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PhD studentship: studying brain inflammation

Led by: Dr Neil Harrison, formerly based at Brighton and Sussex Medical School, now Clinical Professor in Neuroimaging at the Cardiff University Brain Research Imaging Centre.

Aims: An increasing body of work suggests alteration in brain structure and function in M.E./CFS using magnetic resonance imaging (MRI). Additionally there is growing evidence that immune system and autonomic nervous system function is altered in ME/CFS.

Recruiting PhD student Marissa Amato, this project is focusing on differences in brain activity between people with M.E./CFS and fibromyalgia using state-of-the-art HCP (Human Connectome Project) resting state functional connectivity imaging.

It is investigating the neural responses to mild inflammation and how these might contribute to fatigue, post-exertional malaise and pain, and correlate with abnormalities of interoception, immune and autonomic nervous system function and metabolism.

Specifically, this project seeks to answer the following questions:

  • Do patients with M.E./CFS present with differences in neural connectivity as measured by resting-state functional connectivity (rfMRI) compared to controls?
  • Do patients with M.E./CFS show different connectivity responses to an inflammatory stimulus compared to controls?
  • Do these differences in functional connectivity correlate with altered interoception, dysautonomia or levels of inflammation in the blood measured with gene expression (transcriptomics) and metabolism (metabolomics)?
  • Can we use the answers to these questions to inform targeted research into the neurobiological mechanisms of M.E./CFS and highlight possible treatment targets in the future to enhance understanding of this often poorly understood condition and improve the lives of patients?

Dr Harrison says: “The principle hypothesis of the study is that people with M.E/CFS will show increased immune responses to a mild inflammatory challenge and this will be reflected in specific changes in brain activity and connectivity.”

“Using Canadian and Fukuda criteria, we will recruit people with M.E., fibromyalgia and healthy controls. All one hundred participants will undergo two brain-scanning sessions, once after placebo and once after mild inflammation induced by typhoid vaccine. It’s important to note the typhoid vaccine induces only a very mild inflammatory response and has never been associated with problems in people with M.E./CFS.

“Testing a number of variables after each challenge, including pain, fatigue, cognitive dysfunction, dysautonomia, interoception, inflammatory markers and gene expression, will help us better understand how changes in immune activity result in changes in behaviour.’

“This research is important as it will bring state-of-the-art brain imaging into the study of M.E./CFS, a standard this is being increasingly used in other illnesses affecting the brain. This will allow us to look in much greater detail at how M.E./CFS affects brain function and better understand how mild inflammation influences this.

“Importantly, because this brain imaging data will be acquired to the highest international standards, it will also allow us to begin to develop national and international consortia of M.E./CFS brain imaging data that can be used in future studies. At the end of this project, we will agree to share all the brain imaging data with other research groups to ensure more rapid progress in the field of biomedical M.E. research.”

Cost: The total cost of this project is £92,000, with £46,000 funded by Action for M.E. (made possible by donations to our Clare Francis Research Fund, match-funded by Brighton and Sussex Medical School.

Length of study: Three years

Study began: June 2018

More information

Previous research has shown decreased connectivity in left fronto-parietal networks in M.E./CFS compared to controls, which correlate with self-reported fatigue. However, less is known about the differences in brain microstructure and how these change in response to an inflammatory challenge. This is important because of the frequent post-infective onset/exacerbation of symptoms.

Dr Harrison is known internationally for his work in understanding how immune changes in the body affect the brain. He discovered that activation of the human immune system rapidly activates a neural immune-brain communication pathway that projects to a part of the brain called the insula. Individuals with a highly activated pathway experience much worse symptoms of fatigue than those with a less activated pathway.

In addition to the PhD study he is leading, funded by Action for M.E., Dr Harrison is working on two additional projects funded by Arthritis Research UK and the Medical Research Council (MRC).

The MRC-funded study forms part of a larger grant led by Prof Mark John James Edwards, at St George's, University of London. Some concerns have been raised about this study, which was included as a work package in a much larger grant, A unified mechanism for functional neurological symptoms, including that:

  • it is trying to prove that M.E./CFS is a functional neurological disorder
  • it will be used as evidence to move people with M.E. to treatment under the banner of Medically Unexplained Symptoms, which is psychiatric in focus
  • that study participants will be studying ALL patients with functional neurological disorder, and not people with clearly defined M.E.
  • the “treatment” referred to in the study abstract will be behavioural.

We asked Dr Harrison to address this. He says:

“Thank you for asking me about this. To clarify, the grant with Prof Edwards includes several independent work packages including some on non-epileptic attack disorder and functional movement disorder. These are led by Prof Edwards at St Georges and I have no involvement in either of these studies. This M.E./CFS study is completely separate study and is led by me at Brighton and Sussex Medical School.

“I do not conceptualise M.E./CFS as a functional neurological disorder and this study is certainly not trying to prove that M.E./CFS is a functional neurological disorder. My view is that M.E. is a complex, systemic condition, which requires appropriate biomedical treatment; our current study aims to provide important new evidence in support of this.

“Further details on my past and on-going work and its relationship to M.E./CFS can be found in a series of videos I made with a Dutch M.E./CFS charity, ME/CVS Vereniging.

“The principle hypothesis of the M.E./CFS study is that post-exertional malaise (PEM) – a core feature of M.E./CFS – results from heightened and persistent immune activation and immune-brain signalling following a standard exercise challenge. This study forms part of a broader hypothesis being investigated within my group, namely that heightened or more prolonged activation of immune-brain communicatory pathways play an important aetiological role in ME/CFS.

“What we are investigating is the basis of post-exertional malaise in people with M.E./CFS. Essentially, the study is using MRI and blood markers of inflammation to try and better understand post-exertional malaise.

“Everyone taking part in the study comes in twice. On the first day they have a MRI brain scan and some bloods taken. They then complete a carefully monitored exercise test (on an exercise bike where their expired air is measured and power output monitored) and have another blood test. Following this they go home. The next day they come back into the imaging centre. They have another MRI brain scan and another exercise test.

“What we are interested in understanding is why people with M.E./CFS experience post-exertional malaise after exercise. We predict that this will be because exercise induces a stronger inflammatory response (related to the inflammatory cytokine IL-6) and that this ‘over-activates’ the brain system responsible for communicating changes in body physiology to the brain. We predict that this ‘interoceptive’ pathway will remain over-activated in people with M.E./CFS, even a day after exercise.”