24 October, 2003
Professor P M Matthews
Centre for Functional Magnetic Resonance Imaging of the Brain
University of Oxford
Over the last decade it has become clear that not only do the changes associated with MS result in loss of the myelin coating of nerve cells in the brain and spinal cord, they also lead to significant injury to axons and the nerve cells from which they arise. It is possible to study injury and loss of nerves and axons in the brain and spinal cord using a variety of magnetic resonance (MRI) methods. For example, MRI is very sensitive to changes in brain and spinal cord volume that come with loss or shrinkage of nerves and axons. Magnetic resonance spectroscopy (MRS) allows direct measurement in selected regions of the brain of the amount of a specific biochemical, N-acetylaspartate, which is found only in nerves and axons. Both MRI volume and MRS measurements have shown that neuroaxonal injury begins early in the course of MS. Moreover, the studies have established that neuroaxonal injury and loss appears to be the substrate for the progression of irreversible disability in multiple sclerosis. This has made neuroprotection a major target for new directions in therapeutics for MS.
However, the brain has its own, intrinsic protective mechanisms. The brain and spinal cord developed have adaptive mechanisms designed to modify functions in response to altered external or internal conditions. In fact, this is at the basis of learning and memory. The brain learns by changing elements of its connections in ways that appropriately adapt to new circumstances. Recent research has highlighted that the brain also changes its functions very widely in response to even a focal injury. These changes (described as resulting from “plasticity”) can allow normal behaviour to continue despite even substantial injury to the normal brain mechanisms controlling the behaviour by bringing into play new, adaptively recruited pathways to functionally “replace” those that were damaged.
Methods such as functional magnetic resonance imaging (fMRI) now allow brain scientists to map the patterns of activity in the brain associated with perception, movement or thought. Using these techniques, differences in patterns of brain activity have been identified in patients with multiple sclerosis, even when there appear to be no clinical deficits. The extents of these changes correlate with the burden of disease, just as anticipated if they were potentially adaptive processes. This suggests that one factor contributing to recovery from relapses and to maintaining normal behaviours in the earlier stages of the disease before progression sets in, despite continued neuroaxonal injury, may be brain plasticity.
Not only is the notion that the brain can heal itself in at least early stages of the disease exciting. Also, it now appears as though the nature of these adaptive changes can be modulated using common drugs. In recent experiments we have used anti-dementia drug, rivastigmine to demonstrate modulating acetylcholine, one of the neurotransmitters in the brain, allowing rapid changes in patterns of potentially adaptive responses with cognitive tasks. The results suggest that rivastigmine could be an effective treatment for some of the cognitive consequences of multiple sclerosis. More generally, it suggests that the mechanisms of plastic adaptation associated with responses to brain injury may provide an important new general target for therapies.
Understanding neuroaxonal injury has clearly entered “centre stage”
in MS research directed towards limiting the consequences of the disease.
The appreciation for potentially adaptive responses of the brain has opened
up a new set of targets for therapy, as well as providing insights into
the clinical course of the disease.
Copyright © 2003, Multiple Sclerosis Society