Can mathematical models shed light on clinical depression? UPES faculty tells us how

Dr. Melissa Reneaux, Assistant Professor, UPES School of Liberal Studies

A computational neuroscientist by training and Assistant Professor at the School of Liberal Studies UPES, Dr. Melissa Reneaux is working on building mathematical models to understand inflammation-associated depression, and the effect anti-depressants and antihistamines have on alleviating depression

When we talk about mental disorders, we often view them only from a psychological perspective, ignoring the role of bodily functions. However, what happens in our brain has a direct connection with our body. For instance, clinical depression has a direct relationship with bodily inflammation.

“At the onset, clinical depression is seen as a chemical imbalance in the brain caused by a reduction in the level of serotonin – a neurochemical in the brain associated with an individual’s mood. However, recent literature shows that depression may also be associated with bodily swelling (also known as peripheral inflammation),” explains Dr. Melissa Reneaux, Assistant Professor at the School of Liberal Studies, UPES.

Peripheral inflammation increases the level of histamine in the brain – a chemical known to be commonly associated with allergies, runny nose, and sneezing to name a few. “This increase in histamine reduces serotonin levels in the brain, which leads to depression,” she says.

A computational neuroscientist with training in Physics, Dr. Reneaux is working on building mathematical models to understand inflammation-associated depression, and the effect of antidepressants and antihistamines on alleviating depression.

How does mathematics fit into solving biological and psychological questions? “If you think about medical imaging techniques like X-ray, CT scans and Functional Magnetic Resonance Imaging (fMRI) used to detect disease in the body, to using probability and statistics to validate a drug’s effectiveness, all these measures were developed by individuals with a training in mathematical sciences. Here, I am addressing mental disorders using mathematical principles,” she says.

Dr. Reneaux highlights that in mental disorders, the approach followed for treatment is psychological, however, the metrics used are grounded in mathematics. “For instance, in depression there are self-reporting assessments like the Patient Health Questionnaire (PHQ). In this test, individuals are asked a series of questions based on their mood, and the severity of depression is graded. Based on the scores obtained, individual’s are classified as mildly, moderately or severely depressed, and  henceforth the medication course begins.”

As part of her Master’s thesis, Dr. Reneaux worked on understanding rheumatoid arthritis – an auto-immune disease causing severe pain and inflammation in the joints of individuals suffering with this disease – using the principles of physics. She was amazed to see how physics and mathematics could be used to address questions in biology. As her interest in understanding human diseases grew, she decided to use the concepts of physics and mathematics to understand mental illnesses.

It was during her post-doctoral research work at Imperial College London, that she came across a startling revelation. “My research team was working on finding biomarkers in the body of depressed mice. We measured serotonin in the mouse brain while mice were injected with lipopolysaccharide – a chemical that elevates body inflammation. The mice also underwent a chronic mild stress paradigm. We found that another chemical, histamine, which is a marker for bodily inflammation, was also elevated in the mouse brain, which led to a reduction in serotonin. This interaction between histamine and serotonin led to clinical depression,” explains Dr. Reneaux.

This research demonstrated that inflammation in the body could lead to changes in the brain. Dr. Reneaux developed a metric termed Stress Index. “This is a scale that varies from zero to positive values. More the positive value of the Stress Index, greater is the level of stress in the individual. Bodily inflammation causes an increase in stress levels, causing alterations in the level of the neurochemicals, which can be measured,” she adds.

While going through the literature on clinical depression Dr. Reneaux, was shocked to discover that more than 30 crore individuals around the globe were depressed according to the 2017 World Health Organisation (WHO) report. COVID-19 saw a drastic increase in these numbers. About half of the depressed population that happens to be such a large number do not respond to anti-depressant medication. And those individuals who do respond to medication, it took weeks and months for the medication to act on them and make them feel better.

“Antidepressants like the Selective Serotonin Reuptake Inhibitors (SSRIs), which are the first line of treatment for depression, show limited ameliorating effects. Serotonin until recently was known to be the only neurochemical lowered in depression. So, treating depressed individuals with SSRIs, should have made them feel better. However, this was not the case,” she says.

This fact made her team wonder if there was a missing link in the understanding of depression. The depression literature suggested that about a quarter of individuals who had depression also had bodily inflammation which meant they had increased histamine levels. “The experiments conducted by my team observed that rise in histamine reduces serotonin, and subsequently serotonin aided in the production of more histamine. Hence, when serotonin medication was provided to these mice, a rise in serotonin did occur but so did the level of histamine, that led to the lowering of serotonin. There exists a bi-directional interaction between histamine and serotonin. We found that mice for whom the underlying cause of depression was inflammation, when they were treated with a combination of SSRIs and histamine inhibitors showed a rise in serotonin,” informs Dr. Reneaux.

This study now published in the Journal of Neuroinflammation was performed on mice and used chemical recordings from the mouse brain. However, this invasive approach is not feasible in human subjects. So, Dr. Reneaux is presently involved in building a mathematical model that provides measurable outputs as brain wave frequencies to alterations in the level of inflammation. These brain wave frequencies can be measured using non-invasive electroencephalogram (EEG) recordings. “In depression, there is an observed reduction in theta frequency band (3.5 to 7.5 Hertz) in the pre-frontal cortex – the brain region involved in thinking and an increase in theta band activity in the anterior cingulate cortex – the brain region involved in emotions. This mathematical model will show the impact of antidepressants and antihistamines on these brain waves,” Dr. Reneaux describes.

One of the main concerns associated with depression is the high suicide numbers of depressed individuals around the globe. Dr. Reneaux is also working with researchers at the Miami University, Ohio, on a joint project that is investigating reasons for suicidal ideation among youth in Northern India. Dr. Reneaux is passionate about her research as she sees her research work having the potential to directly influence the well-being of people.