Dr. Nikolai Malykhin Uses the Power of Advanced Imaging Technology to Research Tiny Brain Structures Linked to Depression and Aging

Dr. Nikolai Malykhin has been an Associate Professor in the Department of Psychiatry since December 2019, but he’s hardly a newcomer. His ties to the department go back more than a decade and a half.

After earning a medical degree and completing his Residency in Psychiatry in 1999, Dr. Malykhin worked as a practicing Psychiatrist before completing his PhD in Psychiatry in 2003 – all in his native Belarus.

“If you want to be a scientist or Professor in Belarus you have to work for several years as a practicing Psychiatrist to gain more clinical experience, and then you do a PhD in Psychiatry. Only after that can you become an Assistant Professor. It’s a different scientific ladder there,” he explains.

“After I did my PhD I realized I was more passionate about research than clinical work, so I decided to acquire additional training in Neuroimaging, which isn’t a very common field of research in Belarus.”

He was subsequently awarded two Postdoctoral Fellowships from the Canadian Institutes of Health Research (CIHR) and the Alberta Heritage Foundation for Medical Research (AHFMR) to pursue his research at the University of Alberta, where he worked with Department of Psychiatry Professor Dr. Nick Coupland from 2004 to 2008.

Although Dr. Malykhin had opportunities to return to Belarus, he chose to remain at the U of A, which had the best imaging facilities in Canada at that time.

“I was offered a position in 2008 in the Department of Biomedical Engineering, which operates the MRI (Magnetic Resonance Imaging) Centre, where I could continue to pursue my imaging research. I also became an Adjunct Professor in Psychiatry.”

Last December, Dr. Malykhin completed the circuitous academic round trip that started 16 years ago, moving back to the Department of Psychiatry full-time as an Associate Professor to do more translational Neuroscience research. “In that sense I’m new to the department,” he explains.

Dr. Malykhin’s research team and long-term collaborators including Dr. Nick Coupland, Dr. Esther Fujiwara, Dr. Peter Silverstone and Dr. Richard Camicoli – are focused on three key areas: Computational Neuroanatomy, the Aging Brain, and Major Depression. His research is supported by CIHR and the Natural Sciences and Engineering Research Council of Canada (NSERC).

Below is an edited version of our hour-long interview with Dr. Malykhin about his research:

Q: What drew you to this field of research?

A: When I did my PhD I started doing research on patients with Bipolar Disorder and Schizoaffective Disorder with manic symptoms. I was trying to see if atypical antipsychotics have an advantage over mood stabilizers to treat mania. For this pioneering work I received several international awards from the British Association for Psychopharmacology, the European College of Neuropsychopharmacology, and the Western Psychiatric Institute and Clinic in Pittsburgh. That was in 2003-2004 just before I moved to Canada.

Q: Did you continue that work when you moved to the University of Alberta?

A: When I moved to Canada, I started doing research on the opposite pole of the mood spectrum – Depression – with Dr. Nick Coupland. We used different MRI applications to study what happens in the brains of people who suffer from Depression, and the effects of long-term antidepressant treatment on the brain. The structures affected by Depression such as the hippocampus and amygdala are very small, and we used ultra-high resolution high-field MRI (4.7 Tesla) technology to visualize those and understand how they change over time, with disease progression or with treatment.

Q: What did your research show?

A: In 2013 we published the first high-field imaging study of how cellular subfields of the hippocampus are affected by Depression and confirmed for the first time that changes in the hippocampus in depressed patients resemble changes observed in animal studies of chronic stress. Just so you are aware, most preclinical studies of Depression are done in rats using different chronic stress models, so there is very little translational research that allows us to confirm that what happens in rats happens in humans.

Q: Why is that?

A: Humans endure social stresses, primarily. The model for Depression in animal studies is chronic unpredictable stress, which could be physical stress, or temperature changes, or pain, or restrictions of some kind. But psychological stress is difficult to model in rats. A stress vulnerability model, also called the Stress-Diathesis Model, has been proposed as a main model for Depression. In our research we are trying to understand how changes in stress hormones and adverse childhood experiences contribute to the pathophysiology of major Depression.

Q: So vulnerability to stress makes one susceptible to Depression?

A: You’re asking a very good question. There are two things, acute stress and chronic stress. Acute stress may occur when you have to give a presentation to a hundred people. Your stress hormone cortisol level jumps and your heart rate goes up, but once you’re done, you’re fine.

Q: What is chronic stress?

A: Imagine that you have multiple stressors that last for months each year, and you cannot control them or cope with those stressors successfully. That’s chronic stress, and the link between chronic stress and psychiatric conditions like Depression is overwhelming. There have been many studies on this, showing that if people experienced three or more adverse life events in the past, they have a much higher probability of developing not just Depression but other psychiatric disorders including Anxiety Disorders, Addiction or even Psychosis. Stress is not unique to humans but the impact of psychological stress is unique, since this is the major type of stress that we experience in our everyday life.

Q: Did that guide your research then?

A: Yes, so we did several studies on stress hormone cortisol and demonstrated that in both healthy subjects and patients with Depression it can negatively affect specific hippocampal subfields that are particularly vulnerable to the effect of chronic stress in animal studies. Furthermore, we demonstrated that the impact of adverse childhood experiences on the brain is long lasting and could be more severe than the effects of Depression itself.

Q: What about brain plasticity? Can some of these changes to brain structure be reversed?

A: Many studies, including our own, have shown that if people who suffer from Depression start taking antidepressants, their hippocampal volume goes back to normal. So yes, those changes can be reversible. But what happens if you remove those medications, or what happens if you remove the underlying factors which cause chronic stress? What happens to the brain? Those kinds of studies have never been completed. More recently we’ve developed MRI applications to record functional activity from those tiny hippocampal subfields and amygdala subnuclei. We can measure the activity in those structures, see how they are affected in patients, and track progress over the long term. When it comes to clinical psychiatric research this has never been done before, not just in Canada but in the world.

Q: Can you describe your research on the aging brain?

A: Sure. We conducted the largest high-field MRI study of healthy cognitive aging in Canada. We showed that functional MRI changes in the brain start much earlier than we expected (as early as the mid-20s), while structural brain changes including hippocampal volume decline start in your late 50s, so there was good news and bad news. The aging process does not start at one’s retirement age, as we often think.

Q: Can you also look at how the brain processes emotions?

A: Yes, we can detect activity in different amygdala subnuclei during your emotional processing. The amygdala is very small, it’s about the size of an almond, but we can separate the amygdala into different subnuclei and record their activity using functional MRI. When you unconsciously respond to different emotional images, we can predict by amygdala subnuclei activity which emotional picture you are actually viewing.

Q: So what practical outcomes do you envision emerging from this research?

A: Two things. First of all, if you apply these techniques you can monitor disease progression or how people respond to treatment. For instance, the dentate gyrus in the hippocampus is one of the few areas of the brain that produces new neurons. It is linked to memory function and its size is reduced in Depression. Antidepressants tend to increase neurogenesis in the hippocampus, so now we can measure dentate gyrus volume in vivo, we can measure its activation in vivo, and we can track changes in the dentate gyrus with time, disease progression or treatment.

Q: What is the second thing?

A: The second is the ‘bench to bedside’ translation of our findings as they relate to the impact of stress. The idea is that clinicians who see patients regularly will not just try to treat specific symptoms with psychotropic medications, but may also try to get at the history of past or present stressful experiences and their impact. So their treatment would be focused not only on prescribing medications but on increasing the resilience of people to those adverse effects of stress. All the research in behavioural studies of stress shows that even if you can’t change the stressor you can change your emotional responses, and that’s the key.