Phase II Randomized Controlled Trial of Constraint-Induced Movement Therapy in Multiple Sclerosis. Part 2: Effect on White Matter Integrity

Abstract

Background: Constraint-induced movement therapy (CIMT) is a method of physical rehabilitation that has demonstrated clinical efficacy in patients with chronic stroke, cerebral palsy, and multiple sclerosis (MS).

Objective: This pilot randomized controlled trial tested whether CIMT can also induce increases in white matter integrity in patients with MS.

Methods: Twenty adults with chronic hemiparetic MS were randomized to receive either CIMT or complementary and alternative medicine (CAM) treatment (reported in the first article of this pair). Structural white matter change was assessed by tract-based spatial statistics (TBSS); measures included fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD).

Results: CIMT and CAM groups did not differ in pretreatment disability or expectancy to benefit. As noted in the companion paper, the motor activity log (MAL) improved more after CIMT than CAM ( P < .001); the within-group effect size for CIMT was 3.7 (large d' = 0.57), while for CAM it was just 0.7. Improvements in white matter integrity followed CIMT and were observed in the contralateral corpus callosum (FA, P < .05), ipsilateral superior occipital gyrus (AD, P < .05), ipsilateral superior temporal gyrus (FA, P < .05), and contralateral corticospinal tract (MD and RD, P < .05).

Conclusion: CIMT produced a very large improvement in real-world limb use and induced white matter changes in patients with hemiparetic MS when compared with CAM. The findings suggest in preliminary fashion that the adverse changes in white matter integrity induced by MS might be reversed by CIMT.

Clinical trial registration number: ClinicalTrials.gov (NCT01081275).

Keywords: complementary and alternative medicine; constraint-induced movement therapy; magnetic resonance imaging; multiple sclerosis; rehabilitation; white matter.

Figure 1. Changes in Fractional Anisotropy (FA) following CI Movement therapy (CIMT)

Clusters with significant pre- to post-treatment increases in FA are thickened and shown in red/yellow (corrected p < 0.05) and blue (corrected p < 0.1). In the coronal and axial slices, right on the images corresponds to the side of the brain contralateral to the trained upper extremity. Significant clusters of FA increases were observed in the ipsilateral posterior corpus callosum (CC) and contralateral superior occipital gyrus white matter (O1). After lowering the statistical threshold after correction to p = 0.1, additional clusters of FA increases were observed in the ipsilateral corticospinal tract (CST) and contralateral superior temporal gyrus white matter (STG). The green skeleton represents the center of white matter tracts common to all participants (i.e., both CIMT and CAM groups) with FA ≥ 0.2; the skeleton is superimposed on the standard MNI152 T1-weighted anatomical image. Inlaid white text indicates MNI coordinates of the slice.

Figure 2. Changes in diffusivity indices (AD, MD, RD) following CI Movement therapy (CIMT)

Clusters with significant pre- to post-treatment changes are thickened and shown in red/yellow (corrected p < 0.05) and blue (corrected p < 0.1). A) Increases in axial diffusivity (AD) were seen in the ipsilateral STG (p < 0.05) and the contralateral CC (p < 0.1). B) Decreases in mean diffusivity (MD) were seen in the contralateral corticospinal tract (CST) (p < 0.05). C) A decrease in radial diffusivity (RD) was seen in the contralateral CST (p < 0.05). Coordinates are given for the standard MNI152 T1-weighted anatomical image.