Exercise training for neural recovery in a restricted sample of pediatric brain tumor survivors: a controlled clinical trial with crossover of training versus no training

Abstract

Background: Exercise promotes repair processes in the mouse brain and improves cognition in both mice and humans. It is not known whether these benefits translate to human brain injury, particularly the significant injury observed in children treated for brain tumors.

Methods: We conducted a clinical trial with crossover of exercise training versus no training in a restricted sample of children treated with radiation for brain tumors. The primary outcome was change in brain structure using MRI measures of white matter (ie, fractional anisotropy [FA]) and hippocampal volume [mm3]). The secondary outcome was change in reaction time (RT)/accuracy across tests of attention, processing speed, and short-term memory. Linear mixed modeling was used to test the effects of time, training, training setting, and carryover.

Results: Twenty-eight participants completed training in either a group (n=16) or a combined group/home (n=12) setting. Training resulted in increased white matter FA (Δ=0.05, P<.001). A carryover effect was observed for participants ~12 weeks after training (Δ=0.05, P<.001). Training effects were observed for hippocampal volume (Δ=130.98mm3; P=.001) and mean RT (Δ=-457.04ms, P=0.36) but only in the group setting. Related carryover effects for hippocampal volume (Δ=222.81mm3, P=.001), and RT (Δ=-814.90ms, P=.005) were also observed. Decreased RT was predicted by increased FA (R=-0.62, P=.01). There were no changes in accuracy.

Conclusions: Exercise training is an effective means for promoting white matter and hippocampal recovery and improving reaction time in children treated with cranial radiation for brain tumors.

Keywords: brain recovery; cranial radiation; exercise; neuroplasticity; pediatric brain tumor.

© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Figures

Fig. 1.

Consort Diagram. Screening, group assignment, and completion of assessments and training. Eligible participants were identified via database review. Measures of brain imaging, cognition, and fitness were obtained upon study entry (Baseline), at ~ 12 weeks when half of the participants had completed training (Period 1 assessment), and at ~24 weeks following crossover and the remaining participants completed training (Period 2 assessment). The 4 participants who consented but did not complete training were not included in the analyses.

Fig. 2.

Change in fractional anisotropy (FA) following exercise training. (A) Clusters of significant increase in FA following training in all participants. Cluster size was thresholded at P<.05, which is family-wise fully corrected for multiple comparisons across space. Clusters are displayed in red-yellow with study-specific White Matter skeleton shown in blue and superimposed on FMRIB FA template. Images are in radiological convention. Numbers represent Montreal Neurological Institute (MNI) Z-coordinates. Please see eTable 1 for specific white matter bundles in which training effects were observed. (B) Change in mean FA difference scores extracted from regions (shown above) for main effects of time, training, training setting, and training carryover. Scores higher/lower than zero indicate change; positive scores indicate an increase in FA. (C) FA difference scores for individual participants. Participants assigned to no training → training are shown in green, and those assigned to training → no training are shown in orange. The exclusion of a single outlier did not change the results.

Fig. 3.

Change in hippocampal volume following exercise training. (A) Illustration of hippocampal segmentation in sagittal and coronal plane. Images in coronal plane are shown in radiological orientation: red is the right, and blue is the left hippocampus. (B) Change in total hippocampal volume for the interaction of training x training setting and carryover x training setting; I bars indicate 95% confidence intervals. Scores higher/lower than zero indicate change; positive scores indicate an increase in volume. (C) Change in hippocampal volume for individual participants. Participants assigned to no training → training are shown in green, and those assigned to training → no training are shown in orange. The exclusion of a single outlier did not change the results.

Fig. 4.

Change in reaction time (RT) on the Cambridge Neuropsychological Test Automated Battery (CANTAB) following exercise training. We assessed performance across 5 subtests of the CANTAB including rapid visual information processing, matching-to-sample visual search, simple reaction time, choice reaction time, and delayed matching-to-sample. Mean RT was calculated for each participant across all 5 subtests and using only correct trials. (A) Change in RT for the interaction of training x training setting and carryover x training setting; I bars indicate 95% confidence intervals. Scores higher/lower than zero indicate change; negative scores indicate a decrease in reaction time. (B) Change in Reaction Time for individual participants. Participants assigned to no training → training are shown in green, and those assigned to training → no training are shown in orange. With the exclusion of a single outlier, the training X training setting interaction was marginally significant (P=.07), and the carryover X training setting interaction remained significant (P< .05).

Fig. 5.

Tract-Based Spatial Statistics (TBSS) comparison map of trial participants versus healthy children. The top panel shows voxelwise differences between participants prior to exercise training and matched healthy children. Skeletons (blue) were overlaid on mean fractional anisotropy (FA) in FMRIB (MNI) space. Axial images are shown in radiological space with corresponding Z coordinates. Clusters (red) show reduced FA in trial participants versus healthy children. One large cluster consisting of 81 ∙892 voxels is evident, indicating widespread white matter compromise in trial participants prior to exercise training. The bottom panel shows differences in corpus callosum FA versus healthy children as a function of exercise training. Red indicates voxels of reduced FA in trial participants relative to healthy children. Blue indicates the underlying TBSS skeleton. Images (a) and (b) show reduced FA in trial participants in the genu and splenium of the corpus callosum. Images (c) and (d) illustrate fewer voxels with reduced FA in those same regions after exercise. Coordinates are noted in MNI space.