On the Edge
by Women’s Brain Health Initiative:
STRESS, DEPRESSION, & INFLAMMATION’S IMPACT ON THE BRAIN
Whether it is family tensions, trouble at work, or a constant barrage of negative news, stress is an unavoidable fact of life. For a long time, stress was believed to be something experienced only in our brain. More recently, however, researchers have begun taking a broader, full body view of stress and its impacts on our health.
“It’s logical because when you’re stressed, your heart is pumping, your breathing accelerates, and you’ll have a knot in your gut. These are the phenomena people experience but we don’t exactly know if and how they may contribute to the actual brain response, especially if the stressor is lasting for a long period,” said Dr. Caroline Ménard, an Assistant Professor in the Department of Psychiatry and Neuroscience at the Université Laval and a researcher at the CERVO Brain Research Centre.
“Of course, the brain is the master regulator, but we think that there might be a contribution from other parts of the body such as the immune system or the gut microbiota. That’s what we’re trying to understand.”
Dr. Ménard and her colleagues are currently studying how and why stress might contribute to mood disorders such as depression or posttraumatic stress disorder (PTSD).
“I think it’s an exciting and essential field of research,” Dr. Ménard told Mind Over Matter®.
STRESS TOUCHES EVERYBODY, AS WE’VE SEEN IN THE PAST TWO YEARS. IN MY LAB, WE’RE TRYING TO UNDERSTAND BOTH SIDES OF THE COIN: NOT ONLY HOW STRESS CAN LEAD TO DEPRESSION, BUT ALSO WHY SOME PEOPLE ARE MORE RESILIENT THAN OTHERS.
VULNERABILITY VS. RESILIENCE
Supported by a 2019 Azrieli Future Leader in Canadian Brain Research grant from Brain Canada, and made possible through the Canada Brain Research Fund (CBRF), Brain Canada's partnership with the Government of Canada, Dr. Ménard’s research team is looking for answers by observing how mice react to various forms of stress. Importantly, the researchers also confirm (when possible) whether the biological mechanisms identified in mouse models of depression are also present in human samples.
Her focus is on the blood-brain barrier (BBB), a network of cells that forms a physical barrier that helps prevent harmful substances circulating in the blood from reaching the brain, and the gut barrier, which performs a similar function in our intestines.
Through their studies of mice, Dr. Ménard and her team found that during long periods of persistent stress, inflammation could make the BBB more fragile, thereby allowing the passage of deleterious cytokines from the blood into the brain, which could contribute to depression. This finding was subsequently verified in the brains of deceased individuals who had received a diagnosis of major depression.
THE RESEARCHERS ALSO LOOKED FOR VARIANCES BETWEEN WOMEN’S AND MEN’S BRAINS AND FOUND THAT THE BLOOD-BRAIN BARRIER WAS AFFECTED IN DIFFERENT REGIONS, SOMETHING THAT MIGHT EXPLAIN WHY WOMEN AND MEN SOMETIMES EXHIBIT DIFFERENT SYMPTOMS OF DEPRESSION.
While symptoms will vary from person to person, research has indicated that women are more likely to display more “classic” symptoms of depression, such as crying, whereas men may become more irritable.
Sex differences were also found in the way that the mice reacted to stress. For example, males were more affected by simulations of ongoing bullying, whereas the females were more affected by unpredictable stressors such as a delay in receiving food or water.
SEARCHING FOR BETTER TREATMENTS
“We’re really trying to understand the role that these barriers (both the BBB and the gut barrier) play in stress responses, and if they could represent attractive targets to develop novel antidepressants or support the treatments currently available,” noted Dr. Ménard.
IT’S VERY INTRIGUING BECAUSE IN PEOPLE WHO ARE RESISTANT TO ANTIDEPRESSANT TREATMENT, WE SEE THIS INCREASE IN INFLAMMATION IN THE BLOOD, AND WE THINK THAT IT MIGHT COME FROM THE GUT AND POSSIBLY PLAY AN ACTIVE ROLE IN TREATMENT RESISTANCE.
In the last decade there has been increasing interest in the bacteria of our gut and the microbiome and how they can regulate human health, including emotional processes. If the gut barrier becomes leaky due to persistent stress (as Dr. Ménard’s team observed for the BBB), then this may ultimately play a role in making the BBB leaky as well and contribute to the inflammation reaching the brain.
“This is something we’re trying to figure out. Basically, stress is not only in the brain, but also your whole body, including the gut.”
An important aspect of her work is studying why certain individuals are more resilient (i.e., why does one person become depressed after experiencing stress, while another does not). Is it possible to train our brain and body to be resilient? Dr. Ménard suggests that the answers may lie, at least in part, in improving the BBB and the gut barrier to better protect the brain from the effects of inflammation.
“It seems that we can promote resilience. It could be done with diet for the gut and for the BBB, and we know that exercise can improve neurovascular health. That’s the kind of thing we’re trying to tackle by giving running wheels or a diet enriched in good fatty acids to our mice before (as opposed to during) exposure to stress. We hope to understand the biology of resilience and how diet or exercising contribute to positive mental health. In humans it is very challenging to do because people will often decide to eat better and exercise more at the same time.”
In the process, she hopes to discover better ways of diagnosing, treating, and perhaps even preventing depression. Currently, it is challenging for physicians to determine which medication will work best in treating depression for an individual because symptoms and life experiences vary, and the effectiveness of treatments varies between the sexes. For example, some clinical studies suggest that women respond better to selective
serotonin reuptake inhibitors (SSRIs), while men seem to respond better to tricyclic antidepressants.
IMPROVING DIAGNOSIS
Unlike other diseases, like cancer, psychiatric conditions do not have biological markers yet. There is no genetic test or a particular molecule that can be measured in the blood to confirm diagnosis. Consequently, clinicians must rely primarily on questionnaires. When asked to measure emotional distress on a scale between one and ten, different people will give different answers that may not accurately reflect their level of distress.
Dr. Ménard believes that having an unbiased biomarker would be a significant advancement.
“We work hard to find biomarkers that will help guide the choice of treatment or maybe even identify targets that will lead to the development of new treatments that could target systems other than the brain, like the gut and inflammation – treatments that could complement those that we already have and help more people than we do right now,” she said.
“We really call it the holy grail in psychiatry.”
Looking ahead, she aspires to secure funding to expand her studies into the impacts of stress and inflammation on dementia.
Dr. Ménard’s work has potentially profound implications and she credits Brain Canada’s support as crucial, particularly given that she is early in her career as a scientist – a time when grants are harder to obtain.
“The Brain Canada funding is very important because it allows us to open a new line of research and supports the training of the next generation of scientists. We’re very grateful for the support. We couldn’t do this without them.”
She noted that she is constantly asked for advice about how to minimize stress and promote resilience.
“There’s no one recipe; everyone must figure out their own – baking, gardening, listening to or playing music, spending time with family, and/or sometimes just taking a few minutes out of your day to relax can make a difference. But if you do feel badly, then you should not hesitate to seek professional help.”
When asked for her personal recipe, Dr. Ménard laughed as she discussed her love of video games and live concerts.
“It’s very good to get out of my head and not think about the science.”
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Between 30-50% of people with major depressive disorder are resistant to current antidepression treatments.
When we are stressed, our body’s immune system releases inflammatory cells and signals such as proinflammatory cytokines.
Elevated inflammation, including in the brain, is found in people with a variety of other conditions such as Alzheimer’s disease, stroke, and cardiovascular diseases. Clinical studies suggest that individuals with these conditions have higher rates of depression and, conversely, those with depression are more at risk of developing these conditions. It suggests that stress – through its impact not only on the brain, but also on the immune system and the gut barrier – may play a role in higher prevalence of depression in these individuals. However, future studies are required to better understand these relationships.
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