Multiple sclerosis (MS) is a frequently disabling disease that predominantly affects the white matter of the brain. White matter consists of the connecting fibers between brain regions and between the brain and the body. Typical attacks of MS can include vision, gait, balance, and/or sensory problems. From studies separately investigating pathology, cognitive skills, and MRI findings in MS, it is clear that the gray matter, the "information processing part of the brain," is also affected in this disease. Cortical gray matter (or cortex) is the outer part of the brain typically associated with higher cognitive functions, thinking and planning of functions. In a recent pathology study by our team, we established that very early on in MS, one can find severe inflammation and demyelination in the cortical gray matter. This was surprising as most previous studies concluded that lesion formation in the cortex typically occurs in chronic progressive forms of MS. Another surprising conclusion of our study was that white matter lesions seemingly developed in areas "directly connected" with the cortical lesions. This gave us an idea that white matter lesion formation may not be a random event after all; instead, it may be determined by the location of cortical lesions. In our model, cortical lesion formation can be viewed as the disease-initiating event, and white matter lesion formation follows along in white matter pathways directly connected to the lesioned cortical gray matter areas. If proven correct, this would revolutionize our understanding of MS, may lead to the development of more specific tests for MS, and may pave the way to additional studies to help us understand potential therapeutic ramifications of this new theory. Furthermore, since cortical lesions seem to be very important components in progressive MS, we may be able to understand the substrate and driving force of progression much better. In addition, since cognitive symptoms are now universally recognized in MS, and those may tie in with gray matter involvement, our studies will enable direct investigations of cognitive dysfunction in MS. It is currently not clear how much cortical gray matter lesions vs. white matter lesions contribute to cognitive problems, and our study can help sort out these associations.

The above theory would be very difficult to study using pathology-based techniques. However, with recent advances in magnetic resonance imaging (MRI) technology, we are able to visualize white matter tracts and white matter lesions very well. Most recently, a new technique called DIR (double inversion recovery) MRI has become available to visualize cortical lesions. Unfortunately, the currently used version of DIR, while it is more sensitive to cortical lesions than classic, routinely used MRI, is still far from perfect in detecting cortical lesions. Our team has therefore developed an optimized version of DIR for gray matter lesion detection, which we think will show greatly increased sensitivity toward cortical lesions. We already have some data to demonstrate the superiority of this new sequence. Part of the proposal will revolve around further validating this technique. Similarly to all MRI sequences, these are harmless to the body, and our sequences don't even require contrast dye administration. This clearly warrants further investigations as it may have great impact on the understanding of MS. Our hypothesis is that we can improve cortical lesion detection rate with our new methods and that we can demonstrate whether these cortical lesions are truly connected to the typical white matter lesions. Furthermore, by correlating these findings to clinical outcomes (cognitive skills testing and clinical examination), we think this finding could help us understand why and where lesions develop in MS and potentially how this is related to cognitive problems in MS. This could have great impact for future studies, for example, to see whether clinically this could be helpful in monitoring and assessing risk profiles for cognitive dysfunction and even whether treatment strategies would be affected by this phenomenon.