Using MRI to Understand Neurological Conditions: Multiple Sclerosis

By Ekaterina Dobryakova 

Brain mapping techniques are a key tool for understanding the pathophysiology underlying neurological and psychiatric conditions. In this interview we interviewed leading clinically-focussed neuroimagers to find out about the state-of-the-art in applications of MRI techniques in people with multiple sclerosis (MS). 

Actress Selma Blair recently discussed her personal and very emotional struggle with MS with the world, shining a spotlight on this disorder. According to recent estimates, up to 1 million adults in the United States alone have a diagnosis of MS, a neurodegenerative inflammatory disease that diffusely affects the central nervous system. 

While MS cannot be diagnosed using neuroimaging alone, magnetic resonance imaging (MRI) tools are widely used by clinicians who treat individuals with MS and by researchers who study aspects of MS progression, symptoms, and rehabilitation. The MRI approaches used to study MS vary from the more ‘standard’ and long-standing techniques to new ones that are still undergoing development. Neuroimaging research contributes a great deal to understanding various aspects of MS, from cognitive impairment, brain plasticity, to changes not only in the brain but in the spinal cord.  

Dr. Menno Schoonheim is an Assistant Professor in the Vrije Universiteit (VUmc), Amsterdam. He studies brain network alterations and cognitive impairment in individuals with MS.

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“Multiple sclerosis is a strongly heterogeneous disease of the central nervous system featuring white and grey matter damage. One of the main problems the field faces is that the location of white matter pathology is very diverse, making it difficult to link specific symptoms to patterns of such damage and to provide a clear prognosis. ​

Analyzing grey matter atrophy patterns has been more fruitful, as studies have clarified that MS-specific atrophy starts in the thalamus and deep grey matter structures, before transitioning towards the cortex in later (progressive) phases of the disease. Interestingly, thalamic atrophy has been shown to be highly predictive, and specific cortical regions showing a lot of atrophy form the so-called default-mode network. Together with the thalamus, these regions form the strongest network hubs we have in the brain, i.e. they are connected to almost everything. This atrophy pattern also makes sense, given that almost all white matter connections are in some way connected to the thalamus or default-mode network, providing the missing network link between individual white matter lesions and complex symptoms like cognitive impairment. This makes connectivity analyses particularly interesting: Can we use advanced brain network analyses to analyze the efficiency of the functional and structural brain networks to monitor patients and treatment effects? Can we then pinpoint clinically relevant changes more accurately and use this information to make treatment decisions? Can we find possible proof of compensatory phenomena? 

Results have been really promising as, for instance, some people with MS who do not show signs of atrophy can still develop cognitive impairment, which is strongly related to default-mode functional changes. This indicates that some people are much more vulnerable to develop network changes than others, and hence cognitive dysfunction. In addition, functional network changes have shown to hold additive value in explaining clinical dysfunction beyond structural damage in statistical models, i.e. they are partly independent from each other. 

So clinical dysfunction in MS is based on a complex interplay between structural damage to specific tracts, regional grey matter atrophy patterns, functional brain changes and the overall efficiency of the brain network. If we truly want to understand and treat complex (behavioral and cognitive) symptoms in MS, we must therefore apply complex holistic network-based models encompassing all these types of damage, aiming to prevent the so-called “network collapse”, heralding the onset of clinical progression.”

The spinal cord is also vulnerable to damage in MS and has received increasing attention from MR researchers. Paola Valsasina, MSc is a research fellow at the Neuroimaging Research Unit in Vita-Salute San Raffaele University, Milan. She is part of a team of researchers who are studying spinal cord damage in individuals with MS: 

Damage to the spinal cord is one of the most important causes of mobility problems and long-term disability in multiple sclerosis (MS). Several of the most severe clinical complaints of MS patients are associated with spinal cord injury. Therefore, an accurate evaluation of the spinal cord using MRI has become of paramount importance in this disease.

Pathological and imaging abnormalities of the cord in MS patients largely mirror brain involvement in terms of presence of focal lesions, microscopic tissue abnormalities of the white and grey matter, and tissue loss. Focal spinal cord MS-associated lesions are usually limited to two vertebral segments in length and occupy less than half the cross-sectional area. Diffuse areas of mildly increased signal intensity can also be visible in primary progressive MS. Recent advances in spinal cord MRI technology markedly improved lesion detection and lesion volume quantification, and made possible to quantify cord lesion distribution across spinal levels and within the transverse cord section. 

As a consequence of the extensive presence of demyelination and axonal loss, MS patients usually develop spinal cord atrophy. Although a significant reduction of spinal cord area can be seen in the early phases of MS, spinal cord atrophy is more severe and correlated with disability in the progressive forms of the disease. Recent studies found that atrophy is mainly located in the central spinal cord grey matter and along the posterior and lateral cord columns. There seems to be a cranio-caudal gradient in cord atrophy development, with an earlier involvement of the upper cord portions and a subsequent spreading of atrophy to caudal cord levels. A higher rate of cervical cord atrophy development is often found to be associated with clinical disability worsening; therefore, including spinal cord atrophy as an outcome measure of neuroprotection seems to be a promising strategy for future clinical trials. 

​Non-conventional MRI techniques, such as magnetization transfer and diffusion MRI, showed the presence of extensive microstructural abnormalities in the cervical cord of patients with MS, not only in focal T2 lesions, but also in the normal-appearing tissues. Magnetization transfer MRI abnormalities were recently measured in an area corresponding to the expected location of pia mater and subpial regions in the outer cervical spinal cord. Diffusion MRI cord abnormalities were significantly correlated with system-specific and global clinical dysfunction, were associated with a progressive MS disease course, and were predictive of subsequent locomotor disability.

Prof Mara Rocca

While advances in MRI analysis methods are exciting, it can be easy to forget about the value of long-standing techniques and methods. Dr. Maria Rocca is a researcher at the Neuroimaging Research Unit in Vita-Salute San Raffaele University, Milan. She is also part of the MAGNIMS consortium that developed guidelines for the identification of lesions in the MS brain back in the 1990s in order to track MS progression and treatment: ​

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Multiple sclerosis is an extremely complex and heterogeneous disease from a pathological and clinical point of view. This is why, during the past decades, a lot of effort has been spent developing novel MRI techniques and sophisticated methods of analysis to try to identify specific in-vivo imaging biomarkers capable of detecting different aspects of MS pathobiology (demyelination, axonal damage, inflammation, synaptic alteration and inefficiency), which might be the target of therapeutic interventions.
This has somehow diverted attention from focal white matter lesions, that remain among the pathological hallmarks of the disease. The identification and quantification of focal white matter lesions is part of the diagnostic process of MS and it helps to assess treatment effects and monitor disease evolution. White matter lesions can also influence the results derived from advanced MRI techniques, such as volumetric approaches, diffusion tensor MRI, and functional MRI. This means that lesions cannot be forgotten in MS, as technological advancements have not yet provided automated approaches for lesion identification that are better than the ‘gold standard’ in the field, which is lesion identification by human experts.

​The above perspectives demonstrate the versatility of the MRI technology as it is used in MS research. OHBM is no stranger to MS. At the 2017 OHBM Annual Meeting in Vancouver, Canada, conference attendees were able to acquaint themselves with the art of Elizabeth Jameson whose work is inspired by her experiences as an individual with MS. Every year, researchers present their work on MS at OHBM, so come to Montreal in 2020 to learn more about new developments in MS research and brain mapping.