Windows to the brain

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With the huge advances in biology, it can seem that areas such as brain scanning are relatively stagnant, but we are starting to see a growing momentum in the field, allowing researchers to learn more about the ‘real time’ events occurring in individuals with MND.

Hand in hand with the improving technology that allows us to visualise the structures and connections inside people’s brains, as the scanners get more powerful, are the new ideas and techniques that researchers are applying. These help them to get the most from their studies by pooling their data and analysing it in different ways.

Giving the plenary presentation on this neuroimaging session, titled ‘The Past, Present and Future of Neuroimaging in MND’ was Dr Martin Turner, one of our Medical Research Council/ MND Association Lady Edith Wolfson Clinical Research Fellows, who heads the groundbreaking Biomarkers in Oxford project (BioMOx).

Dr Turner described the potential uses of the three main imaging technologies: PET (positron emission tomography) MRS (magnetic resonance spectroscopy) and, in particular, MRI (magnetic resonance imaging) which have developed considerably over the past decade, giving a ‘world tour’ of the results from the leading centres in MND neuroimaging. Indeed, he spent so much time highlighting the work of others that he only briefly mentioned his own very recent and exciting research from the BioMOx study, where he has used advanced imaging techniques to compare how the brains of people with MND are physically linked up (called structural connectivity) with how the brain actually works (called functional connectivity) as compared to unaffected ‘controls’. Having just read his latest findings on the flight over, I think they deserve a slightly fuller mention.

Second results published from BioMOx project
In the study, 25 people with ALS, the most common form of MND, took part in this part of the study, as well as 15 healthy individuals.

As the motor neurones in the brain degenerate, he saw an increase in functional connectivity and activity in other parts of the brain, associated indirectly with movement. This ‘boundary shift’ described by Dr Turner has an extended pattern of activity beyond standard motor systems.

Not surprisingly, the brain has a great capacity to compensate and adapt to damage (recovery from stroke being a prominent example). However, Dr Turner’s study also shared that people with slower progressing forms of MND had much lower levels of increased connectivity than those progressing rapidly, which was more than controls. This wasn’t simply due to people with a slow progression being at an earlier stage of the disease, as those with a slow progression at relatively advanced steps of MND were also included.

He speculates that the increased functional connectivity might actually be an active contributor to disease progression. One possibility is that in recruiting additional brain areas, together with some possible ‘rewiring’ occurring, it is altering with the complex balance of ’excitation and inhibition’ – in other words the way other neurons in the brain send positive or negative signals that control how active the motor neurons are.

This study demonstrates yet another step forward towards the development of robust clinical test for MND to speed up the diagnosis process. Although there is a lot of work to done to confirm these findings, we’re definitely heading in the right direction.

OK – back to the meeting!
Dr Turner highlighted one of the major challenges – namely the question of whether we can apply these techniques to clinical trials (as has been done in multiple sclerosis and which has revolutionised the search for treatments). However, several problems need to be overcome, not least the fact that patients taking part in a trial may be very different in their disease presentation and/or at different stages of the disease. So there is still a lot of noise in the system, which is why Phase III clinical trials often need to involve several hundred patients. Performing multiple MRI scans on each participant would add huge cost to any study.

Dr Turner also highlighted the challenge, but also a tremendous opportunity, to perform ‘comparative MRI’, linking the events going on in mouse models of the disease with those in man. Dr Robyn Wallace, from University of Queensland, elaborated on this theme with her presentation of imaging data from the SOD1 mouse. Using an intensely powerful scanner (10 times more powerful than a standard hospital scanner) she could show evidence of degeneration of the motor nerve tracts in the mouse spinal cord and was able to see these changes from around symptom onset. This is the first study to show that this form of MRI can show changes in the same mouse as the disease progresses. She also performed very detailed MRI studies on the intact spinal cord removed from mice – examination of the spinal column on its own improves the resolution and also allowed her to immediately perform the detailed histological examination of the tissue changes that had occurred. It is hoped that this very detailed work will help in the interpretation of human MRI scans in the future.

Finding out when MND begins
How early can we measure changes in man? Since 1997, Dr Mike Benatar from Emory University, has been performing studies on individuals who carry the SOD1 gene mistake (mutation) but have not yet shown any symptoms of MND, in an attempt to answer the question of when the neurodegenerative process begins, as opposed to when the first symptoms appear. Certainly, research from other fields, such as Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, indicates that the process can start years before.

Dr Benatar reported his findings using both MRI and MRS. To date, he has not been able to show any major ‘structural’ differences (nerve cells that are physically connected in the brain) in his ‘pre-inherited ALS (the most common form of MND)’ individuals compared to healthy individuals of the same age, but he is seeing some metabolic changes using MRS, which can measure the relative signals of a small number of different chemicals in the spinal cord. He is continuing with the study, but extending the range of inherited forms of the disease to include inherited cases of ALS patients and ‘pre-inherited ALS’ volunteers carrying TDP-43, FUS, VCP and C9ORF72 genetic causes.

For those of you who might ask how MRI scans work, here’s a very brief explanation:
Magnetic resonance imaging (MRI) is based on the concept that some molecules in the brain, in particular water molecules, will line up in a particular direction in a strong magnetic field. If a brief pulse of radio waves is then applied from a different direction, it causes the molecules to change direction briefly and then ‘wobble’ as they realign themselves back to the magnetic field.

The amount of wobble and the time taken for the molecules to return to a rest are like a fingerprint. Using computer analysis, MRI can pick up changes in brain structure, connectivity and even brain activity.

Read our official press release on day two of the symposium.

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