Functional implications of focal white matter lesions on neuronal circuits

Multiple sclerosis (MS) and other neurodegenerative disorders like dementia, Alzheimer's, and Parkinson's disease have a large impact on people's lives and society. There are no fully effective treatments available to stop these diseases from progressing.

The human brain is divided into two equal halves: grey and white matter. Most of the research on neurodegenerative disorders has focused on the grey matter of the brain, which contains the neurons, but has overlooked the role of the white matter. New research is showing that lesions within the brain's white matter occur in neurodegenerative disorders. The number of these lesions is linked to problems with thinking and movement. Importantly, these lesions can appear before people experience any symptoms, indicating that these lesions may have a role to play in the disease progression.

MS is characterised by white matter lesions in the brain, and from MS research we know that white matter lesions can be repaired, which allows for full symptomatic recovery. This is because in our brain we have specialised stem cells that can repair white matter lesions. Although white matter lesions can be repaired in MS, this regeneration process eventually fails, more so as we age. The failure of repairing white matter lesions can lead the loss of neurons (neurodegeneration), ongoing brain inflammation, and disability.

Inflammation in the brain, which is a low-level and ongoing process, is common in both neurodegenerative conditions and MS. Our early results from animal studies suggest that repairing white matter lesions reduces inflammation in both the grey and white matter of the brain. It seems that the failure to repair white matter lesions properly may be causing the ongoing brain inflammation. Our data show that inflammation in the brain and changes in neurons are necessary to trigger white matter repair. This suggests that we need to understand how inflammation, neurons, and white matter lesions interact in order to develop effective treatments, as targeting only one part, like the grey matter or the immune system, may not be enough to prevent further damage.

Our research aims to fill this knowledge gap by studying how white matter lesions affect brain function, grey matter inflammation and how repair of white matter lesions is regulated. We hope to learn more about neurodegenerative diseases and whether repairing white matter lesions can reduce brain inflammation, which may be causing the loss of neurons. This research could lead to the development of new treatments that focus on repairing the brain's white matter to preserve brain function. Ultimately, our goal is to reduce the burden of these diseases on individuals, families, and society as a whole.

The effects of white matter lesions in the central nervous system are underexplored. These lesions accumulate in multiple sclerosis (MS) and neurodegenerative disorders, which impose significant socioeconomic burdens, and lack effective treatments to halt disease progression. Emerging evidence indicates the number of white matter lesions correlates with cognitive and dexterity impairment. Across these conditions, lesions precede grey matter atrophy and clinical symptoms, suggesting that they play a causative role in neurodegeneration. In progressive MS, neurodegeneration is thought to be a consequence of failed myelin regeneration. Hence myelin regenerative therapies have been identified as effective protection against neurodegeneration in MS, and may represent a more widely applicable strategy, given the commonality of white matter lesions across age-related neurodegenerative disorders.

We hypothesise that focal white matter lesions evoke functional changes in neuronal circuits that regulate myelin regeneration to restore function.

We will use established methods and in vivo models of myelin regeneration and failed remyelination, to answer the following key outstanding questions that address our hypothesis:

1. What are the functional consequences of focal white matter lesions on circuits?
2. How does circuit function regulate myelin regeneration?
3. What is the role of distal neuroinflammation in regulating circuit function and myelin regeneration?

This research programme will map the consequences of white matter lesions within a circuit, and detail the significance of failed myelin regeneration on circuit function. Demonstrating a causative link between white matter lesions and neurodegenerative disorders will reframe therapeutic strategies to improve neuronal health in a range of neurodegenerative conditions.