Default Network Index: Developing a Mechanistic Biomarker of Memory in Multiple Sclerosis

FY19 MSRP Focus Areas: Correlates of Disease Activity and Progression in MS is directly addressed by the overarching aim: To identify brain changes related to MS disease activity that are correlated with memory decline over the disease course. Biology and Measurement of MS Symptoms is directly addressed by our goal to establish a biological model of memory impairment to guide the development of targeted treatments. Memory impairment is common and debilitating for people with multiple sclerosis, interfering with personal and professional functioning and sometimes leading to loss of employment. Currently, we have no effective treatments to stop or reverse memory decline. This grant aims to establish a comprehensive model of memory impairment in MS to inform development of targeted treatments. Many changes occur in the brains of individuals with MS, including lesions and atrophy of key regions involved in memory processes. We have an abundance of neuroimaging tools to examine these brain changes, but combining all of the information into a single integrative model is challenging. Here, we are proposing to do so by creating a new, summary metric that will facilitate a testable model to help us understand why people with MS have memory decline and, most importantly, to help us develop targeted treatments to stop or reverse memory decline.

Applicability to advance MS patient care: Neuromodulation is an emerging treatment approach using invasive and noninvasive brain stimulation that is being used to improve memory in other clinical populations. Thus far, its use and effectiveness in MS have been limited. Evidence suggests that the success of this approach relies on accurate targeting of critical brain regions involved in memory: the goal of this grant.

What types of patients could potentially be helped and how? Successful achievement of this grant will facilitate the development of treatments that will potentially help many MS patients, from those early in their disease course to patients further along. Memory impairment affects patients at every stage, but reasons (and underlying brain regions affected) may differ over the disease course. Our model will allow us to identify changing areas of the brain supporting memory function across the disease course to promote a precision medicine model, i.e., customizable treatments. We also have data from a diverse sample of patients, allowing us to investigate differences between, e.g., men and women, and across different races/ethnicities.

Potential clinical applications, benefits, and risks: Beyond neuromodulatory treatments, this grant has implications to inform rehabilitation strategies. Increased understanding of specific brain changes leading to memory decline will potentially allow us to identify subprocesses related to memory that could be targeted for cognitive rehabilitation. For example, if the primary cause of memory impairment is atrophy in the hippocampus (the brain's primary memory structure), this may recommend a different strategy than if the cause is related to disconnection among brain areas related to, e.g., language functions that contribute to memory. These distinctions will be clarified through this grant project to inform specific, targeted treatment strategies. Potential benefits are high, and potential risks are low. Neuromodulation is regarded as a safe treatment, having been tested in many clinical populations dating back to the 1960s.

Projected time to achieve a patient-related outcome: Trials of neuromodulatory treatments for cognition MS are under way, but efficacy has been mixed. Therefore, there is already a clear path to developing a meaningful treatment for memory impairment. Treatments showing efficacy in other populations can be successfully adapted for use in MS once we identify precise targets, which will be facilitated by this grant. By the completion of this 3-year grant, we will have established key knowledge for developing effective treatments to be immediately tested in clinical trials and rapidly translated to patient care.