug go from being tested in cell lines, to helping patients.”
Another key motivator for Steven is working alongside people he looks up to. Steven had great admiration for his postdoctoral mentor, Dr. Ravi Majeti at Stanford University, whose vision and energy inspired Steven to pursue a career in research and academic medicine. When Steven was ready to become an independent researcher, he decided to return to Toronto. “The quality of cancer research at Princess Margaret, especially in the leukemia field, is among the best in the world.”
“Scientists at every stage of their career need mentors to help them progress. From my undergraduate to postdoc studies, my mentors played a big role in guiding me in the right direction. Even after I transitioned to an independent researcher at Princess Margaret, I have been fortunate to have the support of many mentors including Drs. John Dick, Aaron Schimmer and Mark Minden, for which I am very grateful throughout the seven years that I’ve been here.”
In December 2022, Steven received the Early Career Award from the Canadian Hematology Society in recognition of his contributions to the field of leukemia research.
Steven Chan (L) receiving the Canadian Hematology Society Early Career Award from Dr. Jason Berman (R), the Chief Executive Officer and Scientific Director of the CHEO Research Institute and the Vice-President of Research at CHEO (Children’s Hospital of Eastern Ontario). Photo credit: Penny Waddington
Steven spends around a quarter of his time treating patients, while the rest of his time is devoted to research. Having his feet in both worlds, he finds good time management is a necessity. “One can be easily overwhelmed by a large number of items on the to-do list,” says Steven. “Before my day begins, I pick one or two tasks to focus on for the day. It helps me focus and also reduces my stress.”
Outside of work, he enjoys family life and spending time with his two daughters. He is very proud that one of his daughters is taking an interest in science—she picked artificial intelligence (AI) for her science fair project two years in a row. Steven himself also wonders how AI will change the world. “There are already AI applications that may soon change how medicine is practiced. I think when my daughters grow up, they will be in a world where AI is everywhere. I hope they will position themselves in a good place as the technology evolves, whether it’s in medicine or in other fields.”
Dr. Chan has received research funding from Servier Laboratories, AbbVie and Celgene/Bristol Myers Squibb. Dr. Chan has received honorarium for consulting work with Jazz Pharmaceuticals, Agios and Celgene/Bristol Myers Squibb.
Meet PMResearch is a monthly column that features Princess Margaret researchers. It showcases the research of world class scientists as well as their passions and interests in career and life—from hobbies and avocations to career trajectories and life philosophies. The researchers that we select are relevant to advocacy/awareness initiatives, or have recently received awards or published papers. We are also showcasing the diversity of our staff in keeping with UHN themes and priorities.
Congratulations to Dr. Tak Mak for receiving the 2023 International Award for Extraordinary Achievement in Cancer Research from the Pezcoller Foundation and the American Association for Cancer Research (AACR).
The award was established in 1997 to recognize researchers who have made significant breakthroughs in basic or translational cancer research. Dr. Mak joins other recipients of this prestigious award, who include Dr. Hans Clevers, who developed organoids that are used extensively in medical research, and Dr. Tony Hunter, who discovered protein tyrosine phosphorylation—a fundamental way through which cells send signals internally and change their behaviour.
Dr. Mak is a Senior Scientist at the Princess Margaret Cancer Centre, where he has established himself as a leading expert in cancer immunology and biology. One of his most significant contributions was the cloning of human T cell receptor genes. This work enabled researchers to better understand the biology of T cells, ultimately paving the way for existing immunotherapies, including CAR-T therapy and TCR-T therapy. His work has also shed light on CTLA-4—a molecule found to prevent T cells from killing cancer cells. This work laid the foundation for CLTA-4 becoming the first immune checkpoint regulator to be targeted in the clinic. His lab is currently working on designing T cell receptors that can recognize specific molecules on cancer cells and help to target them for destruction.
As one of the world’s eminent cancer researchers, Dr. Mak has served as author on over 1000 peer-reviewed articles and co-founded biotechnology companies, while improving the lives of individuals living with cancer. He is a Fellow of the AACR Academy, has received honorary degrees from many universities around the world and has received various international prestigious awards and honors, such as the Albert Szent-Györgyi Prize for Progress in Cancer Research, the Paul Ehrlich Prize and the Ludwig Darmstaedter Prize.
The award will be presented to Dr. Mak at the 2023 AACR Annual Meeting in mid-April in Orlando, Florida. Dr. Mak will also be recognized at a special award ceremony organized by the Pezcoller Foundation in Trento, Italy in May.
Read the press release here.
Dr. Shehroz Khan’s research team at KITE Research Institute recently demonstrated that two different video-based approaches were capable of detecting risky behaviours in individuals living with dementia, while maintaining their privacy.
In Canada, around a third of individuals under 80 years of age with dementia reside in long-term care homes. This portion increases to 42% for those older than 80.
Individuals with dementia can display behaviours that put themselves or others at risk. To identify this risk, certain residents in long-term care homes require continuous monitoring, which places a heavy burden on limited resources. While video surveillance is common, the footage is not always monitored and privacy cannot always be guaranteed.
To address these challenges, Dr. Khan’s research team used real-world video surveillance data collected from a dementia care unit and applied two privacy-protecting approaches to analyze the footage. The first approach that they tested uses software to replace the individuals in the video with ‘stick figures’ that model their pose, actions and interactions with others. The second approach is similar, but replaces individuals with silhouettes that model their behaviour.
The team showed that both were as good at detecting high-risk behaviour as traditional methods.
“The algorithms that we’ve developed can read raw video, identify risk and alert staff in time. And by distilling video footage into positional body data, privacy can be guaranteed,” says Pratik Mishra, a graduate student in Dr. Khan’s group and the lead author of the study.
“This is the first study to utilize the skeleton-based method to model behaviours of risk in people with dementia, while de-identifying the individuals featured in the videos,” says Dr. Khan, Scientist at KITE Research Institute.
“Our proposed approaches set a new standard for detecting behaviours of risk in people with dementia. These tools have the potential to improve the quality of life of long-term care residents, while reducing burden on the health care system.”
This work was supported by AGE-WELL NCE Inc, Alzheimer’s Association, Natural Sciences and Engineering Research Council of Canada, Walter and Maria Schroeder Institute for Brain Innovation and Recovery, and the UHN Foundation. Dr. Shehroz S. Khan is the senior author of the study and an Assistant Professor (Status) in the Institute of Biomedical Engineering (BME) at the University of Toronto.
Mishra PK, Iaboni A, Ye B, Newman K, Mihailidis A, Khan SS. Privacy-protecting behaviours of risk detection in people with dementia using videos. Biomed Eng Online. 2023 Jan 21. doi: 10.1186/s12938-023-01065-3.
Welcome to the latest issue of Research Spotlight.
As Canada’s largest research hospital, UHN is a national and international source for discovery, education and patient care. This newsletter highlights top research advancements from over 5000 members of TeamUHN—a diverse group of trainees, staff, and principal investigators that conduct research at UHN.
Stories in this month’s issue:
● Giving Cues: Researchers are studying whether mixed reality technology can help individuals with dementia.
● Global Impact for a Healthier World: UHN’s electrophysiologist training program makes a difference in Jamaica and Saint Lucia.
● Protein-Level Insights: Study digs deeper than genes by analyzing protein interactions associated with autism.
● Quick to Help: Artificial intelligence system tailors resources to members of online cancer support groups.
Read these stories and more online here. To read previous issues, see the newsletter archive.
On March 9, 2023, the Honourable Jean-Yves Duclos, federal Minister of Health, announced a landmark investment for research into long COVID.
This investment—totalling $20M—will support the Long COVID Web, a national team co-led by TGHRI Senior Scientist Dr. Angela Cheung. The project will enable the team to advance our understanding of this condition, unlock new treatments and improve care for individuals living with long COVID.
“There has been a tremendous national response to the effort to form Long COVID Web,” says Dr. Cheung, who co-leads the network along with Dr. Adeera Levin at the University of British Columbia, Dr. Piush Mandhane at the University of Alberta and Dr. Simon Décary at Université de Sherbrooke. “We had nearly three hundred researchers, clinicians, and community partners from across Canada join in just a few weeks, demonstrating the commitment from many sectors and geographies and the need to understand and better treat long COVID.”
“A key strength of the project, in addition to breadth of collaborating institutions, is the broad scope of our patient partners. By including representation from indigenous populations, underserved communities, the elderly, adults and children, and individuals living with disability, we are ensuring that nobody is left behind,” adds Dr. Cheung.
For most people, the symptoms of COVID-19 are short-lived. However, some people experience symptoms long after the infection is over—a condition known in medical fields as the post-COVID-19 condition, and more commonly referred to as “long COVID”. Over 1.4 million Canadians have experienced long COVID, which can cause chronic tiredness, heart palpitations, shortness of breadth, digestive problems, joint pain and difficulty thinking.
These symptoms often negatively impact the daily lives of those affected, and there is an urgent need to better understand the condition, its prevalence, and how to treat and prevent it.
Dr. Cheung has emerged as a leader in long COVID research in the wake of the pandemic. As well as a Senior Scientist at UHN’s Toronto General Hospital Research Insitute and Schroeder Arthritis Institute, she is the KY and Betty Ho Chair in Integrative Medicine at University of Toronto and a Professor at the Institute of Health Policy, Management and Evaluation. She also holds the Tier 1 Canada Research Chair in Musculoskeletal and Postmenopausal Health.
She is spearheading the Canada-wide RECLAIM clinical trial, which is testing potential therapies for people with long COVID. She also helped to establish the Canadian COVID-19 Prospective Cohort study (CanCOV), which is collecting data on long-term outcomes for COVID-19 patients. For more on Dr. Cheung’s research, listen to Season 3 Episode 10 of UHN's award-winning podcast Behind the Breakthrough.
“Canada’s science community is well positioned to provide the government with the evidence and the expertise needed to address post-COVID condition. Thanks to the experts who contributed to our task force recommendations, we now have a roadmap, a network, and the support of government to take steps toward fully understanding this disease and helping to mitigate its effects on people and our society,” said Dr. Mona Nemer, Canada’s Chief Science Advisor.
Dr. Brad Wouters, UHN’s Executive Vice President, Science and Research, adds, “UHN is excited to take part and host the Long COVID Web. By purposely integrating research, care, and the unique perspectives of patients, this network is poised to understand the underlying biology of long COVID—insights that will be key to developing accurate diagnostic tools, treatments and rehabilitation approaches.”
“The network is also looking at how we need to adapt—both as health care providers and as a society—so that we can better address the long-term consequences of the pandemic.”
To read the press release, click here.
The funding, which will be administered by the Canadian Institutes of Health Research (CIHR), is part of the government’s continued response to address the health challenges of the COVID-19 pandemic. Since March 2020, and not including this latest funding, CIHR has invested $414.8 million in research into COVID-19, of which $17.7 million has been targeted for Long COVID research.
Research conducted at UHN's research institutes spans the full spectrum of diseases and disciplines, including cancer, cardiovascular sciences, transplantation, neural and sensory sciences, musculoskeletal health, rehabilitation sciences, and community and population health.
Learn more about our institutes by clicking below:
