Postcontractile blood oxygenation level-dependent (BOLD) response in Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is characterized by a progressive replacement of muscle by fat and fibrous tissue, muscle weakness, and loss of functional abilities. Impaired vasodilatory and blood flow responses to muscle activation have also been observed in DMD and associated with mislocalization of neuronal nitric oxide synthase mu (nNOSμ) from the sarcolemma. The objective of this study was to determine whether the postcontractile blood oxygen level-dependent (BOLD) MRI response is impaired in DMD and correlated with established markers of disease severity in DMD, including MRI muscle fat fraction (FF) and clinical functional measures. Young boys with DMD (n = 16, 5-14 yr) and unaffected controls (n = 16, 5-14 yr) were evaluated using postcontractile BOLD, FF, and functional assessments. The BOLD response was measured following five brief (2 s) maximal voluntary dorsiflexion contractions, each separated by 1 min of rest. FFs from the anterior compartment lower leg muscles were quantified via chemical shift-encoded imaging. Functional abilities were assessed using the 10 m walk/run and the 6-min walk distance (6MWD). The peak BOLD responses in the tibialis anterior and extensor digitorum longus were reduced (P < 0.001) in DMD compared with controls. Furthermore, the anterior compartment peak BOLD response correlated with function (6MWD ρ = 0.87, P < 0.0001; 10 m walk/run time ρ = -0.78, P < 0.001) and FF (ρ = -0.52, P = 0.05). The reduced postcontractile BOLD response in DMD may reflect impaired microvascular function. The relationship observed between the postcontractile peak BOLD response and functional measures and FF suggests that the BOLD response is altered with disease severity in DMD.NEW & NOTEWORTHY This study examined the postcontractile blood oxygen level-dependent (BOLD) response in boys with Duchenne muscular dystrophy (DMD) and unaffected controls, and correlated this measure to markers of disease severity. Our findings indicate that the postcontractile BOLD response is impaired in DMD after brief muscle contractions, is correlated to disease severity, and may be valuable to implement in future studies to evaluate treatments targeting microvascular function in DMD.

Keywords: Duchenne muscular dystrophy; blood oxygenation level dependent; magnetic resonance imaging; microvascular; skeletal muscle.

Figure 1.

Representative high-resolution water Dixon image used for drawing of region of interest (ROI) for blood oxygen level-dependent analysis (BOLD), and corresponding echo planar image (image 1/360) acquired to measure dynamic BOLD response in a control (A) and a participant with Duchenne muscular dystrophy (DMD; B). EDL, extensor digitorum longus; TA, tibialis anterior.

Figure 2.

Example force (control: A; DMD: B) and postcontractile blood oxygen level-dependent (BOLD) responses in a control and in a participant with Duchenne muscular dystrophy (DMD) of the tibialis anterior (control: C; DMD: D) and extensor digitorum longus (control: E; DMD: F). Five isometric maximal voluntary dorsiflexion contractions were performed separated by 1 min of rest.

Figure 3.

Postcontractile BOLD responses of each contraction and the responses are averaged for an overall average BOLD response of the tibialis anterior (control: A; DMD: B) and extensor digitorum longus (control: C; DMD: D). Contraction artifacts were omitted from the BOLD analysis. The peak BOLD response, time to peak, and half-recovery time were evaluated after fitting the postcontractile BOLD response using a polynomial fitting algorithm. BOLD, blood oxygen level-dependent; DMD, Duchenne muscular dystrophy.

Figure 4.

Parameters of the postcontractile blood oxygen level-dependent (BOLD) response were compared between unaffected controls (n = 15) and participants with Duchenne muscular dystrophy (DMD; n = 15), including the peak BOLD response (A), time to peak (B), and the half recovery time (C) for the tibialis anterior and the peak BOLD response (D), time to peak (E), and half recovery time (F) for the extensor digitorum longus. Welch’s unpaired two-tailed t test was used to compare DMD and unaffected controls. Box and whisker plots represent median, 10/90 percentile, and minimum/maximum. *P < 0.05, **P < 0.001.

Figure 5.

A: correlation plot with initial (x-axis) and repeated (y-axis) of BOLD responses of the tibialis anterior muscle from both control (n = 4) and Duchenne muscular dystrophy (DMD; n = 7) subjects that repeated the BOLD protocol (ICC = 0.94). B: Bland–Altman plot showing limits of agreement (±1.96SD) and bias (0.21) of the (absolute) peak BOLD response. BOLD, blood oxygen level-dependent.

Figure 6.

Correlation between the postcontractile peak BOLD response of the anterior compartment (weighted average of the tibialis anterior and extensor digitorum longus) vs. the 6-min walk distance (6MWD; ρ = 0.87, P < 0.0001, n = 15; A), 10-m walk/run time (ρ = −0.78, P < 0.001, n = 15; B), and fat fraction of the anterior compartment (ρ = −0.52, P = 0.05; C) in participants with DMD. Data were analyzed using Spearman’s correlation analyses. BOLD, blood oxygen level-dependent; DMD, Duchenne muscular dystrophy.