Having accomplished the research and training goals of the K99 phase, I am now prepared to transition to the ROO phase of this CDA. I have published several first-authored papers during the past two years, including my K99 project in the journal "Neurology." Consistent with the "cognitive reserve" (CR) hypothesis, the K99 results showed that lifetime intellectual enrichment lessens the negative impact of neuropathology on learning and memory in persons with multiple sclerosis (MS). I have also met my training goals, as I have acquired the MRI /fMRI analysis skills necessary for the ROO phase. As discussed in the original K99/R00 application, the primary aim of this ROO project is to use fMRI to identify the neurophysiologic basis of CR in MS. Although CR has been conceptualized as a neurophysiologic characteristic ofthe brain, research on CR has relied on behavioral / vocabulary-based estimates of CR. As such, the proposed project will provide the most direct investigation of CR in any neurologic population to date. Pilot fMRI data suggest that activity within the brain's default network (DN) is correlated with traditional vocabulary-based estimates of CR, as well as memory performance on neuropsychological tasks. Of particular note, pilot data suggest that DN activity mediates the relationship between vocabulary knowledge and memory functioning, thereby supporting the notion that DN activity represents the neurophysiologic basis of CR. Consistent with technological advances within the fMRI literature, I will use "resting state functional connectivity" to investigate the underlying functional integrity ofthe DN in persons with MS. I will investigate the correlation between a vocabulary-based estimate of CR and DN functional connectivity. I will also investigate whether the strength of DN functional connectivity mediates the relationship between vocabulary and memory functioning, which would support DN integrity as the neural basis of CR. Given the novelty of this research, a secondary aim investigating the relationship between vocabulary and DN activity in a matched group of healthy controls is necessary to charactize the specificity of the hypothesized relationship. Finally, as a tertiary aim, I will perform the first investigation ofthe neuroanatomical basis of CR in persons with MS.

Public Health Relevance

I have extended the theory of CR to MS over the past two years, mostly through cognitive-behavioral data. This proposed fMRI / neurophysiologic study provides the most direct investigation of CR to date, which will identify biomarkers of lower CR (i.e., risk of memory decline). This will (a) help target 'at risk'persons for early intervention memory rehabilitation, and (b) inform future attempts to build CR in persons with MS.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Quatrano, Louis A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Kessler Foundation, Inc.
West Orange
United States
Zip Code
Sumowski, James F; Leavitt, Victoria M (2014) Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure. Arch Phys Med Rehabil 95:1298-302
Sumowski, James F; Rocca, Maria A; Leavitt, Victoria M et al. (2014) Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS. Neurology 82:1776-83
Sandry, Joshua; Sumowski, James F (2014) Working memory mediates the relationship between intellectual enrichment and long-term memory in multiple sclerosis: an exploratory analysis of cognitive reserve. J Int Neuropsychol Soc 20:868-72
Leavitt, Victoria M; Wylie, Glenn; Chiaravalloti, Nancy et al. (2014) Warmer outdoor temperature is associated with task-related increased BOLD activation in patients with multiple sclerosis. Brain Imaging Behav 8:128-32
Sumowski, James F; Wylie, Glenn R; Leavitt, Victoria M et al. (2013) Default network activity is a sensitive and specific biomarker of memory in multiple sclerosis. Mult Scler 19:199-208
Sumowski, James F; Rocca, Maria A; Leavitt, Victoria M et al. (2013) Brain reserve and cognitive reserve in multiple sclerosis: what you've got and how you use it. Neurology 80:2186-93