Multiple sclerosis-related white matter microstructural change alters the BOLD hemodynamic response

Abstract

Multiple sclerosis (MS) results in inflammatory damage to white matter microstructure. Prior research using bloodoxygen-level dependent (BOLD) imaging indicates MS-related alterations to brain function. What is currently unknown is the extent to which white matter microstructural damage influences BOLD signal in MS. Here we assessed changes in parameters of the BOLD hemodynamic response function (HRF) in patients with relapsing-remitting MS compared to healthy controls. We also used diffusion tensor imaging to assess whether MS-related changes to the BOLD-HRF were affected by changes in white matter microstructural integrity. Our results showed MS-related reductions in BOLD-HRF peak amplitude. These MS-related amplitude decreases were influenced by individual differences in white matter microstructural integrity. Other MS-related factors including altered reaction time, limited spatial extent of BOLD activity, elevated lesion burden, or lesion proximity to regions of interest were not mediators of group differences in BOLD-HRF amplitude. Results are discussed in terms of functional hyperemic mechanisms and implications for analysis of BOLD signal differences.

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

“…Thus, most fMRI studies utilize a canonical HRF in analysis (see Lindquist et al, 2009). However, it is known to vary considerably in aging and disease (e.g., Bonakdarpour, Parrish, & Thompson, 2007;D'Esposito et al, 1999;D'Esposito, Deouell, & Gazzaley, 2003;Hubbard et al, 2016a;Rypma & D'Esposito, 2001;Zou et al, 2011). Because of the reliance upon neural-vascular communication to produce this canonical shape (e.g., Buxton et al, 2004;Martin et al, 2006), comparisons between healthy individuals and those with known neural-vascular coupling compromise would permit testing of hypotheses regarding the importance of an intact neural-vascular coupling system to optimal neural and cognitive performance.…”

“…Greater variation in underlying hemodynamic systems seen in groups such as older adults (Hutchison et al, 2013a,b;Tsvetanov et al, 2015) and MS patients (DeLuca et al, 2008;Pantano et al, 2005;Rocca et al, 2002;Wegner et al, 2008;cf. Genova et al, 2009;Hubbard et al, 2016a;Lee et al, 2000;White et al, 2009) challenges the assumptions necessary for use of canonical HRFs in group comparison studies. In this way, HRFs derived from the use of a canonical function could be biased in their characterization of the BOLD signal response (cf.…”

“…Such bias could underlie the diversity of results that have been observed in BOLD-fMRI of MS. Some studies have observed MS-related increases in BOLD signal of motor cortex during finger tapping (e.g., Pantano et al, 2005;Rocca et al, 2002;Wegner et al, 2008) and prefrontal cortex during a processing speed task (e.g., DeLuca et al, 2008), while others have observed MS-related decreases in motor cortex BOLD signal during finger tapping (e.g., Hubbard et al, 2016a;Lee et al, 2000;White et al, 2009) and prefrontal cortex during a processing speed task (e.g., Genova et al, 2009). Increases in BOLD signal have been suggested to reflect adaptive reorganization (e.g., Bonnet et al, 2010;Kern et al, 2012), but the underlying mechanisms remain poorly understood.…”

“…In this study, we utilized a modeling approach not dependent on the validity of shape assumptions to quantify differences between a healthy group and one with known neuralvascular compromise that probably affects the canonical shape of their HRF (i.e., MS patients; Hubbard et al, 2016a). Thus, we tested two hypotheses.…”

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

“…MS patients show relationships between their BOLD functional responses and white matter diffusion characteristics, demonstrating a link between grey matter function and WMMS in this group [Hubbard et al, a; see also Alshowaeir et al, ; Au Duong et al, ]. Although the two are related, it is important to emphasize a distinction between white matter macrostructural (i.e., lesions) and microstructural (i.e., WMMS) alterations in MS because (1) MS‐related alterations to WMMS exist outside of apparent lesioned tissue [e.g., De Keyser et al, ; Klistorner et al, ; Sorbara et al, ] and (2) measures of WMMS account for variance in measures of MS patients' neural function separate from the degree of patients' macrostructural damage [e.g., Hannoun et al, ; Hubbard et al, ]. In one study, for instance, we found that grey matter BOLD response amplitudes were strongly related to individual differences in MS patients' white matter diffusion characteristics, however, no such relationship was found between grey matter BOLD and the extent of white matter macrostructural damage [i.e., lesion burden; Hubbard et al, a].…”