Using MRI to Investigate the Brain Response to Inflammatory Stimuli
In my previous blog, The Inflamed Brain: How inflammation can affect mood and behaviour — I talked about the FLAME study, a journey between body and mind that was part of my PhD, and I promised that I would come back and tell you the second part of my results.
I completed my PhD almost a year ago, and my research experience keeps shaping and feeding my current work as a clinical psychiatrist. Moreover, the implications of my research studies are still very relevant, and results are still being published (click here to read more of my recent research).
So, here I am, keeping my promise and telling the second part of the story.
My PhD focussed on the link between the immune system and depression, and how inflammation in the body could reach the brain and become brain inflammation.
To better understand this concept, you could have a look at my previous blog, or even think about what happens to you during times of stress or when you have an infection. In these instances, the activation of the immune system triggers the release of inflammatory cytokines (these are specific inflammatory proteins) in the bloodstream. It is thought that if inflammatory cytokines reach the brain, this could lead to a series of brain inflammatory processes, that can could be responsible for the onset of depressive symptoms. If confirmed, this would mean that inflammatory conditions (such as obesity, cardiovascular disorders, infections, diabetes, etc.) might also follow a specific biological pathway leading to the development of depression.
Whilst it is possible to measure inflammation in the body with a simple blood test, how can we confirm the presence of inflammation in the brain, too?
This has been possible by using imaging techniques, such as Positron Emission Tomography (PET). This is a type of brain imaging technique that involves an injection of a small dose of radioactive tracer compound. The radioactivity can target specific tissues of the brain and is detected by a camera, resulting in generating a sequence of brain images. However, a limitation of PET is that it is an expensive technique and involves exposure to radiation. That is why in my PhD, I wanted to explore the potential of another imaging technique, Magnetic Resonance Imaging (MRI).
MRI is considered to be less specific than PET in detecting brain inflammation, but it is much cheaper and less invasive for participants (See below for a brief explanation of how MRI works). In the FLAME study we wanted to compare these two techniques, so participants received both a PET and MRI scan.
What is the FLAME project?
The FLAME study, partly funded by the NIHR Maudsley Biomedical Research Centre, was conducted together with a team of neuroscientists and neuroimaging researchers at King’s College London (a special thanks to Andrew Lawrence and Tobias Wood), under the supervision of Dr Valeria Mondelli. Its aim was to trace inflammation in its journey from the body to the brain, by triggering temporary inflammation in healthy men.
We recreated the conditions of inflammation in seven healthy male volunteers, by administering a drug called Interferon-alpha. Interferon-alpha produces a temporary state of mild inflammation, which lasts up to 72 hours. A single injection of Interferon-alpha is quite safe, producing mild flu-like symptoms which can be easily treated with paracetamol (the study was approved by an ethical committee and all participants gave their consent to take part before starting the study).
After the injection of Interferon-alpha, we measured the resulting body inflammation with blood tests, and brain inflammation with PET imaging and with MRI. Our aim was to test whether the activation of a temporary state of inflammation caused by Interferon-alpha in the body was also associated with inflammation in the brain. An illustration of the study measurements is shown below.
Potential of MRI scans in detecting brain inflammation
We all know that science is hard, most of the time. What we plan to find with an experiment might not lead to the expected results, but to something completely different, although (hopefully) still relevant. In this case, PET imaging was not able to detect the presence of brain inflammation, but the PET data were published in a scientific journal because they were considered interesting and helpful.
By contrast, the unexpected result was that MRI was able to show some changes in the brain of our participants after the injection of Interferon-alpha, which could suggest the presence of inflammatory processes.
To understand how MRI can detect some of these changes, we need to consider how an MRI works and what it represents.
MRI images of the brain show different shades of grey, which reflect different tissue types in the brain. Two important features of brain tissue that are measured separately by MRI are “T1” and “T2” relaxation times. At a microscopic level, these features depend on tissue components (cells/proteins/lipids) and associated water. Changes in water and/or tissue due to biological processes (like inflammation) will cause changes in T1 and/or T2 features.
In the FLAME study, the injection of Interferon-alpha and the associated inflammation in the body as measured in the blood were followed by increased values of T1 in brain MRI. This could indicate an increased amount of water in brain tissue (known as oedema), which is a well-known consequence of inflammation. This was found specifically in the hippocampus, which is an area of the brain that is particularly involved in the development of depression. Interestingly, those participants with a greater degree of “body” inflammation (measured by the blood tests) showed the greatest T1 values in the hippocampus, suggesting that the two mechanisms are somehow related.
Our study, which was published in Brain, Behaviour & Immunity — Health, was done on a very small sample of participants, and so should only be considered preliminary. Moreover, MRI could be useful to assess the inflammatory response in the brain indirectly, by measuring the effect of inflammation on water and tissues. But if these findings are confirmed in future (larger) studies, this data would highlight the potential of MRI to indirectly investigate inflammatory processes in the brain, in a cheaper and less invasive way than PET.
This would allow early identification of people who have both depression and increased inflammation, especially among those who are not responding to antidepressants, and make them eligible candidates for additional treatments, including anti-inflammatory medication.
Our findings add to the growing evidence that psychiatric disorders, including depression, are overall medical disorders, and that the body and mind are definitely in this together!