What if we could stop treating illness by trial and error, and actually understand the signals that our brains are giving us? Host Fiona Sanderson sits down with two of Canada's bold early-career clinician-scientists to explore the cutting edge of mental healthcare - including using brainwave patterns to predict which treatments will work, novel imaging methods that capture the brain in real time, and the surprising promise of psilocybin as a next-generation treatment for bipolar depression.
What if we could stop treating illness by trial and error, and actually understand the signals that our brains are giving us? Host Fiona Sanderson sits down with two of Canada's bold early-career clinician-scientists to explore the cutting edge of mental healthcare - including using brainwave patterns to predict which treatments will work, novel imaging methods that capture the brain in real time, and the surprising promise of psilocybin as a next-generation treatment for bipolar depression.
With more than one in three people worldwide living with a neurological condition, the stakes couldn't be higher…and these researchers are tackling the problem from bench and bedside - asking the questions patients need answered, and harnessing neuroscience to find them.
Featured guests:
Dr. Anthony Gifuni, Assistant Professor in the Department of Psychiatry at McGill University, and a Researcher and Psychiatrist at the Douglas Mental Health University Institute
Dr. Gayatri Saraf, Psychiatrist and Assistant Professor at the Department of Psychiatry at University of Ottawa
This work is supported by The Erika Legacy Foundation.
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Dr. Gayatri Saraf 00:03
I think a lot of the research is driven by the questions that we see in the clinic, why do people not respond to treatments? And, you know, not just if treatments are effective, but when do they work? For whom do they work? In what context and in what circumstances do these treatments work? So, I think it’s a two-way process. Clinical work gives us the questions that we are asking as researchers, and basic sciences and neurosciences give us the tools to explore some of these questions. And then these tools, in turn, hopefully transform clinical care. That’s the dream.
Fiona 00:40
This is Bold Minds: Future Leaders in Canadian Brain Research. I’m your host, Fiona Sanderson. I work at Brain Canada, where our mission is to bring together funders and researchers to enable health innovations for Canadians. The Future Leaders program is made possible thanks to an anchor gift from the Azrieli Foundation and matched by Brain Canada through the Canada Brain Research Fund. Come along with me as we journey into the bold minds and labs of researchers who are redefining our understanding of the brain. [music continues then ends]
[rousing music] Imagine walking into the doctor’s office. Maybe you’re not sleeping well or still feeling tired even after you’ve rested. Maybe you’re finding yourself frustrated or irritable with little things that never used to bother you before, or perhaps you’re not interested in activities you used to really enjoy. Maybe you’ve already experienced depression before and have a hunch what the doctor is going to recommend this time around, or maybe this is feeling brand new. Maybe you’re feeling anxious because you’ve heard from friends or read online that finding the right treatment option might take months or even years. For decades, psychiatry has been navigating mostly in the dark, prescribing medications and therapies based on symptoms alone hoping that something will work. But your brain is as unique as your fingerprint. What helps one person might do nothing for another. Or worse, if it’s the wrong course of treatment, it could even make things harder. Today, we’re exploring the cutting edge of mental health care, where researchers are learning to read the language of the brain itself and using technologies and drugs, both new and old, to treat mental health. This is Bold Minds. [music continues then ends]
Today, I’m joined by….
Dr. Anthony Gifuni 02:37
Anthony Gifuni.
Fiona 02:39
His team at McGill’s Douglas Mental Health University Institute measures brainwave patterns to better predict how patients will respond to specific treatments. Moving mental health care away from trial and error and towards precision medicine.
Dr. Gayatri Saraf 02:52
[whooshing] My name is Gayatri Saraf.
Fiona 02:55
Her work at the University of Ottawa uses novel imaging methods to better understand the neurobiology of bipolar disorder, and mapping how the antidepressant effects of psilocybin could potentially unlock a new, more effective treatment for one million impacted Canadians. Anthony, Gayatri, welcome to Bold Minds.
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Dr. Anthony Gifuni 03:18
Hi, it’s a pleasure and privilege to be here.
Dr. Gayatri Saraf 03:21
Pretty excited to be here.
Fiona 03:23
Anthony, let’s start with you. You’re a psychiatrist and a neuroscientist. What first drew you to the brain? Why study mental health and depressive disorders?
Dr. Anthony Gifuni 03:32
Well, I think there’s something that’s fascinating about research. Initially, you’re just a student in a class reading a textbook, and you start wondering, “Where does that knowledge come from?” And it comes from research. The methods and techniques of trying to push this boundary and acquire new knowledge. And this, you know, it goes way back to this experience at 18 years old at my first summer internship. It was at the Clinical Research Institute in Montreal, and I was immersed in this extraordinarily rich scientific environment in molecular genetics. I guess this is how I got the research bug. And what I was studying was how certain genes are sort of switches that turn on or off other genes and are involved in the embryonic development and then determines the fate of cells and tell them, “Okay, you’re located at this specific place, so you’ll become a hand, you’ll become a foot.” And that is immensely complex and I knew I was sort of stumbling into all those elements that control genes, protein expressions, that are basic constituents of how neurons are shaped and do develop. Well, these are sort of really important things to understand. And from then on, I was a medical student and oriented myself towards what I considered to be sort of the boundary where there are the most sort of mysteries yet to discover. So, I was drawn towards psychiatry basically because I wanted to do research and how important and how transformative it could be to patient care.
Fiona 05:26
I love that. Your origin story as a researcher is really tied to the origin of the brain.
Dr. Anthony Gifuni 05:31
Mm-hmm.
Fiona 05:31
Trying to understand those mysteries. And Gayatri, you know, you’re also a psychiatrist and a neuroscientist. And I’m interested because your clinical specialty is actually antenatal and perinatal mental health care. So, what brought you to research on bipolar disorder?
Dr. Gayatri Saraf 05:47
So, my path into research was certainly not very linear. You know, I trained in India. I did my medical school and psychiatry residency, and like most people who are entering psychiatry residency I believe that I was training primarily to become a clinician working in the community delivering psychiatric care. When working in the clinic, one becomes really acutely aware of some of the clinical questions that are still unanswered in terms of, why do people respond to certain treatments? Why some people experience a relapse and how can we predict and improve our understanding of these treatments? And so, my journey into research was more guided by these clinical questions. And I then moved to Canada and this experience of working across countries and navigating healthcare systems was extremely transformative and foundational. And also, this was my first sort of crush with PET imaging, positron emission tomography, in terms of how it can help us understand the brain, and I was pretty excited by that. My PET imaging research at the time focused on understanding how synapses in the brain, which are connections between neurons in the brain, if synaptic density in the brain is any different in bipolar disorders as compared to healthy controls. And currently, my research focuses mainly on bipolar depression. What we know about bipolar depression is that it is a very understudied condition and that not a lot of effective treatments exist, and the currently available treatments are limited in that there are side effects. And so, my research program currently at the University of Ottawa focuses on bipolar depression and finding—exploring novel treatments, as well as the brain mechanisms that underlies some of these novel treatments.
Fiona 07:40
Thank you for that. And so, you know, sort of continuing along that thread, what is it about the neurobiology of bipolar disorder that makes it so difficult to treat? Is that a loaded question? [chuckles]
Dr. Gayatri Saraf 07:51
I think to reconstruct that question, first of all, we don’t understand as much about the neurobiology of bipolar disorder in general. But what’s also being explored is, you know, how novel treatments like psychedelics work. So, we are just beginning to understand all of this with current advances in neuroscience and brain imaging, and so we are at the precipice of this time where we do have the tools to understand some of that. And we also have novel treatments, which we know have powerful antidepressant effects, and so it’s very exciting to begin to explore how some of these novel treatments might be changing the brain.
Dr. Anthony Gifuni 08:33
If I may add to this, that Gayatri and I, we have a very sort of similar profile as clinician scientists. That, you know, our goal is really we’re at the intersection of neuroscience and psychiatry, that makes it sort of exciting in a way. Because we might be understanding through what we study in the brain and uncovering what is actually an underlying pathology. That this heterogeneity might be hiding, in fact, a different type of disorder. That several pathways do converge onto this presentation that we recognize as bipolar disorder, but they might be different disorders onto themselves. There’s no single gene that explain why someone has a predisposition to depression, to bipolar disorder, or psychotic illness. It’s rather the contribution of hundreds, perhaps thousands of genes, that in their interaction in a specific individual lead to this increased risk. So, even at the basic foundational level of just genes causing disease, because they’re multifactorial it makes them very complex to study and then to even predict whether our treatment will be effective for them.
Fiona 09:58
Yeah, absolutely. So, Anthony, you bring up genetics and the vast complexity of it, and it sounds like that’s just a piece to the puzzle that needs to be solved. How does brain imaging fit into this psychiatry? What kind of brain imaging can we do? What does it tell us about the brain? How does it tell us what a drug is doing in the brain, a drug like psilocybin?
Dr. Gayatri Saraf 10:16
So, that’s a good question. And when Anthony was speaking earlier, I was, you know, reflecting on some of the ways in which we are now understanding and explaining psychiatric disorders in terms of, like, predominantly a biopsychosocial model, where biological vulnerability and environmental influences interact to cause a particular disorder. And this is something that we commonly use in psychiatry. With drugs like psilocybin, we are moving on to a biopsychospiritual social model where we know that they cause immensely transformative experiences and a sense of connectedness. And what’s exciting is that recent advances in brain imaging kind of enable us to measure some of that. And so, I’m particularly drawn to PET imaging because if a structural MRI is like a snapshot of the brain, we can think of PET imaging as more of a movie and more of a real-time picture of how things evolve. And so, this particular imaging modality focuses on the synapses, which are connections between the brain cells, and so we are trying to understand if these connections are, you know, more or less pronounced in people with bipolar disorders. And so, to be able to measure that through PET imaging using this tracer for synaptic density is immensely exciting. And so, what we’re hoping to achieve through some of this research is understanding if psilocybin improves the density of these connections in the human brain. And so, while before a lot of this could only be understood using post-mortem studies, what’s very exciting is that we now have the methods to look at that in the living human brain.
Dr. Anthony Gifuni 12:04
If I may add on brain imaging, in my own research what I’ve been focusing here is using a more portable way of imaging the brain. And PET scan is fantastic, and MRI, but they’re very costly, they’re difficult to access, and, of course, I think they’re still part of our research efforts. And what if there was a way that was easier that we could even implement in an office or in one’s home to measure brain activity? And this is where EEG comes as a potential way of doing this. And it consists in placing electrodes over the scalp and then recording the evoked currents that are produced by the neurons just—in the cortex just beneath. And then the idea is to have this accessible, portable way of measuring brain activity that does respond to the environment, and how that reactivity that we can measure through our electrodes, do they tell something about the individual? About the underlying psychological, psychopathological or mechanism that underpin depression. And also importantly, whether these could serve as therapeutic targets.
Fiona 13:32
So, Anthony, you can measure these electrical signals? You can use electroencephalography or EEG to measure these electric signals in the brain?
Dr. Anthony Gifuni 13:41
Mm-hmm.
Fiona 13:42
How does that help us better understand how the brain responds to abstract things like rejection and inclusion in social situations?
Dr. Anthony Gifuni 13:51
Well, what we’re particularly interested is how the electrical activity of those neurons respond to specific cues from the environment. And something that is intricately linked to mental disorders is our social function. Humans are social species and our brain is wired to respond, react, adapt to the social world. And it does so in a sequential way throughout development in parallel with cognitive development, emotional development, we become increasingly attuned to the social world. So, what we’re doing is we’re actually in the lab using a task that does simulate the essential part of either being included or excluded. It’s a task called a cyberball game that has been studied specifically for this, to study the negative emotional impact of social rejection. And it has actually two phases, one that induces inclusion through participation and interaction with virtual players, and a second part which simulates exclusion. And this, in fact, we know does induce changes in the brain, and this parallels with what subjectively we experience as either the positive or negative emotions of feeling included or feeling excluded. And our hope here is that those elements that respond to those cues during this task have a predictive power that can guide us at selecting treatment in the first episode of depression. The incidence of a first episode depression usually takes place in that time period between adolescence and young adulthood. In fact, a lot of bipolar disorder also do present as a depression initially, and there’s very little way to know whether this will evolve into bipolar disorder. So, it is possible that even those signals that we do, captured can help us understand here the different subtypes of depression and help us determine the prognosis associated with the traditional treatments that now we use simply guided by clinical presentations.
Fiona 16:34
That’s incredible. Research has come so far. Gayatri?
Dr. Gayatri Saraf 16:39
That’s fascinating about how depression initially can present in adolescence and early adulthood. And we know that there’s quite a bit of lag when we look at when people first experience, like, depression versus when they’re first diagnosed with bipolar disorder. And I’m curious as to, Anthony, in your work with adolescence is there, like, a window of timing, you know, in which we need to intervene? And I’m mostly seeing, like, as a psychiatrist working predominantly with adults and doing research in that population, I’m predominantly seeing the downstream effects of someone who has already been diagnosed with bipolar disorder. But I’m curious as to your experience with, you know, the timing and the window of intervention and early intervention approaches.
Dr. Anthony Gifuni 17:27
Yeah, absolutely. I think it’s a critical window of opportunity for prevention and intervention, because the brain is highly responsive to the environment in fact. Social belonging is a fundamental need because our species has survived through being connected with others, and, therefore, our brain is wired to detect cues of social rejection and to seek inclusion. And there’s this—in adolescence, at that period that we want to intervene early, there’s this vulnerability because the brain tries to answer the question, “How do I find belonging, connection with others, outside of my family?” The sensitivity to rejection, the yearning for connection, is often experienced as this powerful force, sometimes that we characterize as peer pressure. And I think what’s critical is that there has to be attention to the environment in which an individual is immersed. It doesn’t mean necessarily that you need to intervene per se on the environment, but that you understand the interaction that are shaping the individual so that there is an awareness about the underlying process. So, paying attention to those processes, I think, is absolutely critical for early intervention.
Fiona 19:07
And Gayatri, do you see the same sort of things on your end in your research?
Dr. Gayatri Saraf 19:11
In terms of the research on novel treatments, that line of research is still very much evolving. So, currently, I’m working on exploring how some of the novel and innovative treatments could be used for bipolar depression, so we are beginning to explore the effects of circadian treatments and I’m currently leading a trial of time-restricted eating in bipolar depression. And so, time-restricted eating is a novel dietary tool, which is a form of fasting that syncs your eating windows with the circadian rhythms.
Fiona 19:44
Circadian rhythms being how the body processes sort of the day and night, right?
Dr. Gayatri Saraf 19:51
That’s right. Yes. We have a biological clock, which is called the circadian clock. And this is trained by some of the cues from the environment like light or social interactions. We are beginning to explore how timing of eating, if that makes a difference, and so we are evaluating this dietary modality called time-restricted eating in bipolar depression, where few treatments exist. And so, we’re exploring that as an add-on to conventional treatments. And then we are also currently conducting a randomized control trial of psilocybin-assisted psychotherapy for people with bipolar II depression, so bipolar II disorder and depression associated with that, and in parallel with the trial for psilocybin-assisted psychotherapy. So, it’s a very exciting line of research and I’m very grateful to the individuals and the places and institutions and funders who make this research possible.
Fiona 20:49
You know, what I’m hearing from both of you and what I really enjoy hearing is that both of your research seems to be very people-centered. You’re looking at the person—the individuals who are dealing with these challenges, and you’re looking at ways to effectively measure what’s happening and treat them in ways that work with their lives. We talked about how what you have in common is that, you know, you’re both clinicians as well as researchers. So, what does it mean to you to see the challenge from both sides? As clinicians, why is research—why is that aspect so important? What does it mean for your patients?
Dr. Gayatri Saraf 21:23
I think a lot of the research is driven by the questions that we see in the clinic in terms of, you know, why do people not respond to treatments? And, you know, not just if treatments are effective, but when do they work? For whom do they work? In what context and in what circumstances do these treatments work? So, that’s where we are moving into the field of personalized medicine now, where we hope to have answers to some of these questions in order to inform some of the treatments that we then carry on in the clinic. So, I think it’s a two-way process. Clinical work gives us the questions that we are asking as researchers, and basic sciences and neurosciences give us the tools to explore some of these questions. And then these tools, in turn, hopefully transform clinical care. That’s the dream.
Dr. Anthony Gifuni 22:14
I think there’s a lot of hope, and I think if there’s disappointment it is legitimate. That there has been in the treatments that we have in psychiatry a certain limitation, and I’m glad to hear that researchers [such as Gayatri 22:27] are sort of now expanding sort of this toolbox with intervention. And with my patients with depression, that suffering and that uncertainty that, “Is that going to work?” Other areas of medicine such as cancer treatment and oncology, you subject patients to treatments such as chemotherapy or radiotherapy, are extremely difficult for the body with a lot of side effects. But shortly after initiating treatment, you have an image or a blood marker that tells you, “Yeah, this treatment that is very expensive or very painful, it is working. The tumor is shrinking. That marker there, it is diminishing at exactly the rate that we expect, so continue. Go on with this treatment. We have confirmation that what we’re doing will allow you to reach recovery.” And we’re lacking this in depression treatment, bipolar treatment, in psychiatry at large. And the goal, really, is to have such a therapeutic target. Both for confirmation or the opposite, that if you’re subjected to a treatment that you don’t have to wait weeks on end and endure side effects, because we have early signs that it’s not working for you. So, it’ll be essential to develop those sorts of markers of response, and I think from the perspective of a patient it’ll be so much more reassuring to know, “Okay, this is actually working.” There’s a public health crisis in just the number of people that feel lonely. And that’s a subjective feeling where you feel disconnected from others, but it is increasing in our modern era where we’re supposed to be connected to each other. Loneliness is toxic for the body, affecting cardiovascular health, the risk of dementia. How the brain ages itself is shaped by whether you feel socially connected to the rest of society. Studying this with patients with depression or bipolar disorder, there’s implication at large to feeling more connected, to build resilience to rejection. And we do this for society at large. That science, specifically brain science, if it can benefit to our collective understanding and translate into the improvement of our lives, I think that’s the best we can hope for.
Fiona 25:03
You took the words right out of my mouth because I was going to ask you, “What’s one question about mental health and the brain you hope gets answered in the next decade?” And I think that was extremely eloquently put. [laughs] Gayatri, maybe I’ll ask you, what’s one question about mental health and the brain you hope gets answered in the next decade?
Dr. Gayatri Saraf 25:22
I think some of the most compelling questions that we’re faced with in mental health, are there novel effective treatments and how do we understand how they work and how can we personalize them? So, what Anthony was talking about was using tools like EEG to better predict response and better understand how these treatments might work, and so the hope is that we can personalize these treatments and see who may benefit most from some of these treatments.
Fiona 25:50
Well, you know, it sounds to me like we’re better equipped now than we’ve ever been to really address these [events’ 25:56] challenges. And I, for one, am grateful that the two of you and many other researchers across Canada and the rest of the world are working really hard on tackling these challenges. So, I’d like to thank you Dr. Gayatri Saraf and Dr. Dr. Anthony Gifuni for chatting with me today and thank you all for joining us on Bold Minds.
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Dr. Dr. Anthony Gifuni 26:15
Thank you.
Dr. Gayatri Saraf 26:16
Thanks for having us here.
Fiona 26:18
Bold Minds is a Brain Canada production with support from the Azrieli Foundation. Our executive producers are Jillian Donnelly and Kate Shingler. Our lead producer is Jess Schmidt, with editing by Morgane Chambrin. Thanks for listening. If you enjoyed this episode, we’d appreciate it if you could send it to a friend. If you want to learn more about Brain Canada and our Future Leaders program, please visit our website at braincanada.ca. [music ends]