The Becker’s new Neuro-immunology Branch Lead Dr Andy Greenhalgh writes about his lab’s work on concussion (or mild traumatic brain injury) in the latest in our ‘Study in Focus‘ series.

His research investigating the role of meningeal inflammation in mild traumatic brain injury (TBI) using mouse models and advanced brain MRI of professional rugby players could lead to new imaging methods and treatments for the increasing number of patients believed to suffer from longer-term complications from mild TBI – including symptoms such as anxiety, mood swings, and neurodegenerative disease later in life. 

The problem

The term concussion is part of our everyday vocabulary, though clinicians and scientists know very little of what causes symptoms after this type of head injury. In the field, we prefer to use the term mild traumatic brain injury (TBI), which refers to a mechanical force resulting in acceleration of the head and may or may not leave the person unconscious for a short period, possibly with memory loss and often associated with headache.

Most mild TBIs occur due to road traffic accidents, falls, and domestic violence, though perhaps they are most commonly associated with contact sports. The above symptoms are likely well-known and usually resolve after a few days. However, in a proportion of people, mild TBI may cause longer-term issues such as mood swings, anxiety, and cognitive issues, and in the case of repetitive mild TBI neurodegenerative disease in later life. We are now only beginning to understand the full consequences of mild TBI, and it is essential we know the underlying mechanisms.

A major issue up to this point is that normal clinical brain scans are not sensitive enough to show problems in the brains of people with a mild TBI. In fact, it is what is often the defining feature. A head injury, acute neurological problems but a clear CT or MRI scan results in a mild TBI diagnosis. But patients’ symptoms show there is clearly something going on in the brain, and we hypothesise the immune system plays a key role.

Examples of MRI scans performed on elite athletes with and without concussion: T1 weighted imaging, Post-contrast FLAIR, Dynamic contrast enhancement (DCE), Susceptibility Weighted Imaging, Arterial Spin Labelling, Diffusion-weighted Imaging

The backstory

I have worked in the field of neuroimmunology for over 15 years and was recruited to The University of Manchester’s Lydia Becker Institute of Immunology and Inflammation as a group leader and Presidential Fellow in July 2020. My career has come full circle after completing my PhD in Manchester with Prof. Dame Nancy Rothwell. It is here that I was first introduced to inflammation in the context of brain injury, through models of stroke and brain haemorrhage and the clinical translation of anti-inflammatory molecules.

During my postdoctoral work at McGill University, Canada, with Dr Sam David I became a fully-fledged neuroimmunologist with a special interest in microglia, the central nervous system’s resident macrophage. I worked on these cells in traumatic spinal cord injury and models of multiple sclerosis, but I was always fascinated by the immune system’s control of brain function in health, and more subtle injuries like mild TBI.

As a result, I moved to the University of Bordeaux, France, as a Marie Skłodowska-Curie Postdoctoral Fellow to begin to study the immune system’s role in mild TBI and whether it is responsible for symptoms following injury. After three years of setting up a new mouse model and learning animal behaviour I returned to Manchester and was awarded an MRC Career Development Award to study the neuroimmunology of mild TBI

Example of macrophage heterogeneity in the meningeal membranes shown by Hyperion Mass Cytometry with various markers of macrophages and endothelial cell. We propose that these cells contribute to changes in brain function after a mild traumatic brain injury (TBI).

Our research

Inflammation is a key regulator of brain injury, mood disorders, and neurodegenerative disease, and neuroinflammation can be driven by brain-resident microglia. However, it is now recognised that immune responses at the brain-periphery interface can also regulate brain function in a variety of contexts, both in health and disease.

A major constituent of these brain borders are the meninges, a group of membranes covering the surface of the brain that are recognised as hubs of inflammation in many disorders. Surprisingly, little is known of the role of the meninges in concussion, despite their proximity to head impacts.

We use a combination of mouse models of mild TBI and a recruitment programme of professional Rugby Super League athletes that undergo advanced brain MRI after a mild TBI. With these approaches, we are testing our hypothesis that meningeal inflammation drives brain changes that are important for the development of mild TBI symptoms.

This work is done at The University of Manchester within the Lydia Becker Institute of Immunology and Inflammation in collaboration with neurosurgeons and neuroimaging experts at Salford Royal NHS Foundation Trust.

If successful we hope to find new ways to image the brains of patients and new target areas for therapies against the effects of concussion. This is extremely important as we currently have little understanding of these processes and no treatment options for those affected.

The future

Our current work is beginning to suggest that in mild TBI there is a robust immune response in the meninges which may explain the brain’s vulnerability to multiple TBIs. We are now testing if this is the case in athletes susceptible to multiple mild TBIs and hope to find new ways of imaging the brains of these people and find new targets for therapies.

Dr Andy Greenhalgh – Neuro-immunology Branch Lead and MRC Career Development Award Research Fellow, Lydia Becker Institute of Immunology and Inflammation, University of Manchester

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