Calibrated imaging reveals altered grey matter metabolism related to white matter microstructure and symptom severity in multiple sclerosis

Abstract

Multiple sclerosis (MS) involves damage to white matter microstructures. This damage has been related to grey matter function as measured by standard, physiologically-nonspecific neuroimaging indices (i.e., blood-oxygen-level dependent signal [BOLD]). Here, we used calibrated functional magnetic resonance imaging and diffusion tensor imaging to examine the extent to which specific, evoked grey matter physiological processes were associated with white matter diffusion in MS. Evoked changes in BOLD, cerebral blood flow (CBF), and oxygen metabolism (CMRO2) were measured in visual cortex. Individual differences in the diffusion tensor measure, radial diffusivity, within occipital tracts were strongly associated with MS patients’ BOLD and CMRO2. However, these relationships were in opposite directions, complicating the interpretation of the relationship between BOLD and white matter microstructural damage in MS. CMRO2 was strongly associated with individual differences in patients’ fatigue and neurological disability, suggesting that alterations to evoked oxygen metabolic processes may be taken as a marker for primary symptoms of MS. This work demonstrates the first application of calibrated and diffusion imaging together and details the first application of calibrated functional MRI in a neurological population. Results lend support for neuroenergetic hypotheses of MS pathophysiology and provide an initial demonstration of the utility of evoked oxygen metabolism signals for neurology research.

BOLD hemodynamic response function changes significantly with healthy aging

“…The numerous underlying physiologic mechanisms that could lead to changes in the shape and timing of the HRF necessitate further investigation with advanced imaging techniques, such as calibrated fMRI. These advanced techniques permit direct assessment of age-differences in the neural and vascular factors underlying BOLD signal (Ances et al, 2009; Gauthier and Hoge, 2012; Hoge et al, 1999; Hubbard et al, 2017; Hutchison et al, 2012; Wise et al, 2013). This work in humans, combined with study of model systems in rodents and primates (Chen et al, 2014; Peters and Sethares, 2002, 2003, 2004), suggests that interpretations of HRF age-differences as reflecting differences in neural activity alone are insufficient to explain the brain-basis of cognitive aging.…”

Preserved canonicality of the BOLD hemodynamic response reflects healthy cognition: Insights into the healthy brain through the window of Multiple Sclerosis

“…Second, the standard-space analyses that we employed to facilitate like-to-like spatial between-groups comparisons may not account for cortical gray-matter atrophy often seen in neurodegenerative diseases such as MS (Azevedo & Pelletier, 2016;Calabrese et al, 2007Calabrese et al, , 2009Fisher et al, 2008;Fisniku et al, 2008;Geurts & Barkhof, 2008;Geurts et al, 2012;Pirko et al, 2007;Vercellino et al, 2009). Calibrated imaging work shows that altered gray-matter metabolism in MS is related to white-matter compromise (Hubbard et al, 2017; see also Varga et al, 2009). More work is certainly needed to disentangle relative influences of white-and gray-matter on HRF shape and cognitive performance.…”

Multiparametric measurement of cerebral physiology using calibrated fMRI

“…2). Although much of the research on relative CMRO 2 has focused on validation within healthy populations, there is demonstrated utility under disrupted physiology such as in ageing (Mohtasib et al, 2012), multiple sclerosis (Hubbard et al, 2017) and HIV (Ances et al, 2011).…”

“…Calibrated fMRI experiments have already been used successfully to study Multiple Sclerosis (MS), demonstrating a clear link between functional CMRO 2 changes and fatigue and neurological disability across patients (Hubbard et al, 2017). With this demonstration of calibrated fMRI as a practical and informative technique in this cohort, and with evidence from the literature that numerous haemodynamic factors may contribute to or be affected in MS, we assert that multiparametric physiological data will greatly improve our understanding of the vascular contributions to this primarily neuroinflammatory and neurodegenerative disease.…”