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White matter (WM) structures, crucial for inter-regional brain communication, are targeted in multiple sclerosis (MS), leading to inflammation, demyelination, and axonal damage. While visible white matter hyperintensities (WMH) on MRI can disrupt specific cognitive processes, subtle damage in normal-appearing white matter (NAWM), detectable through advanced imaging techniques, significantly contributes to cognitive decline. This study focuses on myelin and diffusion-based measures of structural coherence along the cingulum connectome, while considering the fraction of T2-FLAIR WMH and its impact on microstructure. Investigating the cingulum connectome bilaterally using diffusion spectrum imaging reveals tract-specific contributions to cognitive dysfunction in MS, potentially uncovering compensatory mechanisms. Understanding how microstructural changes within specific white matter tracts relate to cognitive deficits, such as information processing speed (IPS), may elucidate distinct neural substrates underlying cognitive impairments in MS and inform targeted therapeutic interventions. In this prospective study, we aim to investigate the relationship between myelin-related measures of white matter microstructure integrity within the cingulum connectome bilaterally (right or left independently) and IPS in 70 participants with relapsing remitting MS (RRMS). Utilizing DSI and high-resolution white matter tract segmentation, we will construct individual "white matter connectomes" to comprehensively assess the microstructural integrity of this critical network. We hypothesize that the structural integrity of the cingulum bundle and its connectome (right or left independently) will be significantly associated with IPS function in people with RRMS. We will test this hypothesis in terms of structural coherence, myelination levels, and WMH load. Specifically, we will investigate the following three related sub hypotheses: H1a. We hypothesize that structural coherence across the cingulum connectome measured by quantitative anisotropy (diffusion QA) is positively associated with IPS function, as measured by SDMT scores. Furthermore, (H1b.) we hypothesize that myelin content (e.g., myelin water fraction (MWF)) moderates the relationship between structural coherence (e.g., QA) in the cingulum connectome and IPS function (e.g., SDMT scores). Building upon the concept of myelin-related compensatory neuroplasticity, we will test a hypothesis that (H1c.) the load of myelin-related WMHs in the cingulum connectome is inversely correlated with IPS function (e.g., SDMT score). We further explore a hypothesis (EH1d) that the load of WMH in the cingulum bundle alone—as opposed to the entire cingulum connectome—is significantly associated with the myelin content across the connected structures. Specifically, we will test if a T2-FLAIR-based measure of cingulum WMH load is positively correlated with total myelin content measured by integrating the MWF across white matter tracts with membership to the cingulum connectome. We expect to find significant correlations between white matter integrity and IPS function, suggesting that IPS, as measured by SDMT performance, is influenced by white matter integrity (i.e., structural coherence, myelination levels, and WMH burden) within the cingulum connectome bilaterally (right or left independently), as measured by DSI. Specifically, we anticipate a positive correlation between mean QA in the cingulum connectome and SDMT performance, indicating that higher white matter integrity is associated with better IPS function. We also expect that increased myelination (MWF) will mediate this positive correlation, suggesting that myelination levels facilitate a stronger association between structural coherence and IPS function. Conversely, we anticipate a negative correlation between WMH load in the cingulum connectome and SDMT performance, indicating that greater WMH burden hinders IPS function. Additionally, we anticipate a positive correlation between the WMH load of the cingulum bundle and the total myelin content (integrated MWF) across the connected white matter tracts within the cingulum connectome, excluding the cingulum bundle itself. This would suggest a compensatory mechanism where increased myelination in connected tracts may offset the detrimental effects of cingulum bundle WMHs.

This ambitious novel was Wolfe’s first and was published in 1929. It is the work that he is perhaps best known for. The story is viewed as having a largely autobiographical influence. It speaks of the protagonist Eugene Gant’s desire to get an education, become a writer, find love, and generally make his way in the world by escaping the small North Carolina mountain town that he grew up in. In the book, the town is known as Altamont—based on Wolfe’s hometown of Asheville. The title is drawn from John Milton’s poem “Lycidas”: Look homeward Angel now, and melt with ruth; And, O ye Dolphins, waft the hapless youth." - Summary by Verla Viera