Blood Oxygenation Level-Dependent Response to Multiple Grip Forces in Multiple Sclerosis: Going Beyond the Main Effect of Movement in Brodmann Area 4a and 4p

Abstract

This study highlights the importance of looking beyond the main effect of movement to study alterations in functional response in the presence of central nervous system pathologies such as multiple sclerosis (MS). Data show that MS selectively affects regional BOLD (blood oxygenation level dependent) responses to variable grip forces (GF). It is known that the anterior and posterior BA 4 areas (BA 4a and BA 4p) are anatomically and functionally distinct. It has also been shown in healthy volunteers that there are linear (first order, typical of BA 4a) and nonlinear (second to fourth order, typical of BA 4p) BOLD responses to different levels of GF applied during a dynamic motor paradigm. After modeling the BOLD response with a polynomial expansion of the applied GFs, the particular case of BA 4a and BA 4p were investigated in healthy volunteers (HV) and MS subjects. The main effect of movement (zeroth order) analysis showed that the BOLD signal is greater in MS compared with healthy volunteers within both BA 4 subregions. At higher order, BOLD-GF responses were similar in BA 4a but showed a marked alteration in BA 4p of MS subjects, with those with greatest disability showing the greatest deviations from the healthy response profile. Therefore, the different behaviors in HV and MS could only be uncovered through a polynomial analysis looking beyond the main effect of movement into the two BA 4 subregions. Future studies will investigate the source of this pathophysiology, combining the present fMRI paradigm with blood perfusion and nonlinear neuronal response analysis.

Keywords: BA 4a; BA 4p; fMRI; force; multiple sclerosis.

FIGURE 1

The cytoarchitectonic assignments of BA 4a and BA 4p projected onto the maximum probability map of the brain as provided by the SPM anatomy toolbox.

FIGURE 2

Mean of the beta values and their standard errors calculated at group level for the main effect of gripping for both groups and sub-regions. There are significantly higher betas (***p = 0.001) in the MS compared to the Healthy volunteers within both sub-regions (BA 4a and 4p).

FIGURE 3

Significant activations of the main effect of gripping within BA 4p and BA 4a in both MS and Healthy volunteers. Colors represents the T-value of the effects at a 0.05 FWE.

FIGURE 4

RRMS patients showed increased activations as their EDSS increased within BA 4p (p = 0.001; r = 0.68) (top plot) and within BA 4a (no sgificant results) (bottom plot) in the main effect of gripping (i.e., 0th order).

FIGURE 5

BOLD responses (Z-axis) of the fitted polynomial-orders of GF (Y-axis) at the defined post-stimulus time (PST) (X-axis) within BA 4a for Healthy volunteers (HV 1-5), MS patients with low (MS 1-5) and high EDSS (MS 6-10)—representing an estimate of the mapping between GF and BOLD based on all components of the polynomial expansion. The top row shows the average group effect while underneath examples of individual subjects are plotted.

FIGURE 6

BOLD responses (Z-axis) of the fitted polynomial-orders of GF (Y-axis) at the defined post-stimulus time (PST) (X-axis) within BA 4p for Healthy volunteers (HV 1-5), MS patients with low (MS 1-5) and high EDSS (MS 6-10)—representing an estimate of the mapping between GF and BOLD based on all components of the polynomial expansion. The top row shows the average group effect while underneath examples of individual subjects are plotted.